Nutrition interventions in patients with gynecological cancers requiring surgery

YGYNO-976618; No. of pages: 8; 4C: Gynecologic Oncology xxx (2017) xxx–xxx

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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno

Nutrition interventions in patients with gynecological cancers requiring surgery Andreas Obermair a,⁎, Marko Simunovic b, Liz Isenring c, Monika Janda b a b c

Queensland Centre for Gynaecological Cancer, QLD, Australia and School of Medicine, The University of Queensland, QLD, Australia School of Public Health and Social Work, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia Faculty of Health Sciences & Medicine, Bond University, QLD, Australia

H I G H L I G H T S • The tested early oral feeding and enteral feeding interventions were safe. • Some reported reduced LOS, intestinal recovery time or complications. • Increasing use of neoadjuvant treatment may reduce the prevalence of malnutrition.

a r t i c l e

i n f o

Article history: Received 22 December 2016 Received in revised form 19 January 2017 Accepted 23 January 2017 Available online xxxx Keywords: Malnutrition Gynecological cancer Nutritional intervention Randomized clinical trial Surgical outcomes Length of hospital stay

a b s t r a c t Objective. Including developing countries, between 20 and 88% of gynecological oncology patients may present with at least mild malnutrition at diagnosis. Significant morbidity and mortality is attributed to malnutrition. Here we reviewed randomized clinical trials of nutritional interventions used to achieve early return to oral diet, enhance recovery from surgery and reduce adverse events in gynecological cancer patients undergoing surgery. Methods. Ebscohost (CINAHL + Medline + PsycINFO), Cochrane, Embase, PubMed and Scopus databases were searched for articles published from 2000 onwards. Potentially eligible articles were screened by two reviewers. Length of hospital stay (LOS), postoperative complications, recovery of intestinal function, quality of life (QOL), hematological and immunological parameters were outcome measures of the nutritional interventions. Results. Seven randomized clinical trials were included in the review. Early clear liquid diet, semiliquid diet, regular diet or immune-enhanced enteral diets were all found to be safe as nutritional interventions. In five of the seven trials significantly better outcomes were observed in the intervention group compared to usual care for one of more of the outcomes intestinal recovery time, LOS, postoperative complications and immunological parameters. However, the nutritional interventions varied greatly between the trials, making it difficult to directly compare their findings. Trial quality was low to moderate. Recommended malnutrition screening and assessment tools and guidelines for treatment are reviewed. Conclusions. From the limited findings it would appear that nutritional interventions of early oral feeding and enteral feeding are safe. Receiving nutritional interventions seems to reduce LOS, intestinal recovery time and postoperative complications for some patients. Increasing use of neoadjuvant treatment may reduce the prevalence of patients presenting malnourished for surgery in the future. Crown Copyright © 2017 Published by Elsevier Inc. All rights reserved.

1. Introduction Gynecological cancer presents a major public health concern worldwide. In the USA alone an estimated 100,000 new cases of gynecological ⁎ Corresponding author at: Queensland Centre for Gynaecological Cancer, Royal Brisbane & Women's Hospital, 6th Floor Ned Hanlon Building, Herston, QLD 4029, Brisbane, Australia. E-mail address: [email protected] (A. Obermair).

(Cervical, Ovarian, Uterine, Vaginal and Vulvar) cancer are diagnosed each year, with approximately 30,000 deaths occurring annually [1]. Symptomatology, availability of screening tests and whether or not patients are commonly diagnosed at early (endometrial cancer) or late stages of disease (ovarian cancer) differ between the gynecological cancer diagnoses subgroups. Regardless of the cancer type however, presentation of late stage gynecological cancers is still common [2–4]. As cancers grow, they produce an increased metabolic demand. If left unchecked, this progressively contributes to a decline in nutritional status,

http://dx.doi.org/10.1016/j.ygyno.2017.01.028 0090-8258/Crown Copyright © 2017 Published by Elsevier Inc. All rights reserved.

Please cite this article as: A. Obermair, et al., Nutrition interventions in patients with gynecological cancers requiring surgery, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.01.028

