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Nutritional optimization during neoadjuvant therapy prior to surgical resection of

esophageal cancer – Systematic A narrative review

Jeremy R. Huddy (BMedSci BMBS, MRCS)1, Fiona M. S. Huddy (RD)2, Sheraz R. Markar

(MSc, MBBChir, MRCS)1, Olga Tucker (FRCS, MD)3.

1 – Department of Surgery & Cancer, Imperial College London

2 – Department of Oesophago-Gastric Surgery, Royal Surrey County Hospital,

Guildford

3 – Department of Oesophago-Gastric Surgery, Heart of England NHS Foundation

Trust and University of Birmingham

Category: Review article

Keywords: Esophageal cancers, nutrition, neoadjuvant, esophageal cancer surgery.

Conflict of interest: Fiona M S Huddy has previously received a one off honorarium

from Lilly for presentation at an advisory board. The authors have no other conflicts

of interest.

Funding source: Sheraz R. Markar is supported by the National Institute of Health

Research.

Abstract word count: 333 words

Manuscript word count: 2975 words

Tables: 6

Figures: 1

Corresponding author and for reprints: Sheraz R. Markar

Address: Department of Surgery & Cancer, 10th Floor QEQM Building, St. Mary’s

Hospital, London , W2 1NY

Telephone No: 0044 20 3312 2124

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Email: [email protected]

Author Contributions: JRH participated in the literature search, data collection,

analysis and interpretation of findings. FMSH participated in the analysis and

interpretation of findings. SRM participated in the study design, literature search,

data collection, analysis and interpretation of findings. OT conceived of the study,

participated in its design, analysis and interpretation of findings. All authors were

involved in drafting the manuscript.

Running head (40 characters): Nutrition in esophageal cancer therapy

ABSTRACT

This systematic narrative review aims to evaluate the evidence for the different

nutritional approaches employed during neoadjuvant therapy in patients with loco-

regional esophageal cancer. Patients with esophageal cancer are often malnourished

and difficult to optimise nutritionally. Whilst evidence suggests neoadjuvant therapy

can offer a survival advantage, associated toxicity can exacerbate poor nutritional

status. There is currently no accepted standard of care regarding optimal nutritional

approach.

A systematic literature search was undertaken. Studies describing the utilization of

an additional nutritional intervention in patients with esophageal cancer receiving

neoadjuvant therapy prior to esophagectomy were included. Primary outcome

measure was 30-day postoperative mortality after esophagectomy. Secondary

outcome measures were loss of weight during neoadjuvant therapy, completion rate

of intended neoadjuvant therapy, complications from nutritional intervention, 30-

day postoperative morbidity after esophagectomy and quality of life during

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mailto:[email protected]

neoadjuvant treatment. Given the heterogeneity of retrieved articles results were

presented as a narrative review.

Twenty-six studies were included of which 16 evaluated esophageal stenting, four

feeding jejunostomy, three gastrostomy, one naso-gastric feeding, one specialist

dietitian input, and one comparative study of esophageal stenting to feeding

jejunostomy. 30-day postoperative mortality was only reported in two of the 26

included studies limiting comparison between nutritional strategies. All studies of

esophageal stents reported improvements in dysphagia with reported weight change

ranging from -5.4kg to +6kg but none reported 30-day postoperative mortality. In

patients undergoing oesophageal stenting for their neoadjuvant treatment overall

migration rate was 29.9%. Studies of laparoscopically inserted jejunostomy were all

retrospective reviews that demonstrated an increase in weight ranging from 0.4 to

11.8kg and similarly no study reported 30-day post-operative mortality. Only one

comparative study was included that compared esophageal stents to jejunostomy.

This study reported no significant difference between the two groups in respect to

complication rates (stents 22% vs jejunostomy 4%, P=0.11) or increase in weight

(stents 4.4kg vs jejunostomy 4.2kg, P=0.59). Quality of life was also poorly reported.

This review demonstrates the uncertainty on the optimal nutritional approach for

patients with resectable esophageal cancer undergoing neoadjuvant treatment prior

to esophagectomy. A prospective, multicenter, observational cohort study is needed

to determine current practice and inform a prospective clinical trial.

