Original research
Br J Sports Med: first published as 10.1136/bjsports-2021-104243 on 1 February 2022. Downloaded from http://bjsm.bmj.com/ on March 2, 2022 at UFMG - Universidade Federal de Minas
► Additional supplemental
material is published online
only. To view, please visit the
journal online (http://d​ x.​doi.​
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104243).
For numbered affiliations see
end of article.
Correspondence to
Andrew Davies, Gastrointestinal
Medicine and Surgery, Guy’s
and St Thomas’ Hospitals NHS
Trust, London SE1 7EH, UK;
​Andrew.​Davies1@g​ stt.​nhs.​uk
Accepted 6 December 2021
© Author(s) (or their
employer(s)) 2022. No
commercial re-­use. See rights
and permissions. Published
by BMJ.
To cite: Zylstra J, Whyte GP,
Beckmann K, et al.
Br J Sports Med Epub ahead
of print: [please include Day
Month Year]. doi:10.1136/
bjsports-2021-104243
Exercise prehabilitation during neoadjuvant
chemotherapy may enhance tumour regression in
oesophageal cancer: results from a prospective non-­
randomised trial
Janine Zylstra ‍ ‍,1,2 Greg P Whyte,2,3,4 Kerri Beckmann,5 James Pate,4
Aida Santaolalla,5 Louise Gervais-­Andre,6 Beth Russell,5 Nick Maisey,7 Justin Waters,8
Gemma Tham,9 Jesper Lagergren,5 Michael Green,10 Mark Kelly,1 Cara Baker,1
Mieke Van Hemelrijck,5 Vicky Goh,6 James Gossage,1 Mike Browning,11
Andrew Davies1,5
ABSTRACT
Background There is increasing evidence for the
use of exercise in cancer patients and data supporting
enhanced tumour volume reduction following
chemotherapy in animal models. To date, there is
no reported histopathological evidence of a similar
oncological benefit in oesophageal cancer.
Methods A prospective non-­randomised trial compared
a structured prehabilitation exercise intervention
during neoadjuvant chemotherapy and surgery versus
conventional best-­practice for oesophageal cancer
patients. Biochemical and body composition analyses
were performed at multiple time points. Outcome
measures included radiological and pathological markers
of disease regression. Logistic regression calculated ORs
with 95% CI for the likelihood of pathological response
adjusting for chemotherapy regimen and chemotherapy
delivery.
Results Comparison of the Intervention (n=21) and
Control (n=19) groups indicated the Intervention group
had higher rates of tumour regression (Mandard TRG
1–3 Intervention n=15/20 (75%) vs Control n=7/19
(36.8%) p=0.025) including adjusted analyses (OR
6.57; 95% CI 1.52 to 28.30). Combined tumour and
node downstaging (Intervention n=9 (42.9%) vs Control
n=3 (15.8%) p=0.089) and Fat Free Mass index were
also improved (Intervention 17.8 vs 18.7 kg/m2; Control
16.3 vs 14.7 kg/m2, p=0.026). Differences in markers of
immunity (CD-­3 and CD-­8) and inflammation (IL-­6, VEGF,
INF-­y, TNFa, MCP-­1 and EGF) were observed.
Conclusion The results suggest improved tumour
regression and downstaging in the exercise intervention
group and should prompt larger studies on this topic.
Trial registration number NCT03626610.
INTRODUCTION
Neoadjuvant chemotherapy (NAC), while poten-
tially beneficial in tumour downstaging before
surgery and improving survival in oesophageal
adenocarcinoma, has a deconditioning effect on
patient fitness.1 2 An increased incidence of sarco-
penia is common following NAC which in combi-
nation with visceral obesity has been associated
with cancer progression and poor chemotherapy
Zylstra J, et al. Br J Sports Med 2022;0:1–9. doi:10.1136/bjsports-2021-104243
response.3–5 While not currently prescribed as part
of standard care, there is burgeoning evidence of
the benefits of exercise in the treatment of cancer.