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A. Obermair et al. / Gynecologic Oncology xxx (2017) xxx–xxx

often recognized when patients first present for diagnosis. It has been reported that malnutrition may be responsible for 20% of gynecological cancer deaths [5,6]. Malnutrition can be defined as a state of deficiency, excess or imbalance of nutrients, causing adverse effects in bodily functions or form [7]. While malnutrition constitutes of both over and undernutrition, studies in gynecological cancer patients undergoing surgery largely focus on undernutrition. The most relevant features describing undernutrition are deficiency in energy, protein and/or decrease in fat free mass. This negative nutritional balance can eventually lead to reduced physical or mental capacity, and adverse clinical outcomes [8,9]. People affected by other chronic diseases in addition to gynecological cancer, are particularly predisposed to the risk of malnutrition. As many as 40 to 80% of all cancer patients are estimated to experience malnutrition at some stage during the clinical course of their disease [10]. Cancer cachexia in contrast is a complex metabolic syndrome caused by cancer. Cachexia differs from malnutrition, as it is a hyper-catabolic state resulting in accelerated muscle loss adjacent to chronic inflammatory responses in the body. Although weight loss is common in cancer patients who are malnourished, weight loss as a result of cachexia is not caused by an inadequate caloric intake alone. While most malnourished cases can be treated with aggressive feeding to increased caloric intake, weight loss in cachexia is not easily reversed [11]. Contemporary studies conducted in Australia and USA, have shown that between 20 and 53% of gynecological cancer patients present with at least mild malnutrition at diagnosis [12,13] (Table 1). Prevalence of malnutrition has been reported to be even higher in developing nations (62–88%) [14–16] (Table 1). Studies reporting these estimates based on malnutrition screening or assessment tools are summarized in Table 1. The British Association for Parenteral and Enteral Nutrition (BAPEN) listed a number of social and physical factors which increase the risk of malnutrition, including social isolation, poverty and cultural norms. Painful mouth/teeth, swallowing difficulties, loss of smell/taste or limited mobility are physical factors that can contribute to the increased risk of malnutrition. Other risk factors include, being over the age of 65 years, high use of drugs, alcohol, or cigarettes or having a chronic progressive condition [17]. Given the high prevalence of malnutrition, and the increased risk of adverse events during surgery in malnourished patients, it was the aim of this review to summarize evidence from randomized clinical trials to reduce the risk of malnutrition, enhance recovery after surgery, and achieve early return to oral diet in the

gynecological cancer setting, and relate the evidence to current guidelines for screening, assessing and overcoming malnutrition. 2. Methods 2.1. Search strategy We searched Ebscohost (CINAHL + Medline + PsycINFO), Cochrane, Embase, PubMed and Scopus. Articles were restricted to human research, published in English and between 01/01/2000 to 25/ 11/2016. The search terms used were: “female genital neoplasm; nutritional support; malnutrition; nutrition; quality of life (QOL); length of stay (LOS); treatment outcome; perioperative care; postoperative care; gynecological surgical procedure; nutritional risk assessment; randomized trial”. The search terms were combined and adjusted to suit each database search builder, details can be seen in supplementary Table 1. A total of 443 potential articles were identified. Reviews, meta-analyses, descriptive studies, or those investigating biomarkers were ineligible. After screening title, abstract and full text of these potentially eligible articles a total of seven articles were included in the final review. Fig. 1 shows a visual of the search strategy and flow of studies. Quality criteria of the studies were assessed and summarized in supplementary Table 3. 3. Results 3.1. Patients and study characteristics A total of seven randomized controlled trials fulfilled the inclusion criteria (a summary of the studies' main characteristics is provided in Table 2; details are in supplementary Table 3). All seven studies evaluated interventions for improving nutritional recovery in gynecological cancer patients undergoing cancer-related surgery. The study participants were all adult females, 18–85 years of age. The sample size within the studies ranged from 40 to 245 participants. The studies were conducted across a number of countries including Australia, Canada, China, Italy, Turkey and the USA. Six of the seven studies had mixed gynecological cancer samples, while Baker et al. [18] only included patients with ovarian cancer. The majority of studies (n = 5) did not report the stage of cancer. The most common surgical procedures

Table 1 Prevalence of malnutrition in gynecological cancer studies. Study

Cancer type

Sample size

Age range (years)

Prevalence of malnutrition

Measuring tool

Das et al., 2014

Various gynecological cancers

60

13–74

PG-SGA

Gupta et al., 2010

Ovarian cancer

98

31–82

Hertlein et al., 2014

Gynecological cancers

272

18–97

Laky et al., 2007

Various gynecological cancers

145

20–91

Laky et al., 2008

Various gynecological cancers

194

20–91

Rodrigues et al., 2015

Various gynecological cancers

146

NA

Yim et al., 2016

Ovarian cancer

213

22–81

Class A = 12% Class B = 48% Class C = 40% Class A = 47% Class B = 29% Class C = 24% Score 0 = 27% Score 1–2 = 31% Score N 3 = 42% Class A = 80% Class B = 20% Class C = 0 Class A = 76/76% Class B = 23/22% Class C = 1/2% Class A = 38% Class B = 47% Class C = 23% Non-mild risk = 78% Moderate-severe risk = 22%

SGA

NRS-2002

PG-SGA

SGA/PG-SGA

PSG-SGA

NRI

Abbreviations: NRI: Nutritional Risk Index, NRS-2002: Nutritional Risk Screening-2002, PG-SGA: Patient Generated Subjective Global Assessment, SGA: Subjective Global Assessment. Malnutrition Classification: NRS-2002 classifies patients into: Score 0 = low risk of malnutrition, Score 1–2 = medium risk of malnutrition, N3 = high risk of malnutrition. SGA and PG-SGA classify patients into: Class A - well-nourished, Class B - moderately malnourished, Class C - severely malnourished.