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INTRODUCTION

Patients with esophageal cancer have complex nutritional needs. At the time of

diagnosis most are malnourished due to local tumour effects with dysphagia,

anorexia and cancer cachexia in addition to psychological factors that negatively

influence adequate dietary intake. Meta-analyses and randomized controlled trials

have demonstrated improved survival benefit of neoadjuvant therapy prior to

esophagectomy compared to surgery alone for patients with loco-regional

esophageal cancer (1–6). Treatment toxicities during neoadjuvant therapy contribute

to further weight loss and nutritional deficiencies (7). Malnutrition during

neoadjuvant therapy is associated with negative outcomes including poor tumour

response, poor treatment tolerance, increased neoadjuvant treatment related

morbidity and reduced of life (QOL) (8,9). Early identification of malnutrition and

appropriate nutritional support leads to improved nutritional status and QOL (10–

17). Furthermore, malnutrition is associated with adverse postoperative outcomes

including immune suppression, increased infection rate, increased morbidity

including pulmonary complications, delayed wound healing, muscle wasting,

prolonged in-hospital stay and increased healthcare costs (8,18–22).

During medical anti-cancer treatment, The European Society for Clinical Nutrition

and Metabolism (ESPEN) guidelines recommend, ‘enteral or, if this is not sufficient or

possible, parenteral nutrition If oral food intake is inadequate despite counselling and

oral nutritional supplements.’ (11,23). Further guidelines by Allum et al recommend

preoperative nutritional support for 10-14 days for malnourished patients with

esophageal and gastric cancer (24), and patients with severe nutritional risk for 10–

14 days prior to any major surgery (11). Specialist oesophago-gastric dietitians are

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ideally placed to assess and manage the complex nutritional problems encountered

in this patient group. Within the UK, there is a requirement for a specialist dietitian

to be a core member of the cancer tumour board.

Several approaches have been employed to optimize nutrition prior to and during

neoadjuvant therapy including esophageal stenting, feeding jejunostomy or

gastrostomy, and nasogastric or nasojejunal feeding (25–27). However, there is no

accepted standard of care or level 1 evidence to guide the optimal nutritional

approach. Treatment decisions differ according to regional practice, physician and

patient preference. The aim of this systematic review artlcle is to evaluate the

evidence in support of these different nutritional approaches during neoadjuvant

therapy for esophageal cancer.

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MATERIALS AND METHODS

A systematicn electronic literature search was undertaken using Embase, Medline,

Web of Science and Cochrane library databases up to December 2016. The search

terms; ‘esophagectomy’, ‘esophageal cancer’, ‘neoadjuvant therapy’, ‘nutrition’,

‘malnutrition’, ‘jejunostomy’, ‘gastrostomy’, ‘esophageal stent’, ‘nasoenteric feeding’

and the Medical Subject Headings (MeSH), ‘esophageal neoplasms’,

‘esophagectomy’, ‘neoadjuvant therapy’, ‘nutritional status’, ‘malnutrition’,

‘jejunostomy’, ‘gastrostomy’, ‘stents’, and ‘enteral nutrition’ were used in

combination with the Boolean operators AND or OR. The electronic search was

supplemented by a hand-search of published abstracts from meetings of the Society

of Academic and Research Surgery, Digestive Disease Week, the Association of

Upper Gastro-Intestinal Surgeons of Great Britain and Ireland, and the American

Society of Clinical Oncology 2005 to 2015. The reference lists of articles obtained

were also searched to identify further relevant citations; as was the Current

Controlled Trials Register (http://www.controlled-trials.com). The quality of evidence

provided by each study was evaluated using the Oxford levels of evidence-based

medicine scoring system (28) and Newcastle-Ottawa Score (29).

Publications were included if they met the following criteria:

Studies where the primary research population included patients with loco-

regional esophageal cancer receiving neoadjuvant therapy prior to curatively-

intended esophagectomy.

Studies that included nutritional assessment before commencing neoadjuvant

therapy.

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Studies that evaluated the utilization of an additional nutritional strategy,

including feeding jejunostomy, gastrostomy, esophageal stenting and

nasoenteric feeding during neoadjuvant therapy.

Publications were excluded if they met any of the following criteria:

Studies not concerning the management of esophageal cancer.

Studies in which the pre-treatment nutritional status of patients was not

assessed or poorly defined.

Review articles

Outcome measures for this systematic review

The primary outcome measure was 30-day postoperative mortality. Secondary

outcome measures were loss of weight during neoadjuvant therapy, completion rate

of intended neoadjuvant therapy, nutritional intervention-related complications

including mortality, 30-day postoperative morbidity and health-related QOL

(assessed by European Organisation for Research and Treatment of Cancer

questionnaires prior to and post nutritional intervention).