One study reported on the molecular basis for
linking exercise to improved cancer outcomes while
also suggesting a role in the prevention of cancer
development and the regulation of cancer progres-
sion.6 A recent systematic review of 27 relevant
observational studies found evidence of reduced
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cancer-­
specific mortality associated with physical
exercise.7 Furthermore, moderate intensity exercise
has been linked to a reduction in both recurrence
and the development of new primary tumours in
patients with breast cancer.8
Recent studies, conducted using animal models,
have reported a positive impact of exercise on
tumour volume shrinkage following chemo-
therapy. One study described a reduction of tumour
volumes, improved perfusion and reduced tumour
hypoxia in exercising mice.9 However, there is to
our knowledge, no evidence in human participants
of the histopathological benefits of exercise in
patients undergoing NAC for oesophageal cancer.
The purpose of the trial was to evaluate the clin-
ical impact of a structured exercise intervention in
patients with operable oesophageal cancer during
NAC compared with those on a standard treatment
pathway. This study specifically assessed the impact
of exercise on measures of chemotherapy response.
METHODS
Study design
Following patient and public involvement consul-
tation, support was received from the Oesophageal
Patients Association to undertake the study.10
Patients underwent a standard pathway of staging
investigations including oesophagogastroduodenos-
copy and tissue biopsy, CT imaging (CT), positron
emission tomography imaging and endoscopic
ultrasound. Staging laparoscopy was used selec-
tively. All patients were discussed in a specialist
upper gastrointestinal multidisciplinary meeting
(UGI MDM).
After completion of staging investigations, the
final clinical cancer tumour node metastasis (TNM)
stage was agreed by the UGI MDM and consensus
   1
 Original research
achieved on patients’ treatment pathways.11 Patients were
reviewed by the clinical team in the out-­ patient department
and assessed for eligibility to participate in the trial, ‘Prehabil-
itation of patients with oEsophageal Malignancy undergoing
Peri-­operative Treatment’ (Pre-­EMPT)—a non-­randomised,
interventional study comparing the effects of a structured
exercise programme, or ‘prehabilitation’ (Intervention), versus
conventional best practice (Control) in patients undergoing NAC
following a diagnosis of operable adenocarcinoma of the lower
oesophagus or gastro-­ oesophageal junction. Inclusion criteria
are described in online supplemental information.
Guy’s and St Thomas National Health Service (NHS) Foun-
dation Trust is a high volume, tertiary specialist centre for
oesophago-­ gastric cancer receiving referrals from a large
geographical area divided into two similar-­sized cancer networks.
All patients being considered for oesophagectomy are assessed
at the surgical centre. Patients received advice from specialist
nurses, dietitians and physiotherapists as to how best to prepare
for the proposed treatment. This multi-­disciplinary input was
considered to be best current practice and included nutritional,
physical activity and smoking cessation advice.
Eligible patients were offered participation in the study, either
the Intervention or Control arms, depending on their region
of origin. Historical data reported no differences in clinical
outcomes in patients from either region. Randomisation into
treatment arms was considered at the outset, however the exer-
cise intervention was delivered by a collaborating institution
within a single geographical area. As a result, the time and finan-
cial constraints for patients regularly travelling from the other
region to receive the intervention was considered excessive.
Clinical commissioning constraints also mandated a minimisa-
tion of travel to the centre from patients within this region. All
surgery was performed at St Thomas’ Hospital, London.
Following informed and written consent to participation in
the trial, patients undertook relevant baseline study procedures
as per study protocol (figure 1). Instruction on physical activity
Figure 1 Flow chart Pre-­EMPT trial. CHHP, Centre for Health and Human Performance; CPEX, cardio-­pulmonary exercise test; HRQL, health-­related
quality of life; Pre-­EMPT, Prehabilitation of patients with oEsophageal Malignancy undergoing Peri-­operative Treatment.