Please cite this article as: A. Obermair, et al., Nutrition interventions in patients with gynecological cancers requiring surgery, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.01.028

A. Obermair et al. / Gynecologic Oncology xxx (2017) xxx–xxx

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Fig. 1. Search strategy flow diagram.

performed were hysterectomy, followed by bowel resection, or resection of obstructions secondary to cancer progression. 3.2. Study measures and interventions Quality of life (QOL) outcomes were examined in three studies using the Functional Assessment of Cancer Therapy, General (FACT-G) questionnaire [18–20]. Baker et al. [18] additionally used the ovarian cancer patients supplement (FACT-O) as well as the EQ5D index and EQ5D visual analogue scale (VAS) and the Hospital Anxiety and Depression Scale (HADS). Minig et al. [19] and Minig et al. [20] used the EORTC QLQ-C30 and EORTC QLQ-OV28 questionnaires. One study used the PG-SGA tool and three studies used the SGA tool for longitudinal nutritional assessment. Three studies did not include an assessment tool for changes in nutritional status, potentially because changes would be hardly perceptible with traditional nutritional assessment, or clinicians are not familiar with the tools or don't have training/resources to use them [18–21]. All seven studies assessed recovery of intestinal activity/resumption of normal feeding. This was assumed normal once bowel sounds, flatus, stool or tolerance to diet was present [18–24]. Length of hospital stay was a common outcome assessed in six studies. Immunological parameters, which included C reactive protein (CRP), white blood cell count (WBC) and lymphocyte levels were examined only in one study.

The control group treatments reflected current standard care and commonly followed a traditional approach to postoperative care, where it has been accepted that paralytic ileus may occur after abdominal surgeries. To prevent postoperative complications such as vomiting, aspiration of gastric contents, wound dehiscence, or anastomotic leakage, feeding is commonly withheld. Once bowel function returns (bowel sounds, flatus, stool), patients are started on a stepwise diet [4, 25]. All seven clinical trials tested non-conventional feeding interventions against such traditional usual care in the control groups. The interventions involved early oral postoperative feeding (clear fluid diet; 1 trial, semiliquid diet; 1 trial or regular diet; 3 trials), enteral feeding (1 trial) and immune-enhanced enteral feeding (1 trial) (Table 2). The quality of the assessed studies was summarized in supplementary Table 3. All seven studies reported the allocation sequencing, and appear to have a low risk of bias, as the intervention and control groups were allocated through a valid process of randomization. However, the studies did not provide a detailed description of the allocations concealment. Attrition was not reported in 2/7 studies, while 4/7 studies had only minimal attrition. Compliance with the nutritional intervention in the Baker et al. [18] was poor, with 20 of 53 patients not receiving the nutrition intervention as per protocol. Blinding of participants and researchers was not possible, given the nature of the interventions. Overall, trial quality was judged as low to moderate across the studies

Please cite this article as: A. Obermair, et al., Nutrition interventions in patients with gynecological cancers requiring surgery, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.01.028

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Table 2 Randomized controlled trials of nutritional interventions in gynecological cancer patients. First author and year

Baker, 2015

Çelik, 2009

Feng, 2008

Minig, 2009a

Minig, 2009b

Pearl, 2002

Steed, 2002

Study type & place Cancer type

RCT/Australia

RCT/Turkey

RCT/China

RCT/Italy

RCT/Italy

RCT/USA

RCT/Canada

Epithelial and Ovarian

Endometrial and Ovarian

Cancer stage Sample size Age range

Advanced 109 Average = 62 Range = 37–85

Not specified 50 Average = I: 63, C: 62 Range = NA

Cervical, Endometrial Ovarian Not specified 60 Average = I:46, C:42 Range = 18–66 Assigned using a computer

Endometrial Fallopian tube, Ovarian Not specified 40 Average = I:54, C:58 Range = 18–75 Using web-based TENALEA randomization system

Cervical, Endometrial, Ovarian, Other 1–4 143 Average = I:54, C:57 Range = 18–75 Using web-based TENALEA randomization system