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RESULTS

The search strategy used yielded a total of 3489 articles. Following the removal of

duplications, all articles were subsequently selected on title, abstract and full text

based on the inclusion and exclusion criteria. Twenty-six studies were selected for

inclusion (Figure 1). Of these, 16 original articles evaluated the use of oesophageal

stenting (30–45), 4 (25,46–48) feeding jejunostomy, 3 (26,49,50) gastrostomy, one

specialist dietitian input (50) and one nasogastric feeding (51). One article (52)

directly compared esophageal stenting to feeding jejunostomy.

Esophageal stenting

Sixteen articles (30–45) evaluated the use of esophageal stenting and included 383

patients. There were nine prospective studies and seven retrospective studies. The

study characteristics are described in table 1 and outcomes in table 2. All studies

recruited patients with grade 2 dysphagia or more (able to swallow only semi-solid

foods) (53). Fifteen studies reported improvement in dysphagia scores. Eleven

studies reported technical success rate ranging from 83-100%, with the seven most

recent studies all reporting 100% success rates. Post-operative mortality was

reported in five studies (30,31,33,34,41) and ranged from 4-13.2%, whilst only one of

these studies specified 30-day post-operative mortality (10%). Seven studies

reported weight change, of which six reported weight loss, ranging from -5.4 to +6kg.

Completion of neoadjuvant therapy was reported in eight studies and ranged from

52.6 to 100%. Fourteen studies reported migration rates and included 321 patients

with an overall incidence of migration seen in 96 patients (29.9%). Other

complications were reported in fifteen studies of 331 patients of chest pain (n=50

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(15.6%)), tumour ingrowth (n=7 (2.2%)), esophago-bronchial or tracheal fistula (n=6

(1.9%)), esophageal perforation (n=5 (1.5%)), requirement for extra support (n=7

(2.2%)), food bolus obstruction (n=2 (0.6%)), stent dysfunction secondary to

inflammation (n=2 (0.6%)), erosion of aortic wall (n=1 (0.3%)), small bowel

perforation (n=1 (0.3%)), endoleak (n=1 (0.3%)), small bowel obstruction (n=1

(0.3%)), significant acid reflux (n=1 (0.3%)) and hematemesis (n=1 (0.3%)).

Three studies reported health related QOL. All three of these used European

Organisation for Research and Treatment of Cancer (EORTC) (54) questionnaires

including QLQ-C30, QLQ-OG25 and QLQ-ES18. In addition two studies used the

Functional Assessment of Cancer Therapy (FACT) (55) questionnaires including FACT-

General, FACT-Esophageal and FACT-Anorexia. All three of these studies

demonstrated improvement in some of the measured symptom specific QOL metrics

including dysphagia, eating restriction and quality of oral feeding. Health related QOL

outcomes from these studies are summarised in Table 2. One study reported a

reduction in physical QOL but the neoadjuvant therapy is a confounder to these

assessments.

Feeding Jejunostomy

Four studies (25,46–48) reported an evaluation of laparoscopically inserted feeding

jejunostomy in 236 patients. All were retrospective reviews of patients who

underwent laparoscopic feeding jejunostomy insertion at staging laparoscopy prior

to neoadjuvant therapy. The study characteristics are described in table 3 and

outcomes in table 4. No studies reported 30-day post-procedural mortality. Three

studies reported change in patient weights with all demonstrating an increase in

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weight ranging from 0.4 to 11.8kg. One study reported completion of neoadjuvant

therapy in greater than 90% of patients. All studies reported complications including

tube blockage (n=11 (4.6%)), dislodgement (n=9 (3.8%)), wound infection (n=7 (3%)),

leakage (n=5 (2.1%)), diarrhea (n=3 (1.3%)), connector breakage (n=2 (0.8%)) and

kinked tube (n=1 (0.4%)). 30-day post-operative mortality after esophagectomy and

health-related QOL were not reported in any study.