2 Zylstra J, et al. Br J Sports Med 2022;0:1–9. doi:10.1136/bjsports-2021-104243
Br J Sports Med: first published as 10.1136/bjsports-2021-104243 on 1 February 2022. Downloaded from http://bjsm.bmj.com/ on March 2, 2022 at UFMG - Universidade Federal de Minas
during NAC was provided by a registered specialist Physiother-
apist to all patients attending a regular surgical-­oncology clinic
at St Thomas’ Hospital, London. In addition, a structured exer-
cise training programme was given to the Intervention group, by
a specialist Exercise Physiologist, at the Centre for Health and
Human Performance (CHHP) in London. The exercise inter-
vention or ‘prehab’ programme undertaken during NAC, was
based on a ‘moderate intensity’ programme in line with WHO,
UK Chief Medical Officer Physical Activity and Macmillan
‘Recommended levels of physical activity for adults aged 18–64
years, ‘also relevant to healthy adults aged 65 and above’, unless
contraindicated’ guidelines, incorporating combined aerobic and
strength training.12 13 ‘Moderate intensity’ was prescribed using
a modified Rating of Perceived Exertion of 4–5 (the modified
scale has a range from 0 to 10, with 0 being no exertion and
10 being maximum effort). Prescribing exercise intensity in this
way enables the patient to self-­monitor intensity when exercising
at home. Patients received training sessions at each monitoring
time point and were encouraged to attend additional sessions
at CHHP. They were also provided with written and diagram-
matic instructions on how to continue the exercise programme
at home. Patients were not withdrawn from the Intervention arm
if they failed to comply with the exercise programme. Similarly,
no restrictions on physical activity were imposed on the Control
group.
According to protocol, baseline trial measures were repeated
within 1 week of completion of NAC. Patients were then
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reviewed in the UGI MDM for suitability for surgery. A third
set of trial evaluations were carried out within a week preceding
surgery.
Oncological and surgical treatment
Oncological practices within the two regions were very
similar. At the commencement of the study, perioperative
treatment with epirubicin, cisplatin and five flurouracil (ECF)

or epirubicin, oxaliplatin and capecitabine (ECX) were consid-
ered to be the first choice regimens.14 Both incorporated three
cycles of chemotherapy before and after surgery. With the
publication of the FLOT trial,15 oncological practice in both
regions changed simultaneously to four cycles of preoperative
and postoperative fluorouracil plus leucovorin, oxaliplatin
and docetaxel (FLOT). The study protocol accommodated this
change in practice. Dose reductions were recorded prospec-
tively. Oesophagectomy included transhiatal and transthoracic
resections at the discretion of the individual surgeon, taking
into account both patient and tumour characteristics.
Outcome measures
Trial end-­points such as clinical outcomes, cardiovascular
fitness parameters and health-­related quality of life will be
reported elsewhere. This study focused on the relationship
between exercise and measures of chemotherapy response.
Pathological analysis
Pathological outcomes were recorded using the Royal College
of Pathologists guidelines.16 All postoperative histopathology
was undertaken by a group of specialist UGI Pathology Consul-
tants at Guy’s and St Thomas’ NHS Foundation Trust. Histo-
logical regression utilised a categorical scoring system based
on the proportion of fibrosis to residual tumour as originally
described by Mandard (Mandard Tumour Regression Grade,
MTRG).17 This measure of tumour regression following
chemotherapy has been shown to be prognostic in oesophageal
cancer patients and is recommended as part of standard histo-
pathological reporting in the UK.18 Lymph node regression
scoring (LNRS) similarly categorised each lymph node by allo-
cating a score based on fibrosis and viable tumour with the best
score per patient being recorded.19 For both primary tumour
and lymph node regression, a score of 1–3 was classified as a
responder (score 1 no residual tumour, score 3 more than 50%
fibrosis) whereas a score of 4–5 was deemed a non-­responder
(score 4 more than 50% viable tumour, score 5 viable tumour
with no evidence of response). Alternative classifications have
been proposed in the literature (eg, MTRG 1–2 vs 3–5) and
these were also analysed.17
Tumour downstaging
Downstaging was defined as a patient in whom the patholog-
ical TNM stage (ypTNM) was less advanced than the clinical
TNM staging (cTNM) at diagnosis, subdivided into T, N and
combined categories.1
Body composition
CT scans of the thorax and abdomen were performed routinely
on all patients at Baseline and following NAC. Axial images
from these staging scans were processed to assess changes in
body composition (fat and muscle). In each participant, axial
images equivalent to a 10 mm z-­axis stack were sampled at the
level of the third Lumbar vertebra. Following Hounsfield unit
thresholding and automated segmentation of subcutaneous
and visceral fat and muscle (FATS software, King’s College
London) parameters including Fat-­to-­Muscle Ratio (FMR), Fat
Free Mass Index (FFMi) and FMi were assessed.3 20 21
Immunity and inflammatory markers
Immunity and inflammatory markers were assessed for changes
and compared between the two cohorts. T lymphocyte subsets,
CD3, CD4 and CD8, were measured using flow cytometry
Zylstra J, et al. Br J Sports Med 2022;0:1–9. doi:10.1136/bjsports-2021-104243
Original research
Br J Sports Med: first published as 10.1136/bjsports-2021-104243 on 1 February 2022. Downloaded from http://bjsm.bmj.com/ on March 2, 2022 at UFMG - Universidade Federal de Minas
Figure 2 Directed acyclic graph depicting potential causal pathways
for any association between the exercise intervention and response to
NAC. NAC, neoadjuvant chemotherapy.