Cervical, Benign Ovarian, Uterine, Other Not specified 245 Average = 57 Range = NA

Non-specific gynecological cancers Not specified 96 Average = I:50, C:52 Range = NA Computer-generated random number list

Randomization Performed centrally, after stratification by treatment site and mode (upfront surgery vs neoadjuvant chemotherapy) Key measures QOL, Nutritional status, LOS, nausea and vomiting, BT, ICU, intestinal recovery

Using blinded envelopes, equal number of envelopes with protocols for either group 1 or 2 were prepared in a blinded fashion Postoperative complications, LOS, CRP, S-Prealb, S-Alb, WBC, lym fr, intestinal recovery

Intervention group

Immunenhancing enteral nutrition

Control group

Significant outcomes

Enteral feeding through nasojejunal tube Standard diet in EOC patients No statistically significant difference between intervention and control

Standard enteral nutrition Intervention has significantly better LOS, wound infection, CRP levels, WBC count, Lymphocyte count, intestinal recovery

LOS, VAS (Abdominal pain), QOL, EBL, nausea and vomiting, postoperative complications, intestinal recovery Early oral Semiliquid diet, followed by regular postoperative feeding (EOF) diet Clear-liquid diet to Traditional oral feeding (TOF) semiliquid diet to regular diet Significantly better Significantly LOS and intestinal increased nausea, recovery observed prealbumin and time of regular diet in intervention resumption is shorter in intervention Nausea and vomiting, Prealb, blood sugar, weight difference, intestinal recovery

LOS, VAS (Abdominal pain), QOL, EBL, nausea and vomiting, postoperative complications, intestinal recovery Early oral postoperative feeding (EOF) Traditional oral feeding (TOF) Significantly better LOS, Reduced complication and postoperative satisfaction in intervention

Computer generated random number list

Nausea, vomiting, LOS, electrolytes, postoperative complications, Hematological Parameters, intestinal recovery Clear liquid diet

LOS, EBL, postoperative complications, intestinal recovery

Regular diet

Traditional feeding

No statistically significant difference between intervention and control

Statistically significant reduction of LOS in intervention group

Early feeding

Abbreviations: BT: Blood Transfusion, C: Control, CRP: C Reactive Protein, EBL: Estimated Blood Loss, EOC: Epithelial Ovarian Cancer, ICU: Intensive Care Unit, I: Intervention, LOS: Length of Hospital Stay, Lym fr: Lymphocyte Fraction, QOL: Quality of Life, S-Alb: Serum Albumin, S-prealb: Serum Prealbumin, WBC: White Blood Cell.

(3 days vs 2 days, p = 0.01). Steed et al. [24] further found the intervention group tolerated a solid diet significantly faster compared to the intervention group (median days before solid diet was tolerated; 2 days for intervention and 4 days for the control group, p = 0.0001). Furthermore, no significant difference was found in the incidence of emesis or postoperative ileus. However, Baker et al. [18], Minig et al. [20], Pearl et al. [23] found no statistically significant difference between the control and intervention groups in the recovery of intestinal function or resumption of diet. A difference in LOS was reported in four of six studies, with the intervention groups having a significantly reduced LOS, 4.1 vs 7.8 days, (p N 0.05), 6.9 vs 9.1 days (p = 0.022), 4.7 vs 5.8 days (p =

3.3. Study outcomes Overall, four of seven studies reported a quicker recovery of intestinal function/resumption of normal feeding, within the intervention group. Çelik et al. [21] reported first signs of intestinal peristaltic (20.6 h vs 22.4 h, p b 0.05) and time to first defecation (1.5 days vs 1.9 days, p b 0.05) to be significantly shorter in the intervention group. Feng et al. [22] recorded a reduced time to regular diet resumption (65.74 h vs 83.37 h, p b 0.001) among the intervention group participants. The median time of flatus elimination in Minig et al. [19] study was significantly different between the intervention and control group Table 3 Nutrition screening and assessment tools. Nutritional tool

Screening tools

Setting

MNA Aged care, community

MUST Acute, community

NRI Acute, community, aged care

MST Acute, community, aged care

NRS-2002 Acute

Assessment tools PG-SGA Acute. community, aged care

SGA Acute, rehab, community, aged care

BMI Biochemical markers Unexpected weight change Food intake change Symptoms not eating Activity past month Metabolic demand Disease stage, other illness Physical exam