Gastrostomy

Three studies (26,49,50) evaluated the use percutaneous gastrostomy (two

percutaneous endoscopic gastrostomy and one percutaneous radiological

gastrostomy). All were retrospective reviews of single centre experiences. The study

characteristics are described in table 5 and outcomes in table 6. Only one study

discussed the contra-indications to gastrostomy placement of portal hypertension,

coagulopathy and abundant ascites. All studies highlighted concerns including the

risks of traversing esophageal tumours, rendering the stomach unsuitable for gastric

conduit, tumour seeding at the site of gastrostomy and injury to the right

gastroepiploic artery. Two studies reported success rates of gastrostomy insertion of

87-96.3%. Gastrostomy related complications occurred in ranging from 3.4-4%

including failure, suppurative wound infection, protracted ileus, persistent gastric

leakage, hemoperitoneum, peritonitis, small bowel obstruction, abdominal pain,

fever, failure and accidental dislodgement. One study reported minor complications

in 12%, most frequently cellulitis requiring antibiotics. Two studies reported mean

weight loss through neoadjuvant therapy, with one reporting a significant

improvement in mean weight loss before and after neoadjuvant therapy (14.3% +/-

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6.9 and 10.7 % +/- 7.8 respectively p=0.011) and the other reporting a gradual

decline in weight loss during chemoradiation with a mean weight loss of patients

undergoing surgery of 3.8% (range 0-9%). Completion rates of neoadjuvant

treatment ranged from 70-95%.

No study reported 30-day mortality after esophagectomy. One study (49) reported a

30-day post-gastrostomy mortality of 13.5% (none being gastrostomy related); one

study (26) reported 60-day post-gastrostomy mortality of 0%; and the third study

(50) reported a 90-day post esophagectomy mortality of 3%.

All included studies described the suture closing of gastrostomy site at the time of

esophagectomy and in all cases where gastric conduit formation was planned the

stomach provided a suitable esophageal substitute. Two studies reported a non-

significant increase in operative time in the gastrostomy group (16-43 minute

increase). None of the included studies assessed health-related QOL.

Intensive nutritional support

One study (56) evaluated the outcome of dietitian-delivered intensive nutritional

support (INS) with the aim of improving intake by 1.2-1.5g protein per kilogram of

body weight per day based on a calculated energy goal (57). Supplementary tube

feeding was instigated when nutritional goals were not met orally. This case-control

study compared 28 patients who received INS with a historic control group of 37

patients. Significantly more patients in the INS group received neoadjuvant therapy

(89 vs. 27%, p=<0.001). The study demonstrated that the INS cohort gained weight

between their first visit and surgery while the control group lost weight. Linear

regression demonstrated a relative weight change in comparison with the control

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group of +2.6% (p=0.048). This change became more pronounced when the INS

group was compared to a sub-group of control patients who underwent neoadjuvant

therapy where the relative weight change was +4.7%. (P=0.009). There were no

significant differences between the groups in respect to in-hospital postoperative

mortality. Post-operative 30-day mortality, completion rate of neoadjuvant therapy

and QOL was not reported.

Nasogastric feeding tubes

One retrospective study of 16 patients evaluated the use of nasogastric feeding

tubes (Dobhoff tubes) during neoadjuvant therapy (51). 4 patients required at least

one intervention to replace or unblock the tubing, while a further four patients

required more than one intervention, two of whom required percutaneous

endoscopic gastrostomy.

Comparative studies

One study compared the efficacy of self-expanding esophageal stenting (SES) (n=12)

versus feeding jejunostomy (n=24) during neoadjuvant therapy (52). Success rates

for SES placement and jejunostomy tube were 83.3 and 100% respectively. In the SES

group eight (72%) experienced post-procedural chest pain and 4 stent migration

(36%). All patients with successful stent deployment had immediate and sustained

improvement in dysphagia score and these was used as a surrogate for QOL. In the

feeding jejunostomy group two wound infection requiring antibiotics and one minor

leak were reported. Both cohorts gained weight during neoadjuvant treatment (SES

mean weight increase from 60.5 to 65kg, p<0.001 versus feeding jejunostomy mean

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weight gain 72.2 to 76kg, p=<0.05). Thirty-day post-esophagectomy and 30-day post-

procedural mortality were not reported.

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DISCUSSION

Published evidence suggests the optimal treatment for resectable advanced loco-

regional esophageal cancer is neoadjuvant therapy followed by esophagectomy (1–

6). The CROSS trial demonstrated improved loco-regional control and distant

metastases-free survival with neoadjuvant chemoradiotherapy and surgery versus

surgery alone (2). (58). In addition a recent network meta-analysis has provided

evidence of a survival advantage of neoadjuvant chemoradiotherapy compared to

neoadjuvant chemotherapy, adjuvant chemotherapy, adjuvant chemoradiotherapy

or surgery alone (59). Neoadjuvant chemoradiotherapy or neoadjuvant

chemotherapy is the accepted standard of care in the USA and UK respectively (3).