on a Beckman Coulter AQUIOS flow cytometer. Groups of
cytokines—lymphokines, interferons, haemopoietic and
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non-­haemopoietic growth factors, measured on a RANDOX
Evidence Investigator, were analysed using Competitive and
Sandwich antibody, chemiluminescent, biochip immunoassays.
Due to the impact of COVID-­19 on laboratory facilities
during the latter part of the study period, data on body compo-
sition and inflammatory markers was only available for 27
patients. (Intervention n=13; Control n=14). Similarly LNRS
availability was limited (Intervention n=12; Control n=13).
Statistical analysis
Study sample size calculations were based on clinical outcome
measures including a reduction in postoperative complica-
tions and hospital length of stay. χ2 and Fisher’s exact tests
were used to analyse categorical data, the latter being used
when the frequency of variables was low. The Mann-­Whitney
U test was used for comparison of non-­normally distributed
continuous data. Logistic regression analysis provided ORs
with 95% CIs (crude and adjusted) for the likelihood of
responder status (primary outcome), according to the study
exposure (exercise Intervention vs Control). Following causal
directed acyclic graph assessment (figure 2), analyses adjusted
for chemotherapy regimen (ECF/ECX vs FLOT) and chemo-
therapy delivery (full vs dose reduction). Other factors, such
as age, sex, tumour stage and functional status, that would be
considered confounders in models assessing survival were not
included as there was no evidence that they would directly
affect chemotherapy response.
RESULTS
Patient demographics
This analysis included 21 patients in the Interventional group
and 19 patients in the Control group who had completed the
perioperative treatment pathway and were in follow-­up. One
patient in each group was unsuitable for surgery after NAC
and results for these patients included baseline and post-­NAC
parameters but no postoperative outcomes. All patients
completed the prescribed chemotherapy with four patients in
3
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Br J Sports Med: first published as 10.1136/bjsports-2021-104243 on 1 February 2022. Downloaded from http://bjsm.bmj.com/ on March 2, 2022 at UFMG - Universidade Federal de Minas
Table 1 Patient demographics
Intervention group % Control group % P value
Number at baseline n=22 52.4 n=20 47.6
Age—median (IQR) 64.0 (40–76.3) 65.8 (42.5–77.9) 0.841
Sex
 Male 18 82 18 90
 Female 4 18 2 10
Clinical stage at diagnosis—TNM 7 and 8
 T-­stage
 1 0 – 0 –
 2 3 13.7 1 5
 3 18 81.8 18 90
 4 1 4.5 1 5
 N-­stage
 0 1 4.5 2 10
 1 12 54.6 10 50
 2 8 36.4 8 40
 3 1 4.5 0 –
Comorbidities (NOGCA)
 None 4 18.2 5 25
 1—Cardiovascular disease 13 59.1 10 50
 2—COPD, asthma 2 9.1 3 15
 3—Chronic renal impairment 1 4.5 1 5
 4—Liver failure/cirrhosis 0 – 0 –
 5—Diabetes 3 13.7 1 5

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 6—Mental illness (requiring medication) 2 9.1 0 –
 7—Cerebro/peripheral vascular disease 2 9.1 0 –
 8—Barrett’s syndrome 1 4.5 1 5
 9—Other significant condition 8 36.4 10 50
BMI (kg/m2)—median (IQR) 25.55 (19.3–37.3) 27.62 (20.5–49.1) .447