✓ ✗ ✓ ✓ ✓ ✓ ✗ ✓ ✓

✓ ✗ ✓ ✓ ✗ ✗ ✗ ✓ ✗

✓ ✓ ✓ ✗ ✗ ✗ ✗ ✗ ✗

✗ ✗ ✓ ✓ ✓ ✗ ✗ ✗ ✗

✓ ✗ ✓ ✓ ✗ ✗ ✗ ✓ ✗

✓ ✗ ✓ ✓ ✓ ✓ ✓ ✓ ✓

✓ ✗ ✓ ✓ ✓ ✓ ✗ ✗ ✓

Abbreviations: MNA: Mini Nutritional Assessment, MST: Malnutrition Screening Tool, MUST: Malnutrition Universal Screening Tool, NRI: Nutrition Risk Index, NRS-2002: Nutrition Risk Screening-2002, PG-SGA: Patient Generated Subjective Global Assessment, SGA: Subjective Global Assessment.

Please cite this article as: A. Obermair, et al., Nutrition interventions in patients with gynecological cancers requiring surgery, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.01.028

A. Obermair et al. / Gynecologic Oncology xxx (2017) xxx–xxx

0.006) and 4 vs 6 days (p = 0.001), respectively in the studies by Minig et al. [19], Minig et al. [20], Çelik et al. [21], Steed et al. [24]. There was no significant difference in LOS reported by 2/6 studies [18,23]. Also only 2/ 6 studies reported a difference in postoperative complications among the intervention group. In Çelik et al. [21] study in which the intervention group received Immune-enhancing Enteral Nutrition (IEN), a statistically significant difference in postoperative wound infections was reported (1 vs 5, p N 0.05). Minig et al. [20] reported a significantly reduced postoperative complication rate in the intervention group (17% vs 39%, p = 0.003). There was no statistically significant difference in postoperative complications reported by Baker et al. [18], Minig et al. [19], Pearl et al. [23] and Steed et al. [24]. Only 1/6 studies found a statistically significant difference in development of nausea and vomiting, with a higher incidence in the intervention group (56.7% vs 23.3%, p = 0.008) Feng et al. [22]. In their study the intervention group was given a semi-liquid diet and the control a clear liquid diet. Only 3/7 studies measured QOL, all concluded that there was no statistically significant difference between the intervention and control groups [18–20]. Three studies examined changes in biochemical markers. Çelik et al. [21] study found postoperative CRP levels, WBC count and Lymphocyte count were significantly higher (p N 0.05) in the intervention group. However, there was no statistically significant difference in albumin or prealbumin levels between the two groups. Feng et al. [22] study found significantly higher prealbumin levels (~ 216.49 mg/L vs ~ 159.69 mg/L, p = 0.001) in the control group following surgery, while Pearl et al. [23] found no statistically significant difference in hematological parameters and electrolytes between the control and intervention group. 4. Discussion The high prevalence of malnutrition in gynecological cancer patients gives reason for concern. In Australia and USA, between 20 and 53% of gynecological cancer patients present with at least mild malnutrition [12,13]. A study in Germany by Hertlein et al. [26] found that only 22% of patients presented with normal nutritional status. Prevalence in non-western nations is rarely assessed, but given that late presentation of cancer is even more common, it's likely that malnutrition will affect many patients treated in those settings. Studies in India and Brazil, reported as many as 62–88% of gynecological cancer patients present with malnutrition [15,16]. Malnutrition has been reported to account for 20% of all cancer deaths [6]. Risk of malnutrition is greatest in patients with ovarian cancer. Ovarian cancer diagnosis has been associated with a 67% chance of being malnourished as opposed to 21% of patients with other gynecological cancers [27]. Furthermore, patients presenting with ovarian cancer had 19 times greater odds to be malnourished compared to patients with benign conditions [13]. Malnutrition in cancer patients often arises through the individual's inability to ingest or absorb adequate nutrients. Surgery requires starving the patient, and depending on the length of starvation may result in postoperative protein catabolism. Receiving anti-cancer treatment is known to affect appetite, resulting in further reduced dietary intake subsequent to surgery. In cases where bowel obstruction is common, malabsorption of nutrients becomes an issue. With difficulties in gastric emptying, increased bacterial outgrowth and gas, can also affect the intake of food. Metabolic demand is another parameter known to increase as cancers grow, resulting in overuse of conserved proteins. The combination of reduced nutrition intake, reduced nutritional absorption, and increased metabolic demand can result in a negative nutritional balance and a diminishing nutritional status [5,28–30]. 4.1. Impact of intervention studies In advanced stages of gynecological cancer, complex surgical procedures are often required to achieve optimal cytoreduction, most frequently hysterectomy with or without bowel resections [18,20,23,24].