With increasing use of neoadjuvant chemoradiotherapy protocols for nutritional

optimization during neoadjuvant therapy should be prioritized to enable completion

of prescribed treatment cycles, improve treatment response rates and reduce

treatment-related toxicity. Importantly, optimizing nutritional status during

neoadjuvant treatment has a causal link to improved surgical outcome (8,18–22).

However, the uncertainty regarding the optimal nutritional approach has led to

regional variability in nutritional strategies in patients with loco-regional disease

receiving neoadjuvant therapy. This systematic review clearly demonstrates the

paucity of evidence to define the optimal nutritional approach. The evidence is

limited to case series with few prospective, multi-centre or comparative studies. No

randomised controlled trials or cost-effectiveness studies were identified. Evaluation

is mostly limited to studies that are insufficiently powered to report objective

nutritional outcomes, QOL and mortality. Study outcomes relied on weight change

with no additional measures of nutritional status such as grip strength. Furthermore,

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the primary endpoint of 30-day post-operative mortality was particularly poorly

reported in the included studies. Therefore, based on the limited poor quality data

available this systematic review cannot clearly identify the optimal strategy to

improve nutrition in this patient cohort.

Esophageal stenting was the most frequently reported intervention in fifteen studies.

The majority used improvement in dysphagia as the primary outcome measure with

all studies demonstrating improvement without a corresponding consistent

improvement in nutritional parameters including weight. The reported complication

rate was low but included life-threatening aortic erosion and tracheo-esophageal

fistula and variable stent migration rates of 9-65% (30–39,42,44,45) while the

proportion of patients proceeding to esophagectomy ranged from 15-100%.

Although some centers have published good outcomes following esophageal

stenting as a bridge to esophagectomy (30,42,45) a recent systematic review (60)

concluded that stent insertion before neoadjuvant therapy could not be supported

given the lack of evidence to demonstrate a consistent benefit to weight or

nutritional markers, the required extra interventions due to pain or migration,

variation in the numbers of patients proceeding to surgery and life threatening

complications.

Feeding jejunostomy insertion at esophagectomy is common practice in many

centers. Earlier insertion at the time of staging laparoscopy is increasingly performed

in patients with significant dysphagia and malnutrition. In three of the four studies

reporting feeding jejunostomy use rates of progression to surgery were high at >85%

although only one study reported weight gain. Reported complication rates are

comparable to esophageal stenting and less severe although Clavien Dindo scoring

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(61) was not documented in the majority. One study investigating gastrostomy

reportedly had a post gastrostomy 30-day mortality of 13.5%. This is exceeding high

and not consistent with the other included studies, no reason for this high figure was

provided.

Huerter et al report their experience of 127 patients undergoing neoadjuvant

treatment for esophageal cancer (62), of whom 61 (48%) received enteral feeding

access following nutritional assessment. This included 49 patients who underwent

laparoscopic feeding jejunostomy and the remaining 12 patients having

percutaneous endoscopic gastrostomy. Their results demonstrated a 36% incidence

of adverse events for tube placement including bleeding, infection, dislodgement

and tube site problems. Whilst multivariate regression did demonstrate that enteral

access was associated with nutritional stability during neoadjuvant therapy, all

patients proceeded to esophagectomy with outcomes similar between the enteral

access and no enteral access groups. However, this study is retrospective and it is

therefore not known if those patients who had supplementary feeding would have

been able to complete their neoadjuvant therapy and proceed to surgery without it.

This study was not included in the analysis as it was not possible to separate the

patients who had jejunostomy or PEG placement. Also 27.9% of patients who had

enteral access tubes placed did not use it consistently or at all during their

neoadjuvant treatment. A recent review (63) of 299 consecutive laparoscopic

feeding jejunostomies reported low complication rates and a 30-day mortality of 4%

in keeping with the findings of this current review.

QOL was reported poorly. Only three studies, all evaluating esophageal stenting,

reported QOL. These demonstrated improvement in some of the scores measured

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but in the main these were symptom specific rather than global QOL evaluations.

The physical, psychological and emotional consequences for patients of living with

different nutritional interventions and associated feeding regimes are unknown.

Validated esophageal cancer specific QOL questionnaires do allow the differentiation

of specific symptoms including dysphagia, eating restrictions, pain and discomfort.

Studies are required to investigate the impact of the differing nutritional approaches

on patient-reported outcome measures including QOL in addition to clinical

outcomes.