Number proceeded to surgery n=21 95.5 n=19 95
Hospital length of stay
 Median (range) days 10.5 (9–41) 11 (8–44)
Postoperative complications
 None 13 62 8 42.1
Clavien-D
­ indo
 1, 2 5 23.8 5 26.3
 3a 0 5 26.3
 3b 1 4.73 1 5.3
 4 1 4.73 0
 5 1 4.73 0
In-­hospital mortality
 Yes 1 5 0 0
 No 20 95 19 100
30-­day mortality
 Yes 0 0 0 0
 No 21 100 19 100
90-­day mortality
 Yes 1 5 0 0
 No 20 95 19 100
BMI, body mass index; COPD, chronic obstructive pulmonary disease; NOGCA, National Oesophago-­Gastric Cancer Audit; TNM, tumour node metastasis.

the Invention arm and two patients in the Control arm having
dose reductions or a delay during treatment. At diagnosis,
there were comparable baseline demographics of age, sex and
tumour characteristics between the two groups (table 1).
Primary tumour regression
MTRG of the primary tumour was significantly improved in
the exercise group using both definitions of responders vs
non-­
responders (MTRG 1–3 Intervention n=15/20 (75%),
Control n=7/19 (36.8%), p=0.025 and MTRG 1–2 Inter-
vention n=7/20 (35%), Control n=1/19 (5.3%), p=0.044)
(table 2). Similarly, crude MTRG 1–3 (Intervention OR 6.50;
95% CI 1.60 to 26.40); MTRG 1–2 (Intervention OR 12.00;
95% CI 1.32 to 108.67) and adjusted logistic regression
analysis MTRG 1–3 (Intervention OR 6.57; 95% CI 1.52 to
28.30); MTRG 1–2 (Intervention OR 17.90; 95% CI 1.73 to
185.40) demonstrated significantly improved tumour regres-
sion in the exercise group (tables 2 and 3).

4 Zylstra J, et al. Br J Sports Med 2022;0:1–9. doi:10.1136/bjsports-2021-104243

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Br J Sports Med: first published as 10.1136/bjsports-2021-104243 on 1 February 2022. Downloaded from http://bjsm.bmj.com/ on March 2, 2022 at UFMG - Universidade Federal de Minas
Table 2 Oncological outcome measures
Intervention group Control group
Variables n=21 % n=19 % P value
Oncological
NAC regimen* FLOT 11 55 8 42.1 0.527
  Other 9 45 11 57.9
NAC completed* Yes 15 75 16 84.2 1.000
  Dose reduced 4 20 3 15.8
  Delayed 1 5 0 0
Histopathological:

Mandard Tumour Regression Grade

Best score per patient 1 2 9.5 1 5.25
  2 5 23.8 0 0.0
  3 8 38.1 6 31.6
  4 3 14.3 11 57.9
  5 2 9.5 1 5.25
 Combined* 1–3 15 75 7 36.8 0.025
  4–5 5 23.8 12 63.2
 Combined* 1–2 7 35 1 5.3 0.044
  3–5 13 65 18 94.7
Lymph Node Regression Score
 Best score per patient 1–3 4 50 2 25 0.608
  4–5 4 50 6 75

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  Neg LN 4 5
 Combined 1–2 4 50 1 12.5 0.282
  3–5 4 50 7 87.5
 Worst score per patient 1–2 4 50 0 0 0.077
  3–5 4 50 8 100
Downstaging (cTNM-­ypTNM)
 T-­downstaging Yes 14 66.7 6 31.6 0.056
  No 7 33.3 13 68.4
 N-­downstaging Yes 12 57.1 9 47.4 0.752
  No 9 42.9 10 52.6
 Combined downstaging Yes 9 42.9 3 15.8 0.089
  No/mixed 12 57.1 16 84.2
 Surgical resection margin status R0 14 71.4 14 73.4 1.000
  R1 6 28.6 5 26.3
*Denotes patients with available MTRG (n=20); p values for categorical values Fisher’s exact test unless stated otherwise.
cTNM, Clinical TNM stage; FLOT, fluorouracil plus leucovorin, oxaliplatin and docetaxel; LNs, lymph nodes; NAC, neo-­adjuvant chemotherapy; ypTNM, pathological TNM stage.