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These procedures can result in additional strain and elevated production of pro-inflammatory cytokines, further contributing to proteolysis and subsequent loss of lean tissue. Furthermore, findings from cohort studies showed malnourished patients tolerated major surgery less well compared to well-nourished patients, with higher incidence of postoperative infections, blood loss during surgery and mortality [30–33]. For these reasons, several clinical trials have considered nutritional interventions to prevent further degradation of nutritional status. Nutritional interventions were administered as supplementary foods or drinks, to provide part or full nutritional requirements for the patient. Interventions introducing early postoperative feeding would aim to promote the regeneration of mucosal villi, to decrease the risk of bacterial translocation, improve immune function and reduce the risk of postoperative localized infections or sepsis. Early resumption of solid meals is also aimed to avoid postoperative protein catabolism, reducing the risk of wound complications. However, early oral feeding, enteral nutrition and parenteral nutrition interventions have all been challenged in the past as being unsafe. Complications reported in such studies have included postprandial nausea, vomiting and the possibility for subsequent gastric content aspiration [28,34,35]. In contrast to these concerns, all seven clinical trials reviewed in this article reported the early oral or enteral nutrition interventions to be safe. Furthermore, five of the articles found nutritional interventions to improve intestinal recovery, reduce hospital stay or postoperative complications (Table 2). In contrast, two clinical trials found no benefit of enteral nutrition or administering a clear liquid diet as opposed to a normal diet postoperatively (Table 2). The number of clinical trials available for inclusion in this review was small. The interventions were heterogeneous, including early oral postoperative feeding (clear fluid diet; 1 trial, semiliquid diet; 1 trial and regular diet; 3 trials), enteral feeding (1 trial) and immuneenhanced enteral feeding (1 trial) (Table 2). As the interventions were not consistent across the clinical trials, it was difficult to directly compare their findings. While all seven studies reviewed reported some outcomes related to nutritional status, clinical outcomes or quality of life, none reported on all relevant outcomes. The limited findings from the seven clinical trials indicated that early oral intake with progressive advancement from a liquid diet to a normal diet was safe and well tolerated following major abdominal surgery in gynecological cancer patients. Compared to patients who received traditional oral feeding postoperatively, LOS was significantly shorter in the early feeding group [19–21, 24]. While Feng et al. [22] found early intake of a semiliquid diet postoperatively to be safe and well tolerated, they did report significantly higher nausea in the early feeding group. Results by Pearl et al. [23] further support the safety of a regular diet as the first postoperative meal following major abdominal surgery. Postoperative satisfaction has been reported to be higher in the early feeding groups, with increased number of postoperative complications and infections in the traditional feeding group [20,21]. The use of perioperative immune-enhanced nutrition was further found to be safe and effective in increasing immunological response following gynecological cancer surgery. The purpose of enteral feeding was to produce caloric intake as soon as tolerable, with the presumption the increased nutritional intake would improve QOL and reduce hospital stay, however this could not be confirmed by Baker et al. [18]. 4.2. Malnutrition screening tools Given that the evidence is based to only a small number of studies what steps should clinicians consider if malnutrition is suspected? In identifying nutritional status, nutritional screening should be considered. Screening tools should be quick and easy to use and identify common variables such as weight loss, BMI, loss of appetite, reduced food intake and grading of the disease process, to give an interpretation of the chronic protein energy status [36]. In total, we found five malnutrition screening tools and two malnutrition assessment tools (listed in Table 3). This includes the Mini Nutritional Assessment (MNA), the

Please cite this article as: A. Obermair, et al., Nutrition interventions in patients with gynecological cancers requiring surgery, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.01.028