This systematic narrative review has limitations. The primary outcome of 30-day

post-operative mortality was poorly reported and therefore the optimal nutritional

strategy to improve survival could not be determined. 30-day post-operative

mortality was selected as the primary outcome in keeping with the recommendation

of the Esophagectomy Complications Consensus Group who agreed that 30-day

mortality should be recorded as a quality and outcome measure following

esophagectomy (64). We recognise that the review is heavily weighted by studies of

stent placement (16/26 studies with 383 patients). Eleven of these studies evaluated

dysphagia scores as a primary outcome and we acknowledge that dysphagia

does necessarily equate to malnutrition. We have not presented health economic

data as evaluation of the costthe cost effectiveness of stent placement and

reintervention was not the remit of this systematic review. Data on unplanned

hospital admissions and emergency department visits for dehydration and/or

complications for the nutritional approaches was lacking. These limitations further

support the need for a prospective, well designed, multicenter, randomized

controlled trial to compare the effectiveness of the current approaches for

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nutritional optimization in patients undergoing neoadjuvant chemotherapy prior to

oesophagectomy, and their impact on survival and health related QOL benefits.

This review highlights the lack of an accepted standard of care or level 1 evidence to

guide management plan in determining the optimal nutritional approach in patients

with resectable loco-regional esophageal cancer undergoing neoadjuvant therapy.

Prior to designing and undertaking such a trial a prospective, multicenter,

observational cohort study will be needed to determine the number of patients who

may be potentailly eligible and to collect evidence of current multidisciplinary team

treatment decision making for this group of patients.

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Figure 1: PRISMA flow diagram of literature search

30

Table 1: Study characteristics of included studies evaluating the use of esophageal stenting during neoadjuvant treatment

Author and Year

Type of study Evidence Level

N-O Score (max = 9)

Outcomes assessed n Age Male Success rate

Siddiqui et al 2007 (45)

Retrospective IV 5 Efficacy of treatment, stent-related complications and changes in nutritional status of the patient.

6 62.5 (47-82)

4 (66.7%)

83%

Martin et al 2009 (44)

Retrospective IV 5 Dysphagia score and outcome

5 63 (50-82)

3 (60%) Not stated (only stented patients included)

Bower et al 2009 (30)

Retrospective IV 4 Complications, dysphagia score, nutritional changes (albumin and body weight), progression to surgery

25 64 (48-82)

21 (84%) Not stated (only stented patients included)

Adler et al 2009 (32)

Prospective III 5 Dysphagia scores and patient weights

13 63.3 +/- 12.3

13 (100%)

11 (85%) (2 (15%) initial placement was sub-optimal and therefore replaced in same

31

procedure)Langer et al 2010 (31)

Prospective III 5 Success of insertion, complications, change in dysphagia score, change in albumin

38 66 (30.3-88.2)

26 97.4

Lopes et al 2010 (38)

Retrospective IV 5 Dysphagia scores, complications, tissue reaction, ease of removal

11 60.5 10 (90.9%)

90.9%

Brown et al 2011 (33)

Prospective III 5 Esophageal cancer patients undergoing neoadjuvant therapy prior to resection.

32 61 (39-82)

26 (81%) 100%

Pellen et al 2012 (34)

Retrospective IV 6 Patients with oesophageal cancer recommended for neoadjuvant treatment with endoscopically significant stenosis or dysphagia score of 3 or more

16 63 (53-76)

9 (56%) 100%

Siddiqui et al 2012 (35)

Retrospective IV 5 Patients with locally advanced oesophageal cancer.

55 65.8 +/- 11.1

43 100%

Krokidis et al

Prospective III 5 Patients undergoing neoadjuvant

11 64.9 +/-

9 100%

32

2013 (36)

treatment or radical radiotherapy after stent insertion.

7.5

Laquiere et al 2014 (37)

Prospective III 5 Patients undergoing neoadjuvant chemoradiotherapy for advanced oesophageal cancer with grade 2 dysphagia or more

20 61.5 (43-82)

15 (75%) 100%

Martin et al 2014 (39)

Prospective III 5 Esophageal cancer patients undergoing neoadjuvant treatment prior to oesophagectomy.

52 61 (39-82)

42 (81%) Not stated

Van den Berg et al 2014 (40)

Prospective III 4 Consecutive patients with oesophageal cancer scheduled for neoadjuvant therapy and complaining of dysphagia (grade 2 or more).