Lymph node regression score
Four patients in the Intervention group and five patients in the
Control group had negative lymph nodes with no evidence of
prior tumour involvement. Of the remaining patients, those in the
Intervention group had a non-­statistically significant higher rate of
lymph node regression using both definitions of responders versus
non-­responders (LNRS 1–3 vs 4–5 Intervention n=4/8 (50%) vs
Control n=2/8 (25%) p=0.608; LNRS 1–2 vs 3–5 Intervention
n=4/8 (50%) vs Control n=1/8 (12.5%) p=0.282). Using an
alternative classification (worst response per patient) as proposed
prior to commencement of the study, showed an improvement in
lymph node regression in the Intervention group (Intervention
n=4/8 (50%) vs Control n=0/8 (0%) p=0.077). (table 2)
Downstaging
The patients in the Intervention group had evidence of improved
CT-­
based downstaging for T Stage (downstaged Intervention
n=14 (66.7%) vs Control n=6 (31.6%), p=0.056; OR 4.33

Table 3 Logistic regression model

Crude Adjusted
Variable OR 95% CI OR 95% CI
Mandard responder 1–3 vs 4–5 Control 1.00 Ref. 1.00 Ref.
Intervention 6.50 1.60 to 26.40 6.57 1.52 to 28.30
Mandard responder 1–2 vs 3–5 Control 1.00 Ref. 1.00 Ref.
Intervention 12.00 1.32 to 108.67 17.90 1.73 to 185.4
Model adjustment for NAC regimen and chemotherapy delivery.
NAC, neoadjuvant chemotherapy.

Zylstra J, et al. Br J Sports Med 2022;0:1–9. doi:10.1136/bjsports-2021-104243 5

 Original research
Figure 3 Represents change in weight in relation to changes in FMR, FM index and FFM index in Interventional versus Control groups. The
Intervention group remained largely weight stable while improving FFM index. The Control group showed small increase in weight and increase in
FMR. FFM, Fat Free Mass; FMR, fat-­to-­muscle ratio; NAC, neoadjuvant chemotherapy.
95% CI 1.15 to 16.33). N Stage (downstagedIntervention n=12
(57.1%) vs Control n=9 (47.4%), p=0.752; OR 1.48 95% CI
0.43 to 5.16) and combined T and N Stage (downstaged Inter-
vention n=9/21 (42.9%) vs Control n=3/19 (15.8%), p=0.089;
OR 4.00 95% CI 0.89 to 18.04) were improved although not
statistically significant (table 2).
Body composition
Patients in the exercise Intervention group had an improved
median FMR of −7.15% after prehabilitation, with increases
in skeletal muscle and decreases in visceral and subcutaneous
fat areas compared with baseline scans, while remaining weight
stable. The Control group, who were already in the overweight
category at diagnosis, increased FMR by +12.4% with overall
weight gain, associated with increased visceral and skeletal fat,
and reduced muscle mass.
FFMi and FMi, normalised for patient height and weight,
also improved in the Intervention group (median FFMi inter-
vention +2.3% vs −1.9% Control, p=0.03). There was a corre-
sponding reduction in overall fat mass in the Intervention group,
especially visceral fat (median FMI improvement of −3.8%
Intervention vs +0.7% Control, p=0.689) (figure 3).
Inflammatory and immunity markers
Online supplemental tables 5 and 6 summarise the changes in
inflammatory and immune markers after NAC. The Interven-
tion group exhibited significantly higher median T lymphocyte
counts post-­NAC compared with the Control group (CD-­ 3:
1681.2 vs 981.08, p=0.03; CD-­8: 29.41 vs 0.98, p=0.03).