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Malnutrition Universal Screening Tool (MUST), the Malnutrition Screening Tool (MST), the Nutritional Risk Index (NRI) and the Nutritional Risk Screening-2002 (NRS-2002), used for a variety of settings (Table 3). The MNA screening tool was developed for older adults, with a focus on nutrition risk to determine appropriate interventions. MUST is a popular screening tool recommended by BAPEN. It is developed to be used in all care settings, with the possibility of continuity of care across different settings. NRS-2002 is a screening tool recommended by the ESPEN, developed for a hospital setting. The NRS-2002 comprises of the nutritional component of MUST with the addition of grading the severity of the disease as it correlates to increased nutritional requirements. The NRS-2002 is designed to incorporate all possible patient categories in a hospital. It allows for further categorization of a particular diagnosis [37,38]. The MST is a very simple screening tool developed for a range of different settings. The tool is made for identification of nutritional risk using minimum nutritional parameters. 4.3. Malnutrition assessment tools Once the screening measure indicates a likely cause is obtained, clinicians should consider if the patient has been affected by an acute illness. In acute pathophysiology, where patients had no nutritional intake for over five days, the risk of malnutrition becomes likely. Based on findings the management guidelines should be followed and commonly recommend action to either treat, performs further observation or provide routine care for the patient [9]. Diagnosis of malnutrition cannot be done until a full nutritional assessment has been conducted either using a validated nutrition assessment tool (e.g. SGA, PG-SGA) or via a health professional trained in nutrition e.g. usually a dietitian [38]. Measures used for malnutrition screening and diagnosis have shown to overlap, as many are used for both purposes. However, Cederholm et al. [36] stress that screening tools should have high sensitivity while diagnostic tools should have high specificity. Commonly used malnutrition assessment tools, are the Subjective Global Assessment (SGA), developed for use in a variety of patients and settings. The SGA method consists of five historical and four physical examination components [39], including: weight loss in the previous six months, usual patterns of dietary intake (whether current intake is normal or abnormal; duration and severity of abnormal intake), gastrointestinal symptoms which have persisted 1 to N 14 days (anorexia, nausea, vomiting or diarrhea), the patient's functional capacity (from being bedridden to having full capacity), and the metabolic demand of the underlying disease [39]. Physical examinations include: loss of subcutaneous fat; measured at the triceps and lower ribs, muscle wasting; detected by palpation of the quadriceps and deltoids, looking for loss in bulk and tone of muscle, presence of edema in the ankles and sacral region and presence of ascites [39]. Specific for cancer patients, the SGA has been modified into the patient-generated-subjective global assessment (PG-SGA) [40]. The PG-SGA contains further questions concerning nutritional symptoms and short-term weight loss. The PG-SGA adds questions regarding current weight/height, weight six months ago and weight one month ago, and if there have been any weight changes in the past two weeks. Changes in food intake over the last month; symptoms which have prevented eating in the last two weeks; physical activity in the last month; percentage of weight loss in the last month; and metabolic stress score are determined by variables known to increase protein and caloric needs [40]. The end result provides a global rating of the patient's nutritional status which is rated either as wellnourished (Stage A), suspected of being malnourished (Stage B) or severely malnourished (Stage C). Table 3 summarizes commonly use tools, and their features. 4.4. Guidelines for treating malnutrition Following a full nutritional assessment and subsequent diagnosis of malnutrition, a number of international guidelines offer

recommendations for the treatment of malnutrition. Our review found four relevant guidelines for the treatment of malnutrition including, the European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines for nutrition in cancer patients, The American Society of Parenteral and Enteral Nutrition (ASPEN) Clinical Guidelines: Nutrition Support Therapy During Adult Anticancer Treatment and in Hematopoietic Cell Transplantation, the National Institute for Health and Care Excellence (NICE) Nutrition support for adults: oral nutrition support, enteral tube feeding and parenteral nutrition and the Dietitian's Association of Australia (DAA) Evidence Based Practice Guidelines for Nutritional Management of Malnutrition in Adult Patients across the Continuum of Care [7,11,41,42]. All guidelines are evidence based, from which recommendations are made accordingly. In patients who are malnourished, nutritional interventions aim to improve nutritional intake and reduce the consequences of metabolic irregularities. Improvement in nutritional status aims to maintain muscle mass, improve physical performance and QOL. Given the high incidence of undernutrition and metabolic dysfunction in cancer patients, the guidelines recommend to start nutritional interventions early to prevent further deterioration of nutritional status [7,11,41,42]. The ESPEN recommends nutritional counselling as the first step in improving nutritional intake. Collectively the guidelines recommend oral nutritional therapy, for patients who are able to swallow safely. Patients who are unable to receive nutritional support orally, enteral tube feeding should be considered. Enteral nutrition should only be provided to malnourished/at risk patients whose gastrointestinal tract is accessible and functional. Patient for who enteral nutrition is not suitable, total parenteral nutrition should be considered. Additionally, nutritional supplements may be administered such as immune-enhanced nutrition, to support the recovery of patients or prepare them for surgery [7,11,41,42]. Monitoring individual energy and substrate requirements and patient nutritional status, is recommended by all the guidelines apart from ASPEN, to ensure energy requirements are met and that nutritional progress is being made (Table 4). Recommendations for maintenance of physical activity to support muscle mass and prevent wasting are included in the DAA and ESPEN guidelines. The DAA guidelines are the only document which does not provide recommendations for patients undergoing surgery [7,11,41,42] (Table 4). 4.5. Guidelines for cancer patients undergoing surgery From the identified guidelines, only the ASPEN and ESPEN guidelines provide recommendations specifically for cancer patients (Table 4). Furthermore, they offer interventions specific for patients scheduled to undergo cancer-related surgery [43]. They state that it is imperative that patients' underlying illness, their activity levels, gastrointestinal tolerance, metabolic instability, refeeding issues and required duration of Table 4 Guidelines for treatment of malnutrition. Guidelines