10 68 +/-7.7

7 (70%) 100%

Mariette et al 2015 (41)

Retrospective IV 5 Patients who had undergone oesophagectomy with curative intent and had undergone insertion of self-

38 64.5 (34-81)

33 (86.8%)

Not stated

33

expanding metallic stent as a bridge to surgery (60.5% had neoadjuvant treatment)

Phillips et al 2015 (42)

Prospective III 5 Patients with stage 2/3 junctional adenocarcinoma undergoing neoadjuvant therapy and who underwent stenting for symptoms of gastro-oesophageal reflux

40 62 (47-83)

32 (80%) Not stated

Mão-de-Ferro et al (43)

Properspective III 5 Nutritional status and dysphagia

11 64 (56-75)

10 (91%) 100%

Table 2: Study outcomes of included studies evaluating the use of esophageal stenting during neoadjuvant treatment

Author and Year

Mean weight change

Quality of Life Improvement in dysphagia score

Completion of neoadjuvant treatment

Number preceeding to surgery

Migration Complications (n) Post-operative Mortality

Siddiqui et al 2007

+6kg Not assessed Yes Not stated 6 (100%) 1 (20%) 0 Not stated

34

Martin et al 2009

Not assessed Not assessed Yes 5 (100%) Not stated 1 (20%) 0 Not stated

Bower et al 2009

-1.5% Not assessed Yes 23 (92%) 14 (56%) 6 (24%) Extra support required via nasoduodenal tube 2 (8%)Chest Pain 1 (4%)

0 (post-operative)

Adler et al 2009

Not stated Not assessed Yes Not stated 3 (23%) 6 (46%) Chest pain 12 (92.3%)Requirement for PEG tube – 2 (15%)

Not stated

Langer et al 2010

Not stated Not assessed Yes 20 (52.6%) 26 (68.4%) 12 (46%) Erosion of aortic wall – 1Small bowel perforation – 1Oesophago-tracheo-bronchial fistula – 2Perforation at stent placement - 1

1 (4%) (Post-operative mortality)

Lopes et al 2010

Not stated Not assessed Yes 10 (100%) 2 (20%) 2 (20%) Chest Pain - 3 (30%)Tracheo-oesophageal fistula – 1

Not stated

35

Brown et al 2011

-7.3kg Not assessed Yes Not stated 20 8 (25%) Chest Pain – 2 (6.3%)Endoleak – 1 (3.1%)

0 (peri-operative mortality)

Pellen et al 2012

-2.2kg Not assessed Yes Not stated 10 (62.5%) 7 (43.8%) Food bolus obstruction – 2 (12.5%)Small bowel obstruction -1 (6.3%)Tumour ingrowth – 1 (6.3%)

1 (10%) (30-day mortality)

Siddiqui et al 2012

+1.8kg Not assessed Yes Not stated 8 (15%) 17 (31%) Chest pain – 8 (15%)Significant acid reflux - 1 (2%)Odynophagia – 1 (2%)Food impaction 1 (2%)Oesophageal perforation 1(2%)

Not stated

Krokidis et al 2013

Not stated Not assessed Yes Not stated 1 (9%)(3 (27% awaiting surgery))

1 (9%) Aspiration and haematemesis - 1 (9%)Tracheobronchial aspiration and

Not stated

36

tracheoesophageal fistula – 1 (9%)Aspiration pneumonia and fistula with the bronchial tree – 1 (9%)Stent dysfunction from tumour growth – 3 (27%)Stent dysfunction from inflammation – 2 (18%)

Laquiere et al 2014

Not stated QLQ-ES18 scores revealed an improvement of both dysphagia and alimentary parameters following stent placement. No difference in parameters for pain,

Yes 100% 3 (20%) 3 (15%) Chest pain – 13 (65%)Perforation – 1 (5%)Orotracheal fistula – 1 (5%)Tumour overgrowth – 2 (10%)

Not stated

37

swallowing disorders, anorexia and anosmia.

Martin et al 2014

-3.2kg Statistically significant improvements in terms of dysphagia, eating restriction, and pain and discomfort.No change in social quality of life.Worsening of physical QOL during patients’ neoadjuvant therapy (not significant).Worsening of emotional quality of life at week 3 but returned to

Yes Chemotherapy – 34 (93%)Radiotherapy - 27 (75%)

Not stated 3 (5.8%) Not stated Not stated

38

baseline by completion of treatment.