Following NAC, IL-­6 levels increased in both groups (Inter-
vention 27.9% vs Control 126.4%; p=0.04). TNFa levels
reduced in the Intervention group compared with an increase in
the Control group (Intervention −1.77% vs Control +28.3%,
p=0.25). IFN-­y increased in both groups (Intervention 223.6%
vs Control 57.24%, p=0.36). MCP-­ 1 increased more in the
Control group (Intervention 52.1% vs Control 169.7%, p=0.09)
(figure 4).
6 Zylstra J, et al. Br J Sports Med 2022;0:1–9. doi:10.1136/bjsports-2021-104243
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Gerais. Protected by copyright.
DISCUSSION
The results from this prospective trial suggest there may be
novel and important clinical benefits of a structured exercise
programme during NAC for oesophageal adenocarcinoma.
Prehabilitation in this patient group appears to be able to
respect the limitations imposed on patients by chemotherapy
schedules. Perhaps most importantly there is some evidence,
although in a small group of patients, of improved patho-
logical, radiological and immunological responses to chemo-
therapy in the exercise Intervention group.
Some methodological issues merit consideration. This study,
while prospective, was not formally randomised for the reasons
outlined above, which introduces the risk of confounding.
However, the geographical regions were similarly sized with
comparable oncological practices. Many aspects of patient
care were consistent, such as MDM decision making, the loca-
tion of surgery and pathological analysis, all of which occurred
at one central site. As patients were all deemed to be oncolog-
ically suitable and physically fit enough to tolerate NAC and
surgery prior to inclusion in the study, heterogeneity between
the groups was reduced. Therefore, as expected, demographics
and staging at diagnosis were very similar, although some non-­
significant differences in the groups were observed, such as a
higher body mass index in the Control group. Some changes in
practice occurred following commencement of the study such
as the adoption of the ‘FLOT’ regimen as first choice chemo-
therapy. Numerous other prospective trials have also adapted
to this by adjusting their protocols.22 While the proportions of
patients receiving FLOT differed slightly between the groups,
this was adjusted for in the analysis. However, the possibility
of unmeasured confounding remains in studies of this kind.
The study numbers were relatively small, lacking statistical
power, and therefore susceptible to sparse-­data bias.23 None-
theless, some statistically significant differences in the groups
were observed particularly with regards to pathological
tumour regression, immunological markers and body compo-
sition. While these findings are certainly of clinical interest,

Figure 4 Shows the differences in immunity and inflammatory markers between the Intervention and Control groups. Patients in the Intervention
group show a higher CD-­3, CD-­4 and CD-­8 counts suggesting improved adaptive immune function. Higher inflammatory responses are noted in
patients in the Control group in markers associated with tumour growth and disease progression. NAC, neoadjuvant chemotherapy.
they need to be interpreted with some caution pending valida-
tion in larger studies.
Tumour downstaging and response to chemotherapy are
arguably the most important prognostic factors in oesoph-
ageal cancer.1 A high proportion of patients undergoing
oesophagectomy have evidence of micrometastases at the time
of surgery and the introduction of NAC has been associated
with improvements in survival, cancer recurrence and systemic
control.22 Nonetheless, a significant proportion of patients do
not respond to chemotherapy and these patients have poorer
outcomes.24 Oesophageal cancer, because of its neoadjuvant
treatment strategy and established pathological methods
of quantifying tumour regression, is an ideal tumour group
on which to examine hypotheses of exercise-­related chemo-
therapy response.17 19 That structured exercise programmes
might contribute to improved cancer regression, possibly
through enhanced immunological and/or inflammatory modu-
lation, is potentially clinically significant. The results from this
analysis, showing improvements in pathological regression
in the primary tumour and clinical downstaging are hypoth-
esis generating and the first to be demonstrated in a clinical
trial in oesophageal cancer. The results also concur with an
increasing body of evidence supporting exercise in animal
cancer models.25
Differences in some of the other study outcome measures
may provide some potential mechanisms for the observed
improvements in chemotherapy response. However, these
interactions are likely to be complex and must be considered
theoretical at this stage. The Intervention group exhibited
significantly higher median T lymphocyte counts (CD-­3 and
CD-­ 8) than the Control group suggesting improved adap-
tive immune function and tumour-­cell destruction capability,
despite immunosuppressive chemotherapy. Following NAC,
IL-­6 levels increased significantly more in the Control group.