ASPEN [41]

DAA [42]

ESPEN [11]

NICE [7]

Evidence based Nutritional screening and assessment Nutritional therapy

✓ ✓

✓ ✓

✓ ✓

✓ ✓

E, NS, P, O ✗ ✗

E, NC, NS, O, P ✓ ✓

E, NS, NC, O, P ✓ ✓

E, NS, O, P ✓ ✓

✗ ✓ ✓

✓ ✗ ✗

✓ ✓ ✓

✗ ✓ ✗

Nutritional monitoring Energy and substrate requirements Muscle exercise Surgical patients Specific for cancer

Abbreviations: ASPEN: American Society of Parenteral and Enteral Nutrition, E = Enteral Nutrition, ESPEN: European Society for Clinical Nutrition and Metabolism, DAA: Dietitian's Association of Australia, NC = Nutritional Counselling, NICE: National Institute for Health and Care Excellence, NS = Nutritional Supplements, O = Oral Nutrition, P = Parenteral Nutrition.

Please cite this article as: A. Obermair, et al., Nutrition interventions in patients with gynecological cancers requiring surgery, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.01.028

A. Obermair et al. / Gynecologic Oncology xxx (2017) xxx–xxx

nutritional support are considered [11,41]. Perioperative nutritional support may be beneficial if provided one to two weeks prior to surgery. Immune-enhanced enteral nutrition, has particularly shown a positive postoperative outcome, in malnourished patients undergoing cancer surgery. Immune-enhanced nutrition is thought to produce a positive postoperative outcome as it improves patient immune-competency and reduces inflammatory response [11,31,41]. Despite these positive findings, in patients undergoing major surgery, nutritional support therapy must be carefully considered. The reason is that currently, there is limited evidence to suggest nutritional improvement when using enteral nutrition or total parenteral nutrition, as opposed to standard oral feeding after bowel activity can be noticed. Therefore, the potential benefits should always be weighed against the potential risk of nutritional support therapy [41].

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focus on this patient group. Enteral nutrition does not appear to be well tolerated in this group, and the impact of early oral feeding on their recovery is minimal [18]. With the increasing use of neoadjuvant chemotherapy, a suitable pathway to treatment for the malnourished patient requires further research. Conflict of interest The authors declare no conflict of interest. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ygyno.2017.01.028.

4.6. Limitations of the reviewed literature The majority of clinical trials reviewed used a mixed sample of gynecological cancer patients, but failed to specify which stage of cancer was present in the study population. Furthermore, the studies did not report the outcomes separately for each gynecological cancer, making it difficult to assess whether the benefit, if any, was consistent over all cancer types. As ovarian cancer is often diagnosed in its later stages and more often associated with malnutrition compared to other gynecological cancers, it would be important to specify response to nutritional treatment separately. The seven clinical trials used a wide variety of screening or assessment tools, nutrition treatments and outcome measures. Greater consistency in future studies would ease to compare the relative effectiveness. Of the seven studies, only one reported details on blinding and masking Baker et al. [18], no other study included a description of the masking process. Albumin and prealbumin levels prior to surgical interventions have been shown to be significant predictors of clinical outcomes in gynecological cancer patients [30,32,44]. Despite their reported significance, most of the clinical trials reviewed did not include either albumin or prealbumin as predictors of surgical outcomes in their research. 4.7. Conclusion In summary, the reviewed literature suggests that nutritional interventions of early postoperative feeding, can reduce LOS in gynecological cancer patients undergoing major surgery. However, postoperative complications, particularly infections were found to be higher in the control groups. Albumin and prealbumin are significant variables at predicting surgical outcomes. They could potentially be used in conjunction with nutritional measures such as nutritional intake, weight loss, and nutrition impact symptoms to give an indication of nutritional status. Quality of life following gynecological surgery, is another variable which was not extensively measured in the clinical trials reviewed. All seven studies were conducted in developed countries; the research is therefore only representative of malnutrition in gynecological cancer in the advanced economies of the world. 4.8. Future directions Development of an international consistent gold standard to ensure consensus in screening and treatment guidelines would be beneficial. Without a gold standard it can be difficult to make direct comparisons between studies. Current research on the topic is only limited to a small number of studies, which are only representative of participants from developed economies. More research is needed in examining the association between nutritional parameters and patient outcomes, such as QOL. Furthermore, the method of nutritional administration, in particular enteral nutrition is inconclusive and should be further researched. In our personal experience, malnutrition is mainly a problem for patients with advanced ovarian cancer, and future trials should

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