Van den Berg et al 2014

-5.4kg (range 0.2-11) (-6.5%)

Not assessed Yes 9 (90%) 6 (60%) Not stated Chest pain – 6 (60%)Stent obstruction from tumour in growth – 1 (10%)

Not stated

Mariette et al 2015

Not assessed Not assessed Not stated Not applicable 38 (100%) (This was part of inclusion criteria)

Not stated Tumour perforation at insertion – 2

5 (13.2%) (post-operative in-hospital mortality)

Phillips et al 2015

Not assessed Significantly improved and sustained swallowing quality of life from 2 weeks up to 10 weeks post insertion. Reflux symptoms QOL was similar at 2

Yes 95% Not assessed

25 (62.5%) Chest pain – 5 (12.5%)

Not stated

39

weeks but improved after this point.

Mão-de-Ferro et al

Not assessed Not assessed Yes Not stated 4 (36%) 4 (36%) Esophageal perforation - 1(9%)Requirement for nasogastric feeding - 3 (27%)

Not stated

Table 3: Study characteristics of included studies evaluating feeding jejunostomy during neoadjuvant treatment

Author and Year


N-O Score (max = 9)

n Age Male

Grondona et al 2005 (47)

Retrospective IV 3 18 63 (53-73) 11

Jenkinson et al 2005 (25)

Retrospective IV 3 43 66 (42-82) 30

Ben-David et al 2013 (46)

Retrospective IV 5 153 63 115

Tsujimoto et al 2015 (48)

Retrospective IV 5 22 (9 patients with oesophageal

69.4 +/- 6.0 (range 48-79)

22

40

cancer undergoing neoadjuvant therapy)

Table 4: Study outcomes of included studies evaluating feeding jejunostomy during neoadjuvant treatment

Author and Year

Mean weight loss

Number of patients who required jejunostomy feeding

Median duration of feeding through jejunostomy



Complications (n)

Mortality

Grondona et al 2005

Not assessed 14 30 days Not stated 5 Leakage and wound infection – 1Wound infection – 1Kinked tube requiring removal – 1Accidental displacement - 1

Not stated

Jenkinson et al 2005

+1.1kg 20 Not stated Not stated 100% (inclusion criteria)

Dislodgement – 6 (20%)Blockage – 4 (13%)

Not stated

41

Connector breakage – 2 (7%)

Ben-David et al 2013

+11.8kg All Approximately a 10-week course of supplementary nutrition

>90% 86% Dislodgement – 2Leak – 4Clogging – 5Superficial wound infection – 4

Mortality rate in patients having laparoscopic jejunostomy and esophagectomy was 1%

Tsujimoto et al 2015

+0.4kg Not stated Not stated Not stated 9 (100%) Diarrhoea – 3 (13.6%)Tube obstruction – 2 (9%)

Not stated

Table 5: Study characteristics of included studies evaluating gastrostomy during neoadjuvant treatment

42

Table 6: Study outcomes of included studies evaluating gastrostomy during neoadjuvant treatment

Author and Year

Mean weight loss

Median duration of feeding



Removal rate

Complications (n) Mortality

Author and Year


N-O Score (max = 9)

n Age Male Guidance Success rate

Margolis et al 2003 (49)

Retrospective IV 5 179 61.4 (38-81)

Endoscopic 103/119 (87%)

Tessier et al 2013 (26)

Retrospective IV 5 269 (139 of whom were pre-operative and 130 were having CRT treatment alone)

60.5 6.3:1 Radiological 259 (96.3%)

Wright et al 2014 (50)

Retrospective IV 3 15 58 73% Endoscopic Not stated

43

through gastrostomy

Margolis et al 2003

3.8% (0-9)

15 weeks (3 days to 10 months)

71 (70%) 61 4 (4%) Major 4 (4%)Suppurative wound infections – 2Protracted Ileus – 1Persistent leakage – 1Minor 12 (12%)

13.5% (30 day mortality, 0% PEG related)

Tessier et al 2013

10.7% +/- 7.8

14.5 weeks (1-53)

93.7% in CRT group and 95% on chemotherapy group

83 5 (1.9%) 9 (3.4%)Haemoperitoneum – 1Peritonitis – 2Small bowel obstruction -1Abdominal pain and fever (normal laparoscopy ) – 1Failure requiring laparotomy and surgical jejunostomy – 1Accidental dislodgement - 1

0% (procedure related mortality)

Wright et al 2014

Not stated

Not stated Not stated 15 (100%) (was part of study inclusion

Not stated

Not stated 7% (90 day mortality)

44

criteria)

45

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