This marker has been directly associated with tumour cell
Zylstra J, et al. Br J Sports Med 2022;0:1–9. doi:10.1136/bjsports-2021-104243
Original research
Br J Sports Med: first published as 10.1136/bjsports-2021-104243 on 1 February 2022. Downloaded from http://bjsm.bmj.com/ on March 2, 2022 at UFMG - Universidade Federal de Minas
Gerais. Protected by copyright.
growth and disease progression.26 TNFa levels, which have
been associated with visceral fat and tumour promotion, were
reduced in the Intervention group compared with an increase
in the Control group. IFN-­ y, which has been proposed to
have a tumour-­ suppressive role, increased in both groups
but significantly more so in the Intervention group.27 MCP-­1
increased more in the Control group and is believed to regu-
late the tumour cell and macrophage cell cycles, potentially
having a role in promoting tumour progression.28
Patients undertaking a structured exercise programme
during NAC improved muscle mass compared with the
Control group. This might be particularly relevant in an age-­
associated condition, such as oesophageal adenocarcinoma, in
which sarcopenia is prevalent. Sarcopenia, obesity and sarco-
penic obesity, are associated with cancer development and
progression in general.29 NAC for oesophageal adenocarci-
noma is frequently associated with sarcopenia.3 In this trial,
a reversal of sarcopenia and sarcopenic obesity was observed
in patients undertaking the exercise intervention. Analysis
of body composition demonstrated that these patients expe-
rienced reduced overall Fat Mass—both subcutaneous and
visceral—and reduced FMR, while largely maintaining body
mass. Conversely, there was an increase in overall Fat Mass,
but particularly visceral fat in the Control group, which has
been associated with inflammation and immunosuppression in
patients with cancer.29
Patient fitness is an important component of clinical
decision-­making in oesophageal cancer. Patients undergoing
multimodality treatment experience the cumulative physiolog-
ical insults of chemotherapy and major surgery. Patients who
are deemed unable to tolerate such deconditioning treatment
may be offered a less radical therapeutic approach. While not
directly related to the outcome measures of this study, results
from this trial suggest that a structured exercise intervention
ameliorates some of this treatment-­related deconditioning and
7
 Original research
improves body composition. This potentially increases the
choices for radical treatment in a greater number of patients
with cancer.
CONCLUSION
In conclusion, the initial results of this prospective clinical
trial are the first to suggest a possible association between a
structured exercise programme (prehabilitation) and improved
chemotherapy response in oesophageal cancer. Numerous
biochemical and CT-­based parameters differed between the
Intervention and Control groups, suggesting reduced inflam-
mation, improved immune function and improved body
composition in the Intervention group. These may represent
some of the potential mechanisms by which the chemotherapy
response may have been enhanced. While the limitations in
patient numbers and non-­randomised design mandate caution,
the impact for patients is potentially significant. Further
work to confirm or refute these findings is urgently required
including whether or not improvements in chemotherapy
response may translate into a survival advantage. Pending this,
the present results further strengthen the rationale for exercise
to be prescribed as standard care in patients undergoing treat-
ment for cancer.
What are the findings?
► First reported pathological evidence in humans with
oesophageal cancer that exercise may enhance tumour
regression during chemotherapy.
► Exercise prehabilitation during neoadjuvant chemotherapy
appears beneficial to pathophysiological, immunity and
inflammatory markers.
► Reversal of sarcopenia and sarcopenic obesity in patients
undertaking exercise intervention during chemotherapy.
How might it impact on clinical practice in the future?
► Studies assessing the potential benefits of prehabilitation
should now include measures of chemotherapy response in
their study protocols.
► Strengthens the argument for prehabilitation being the
standard of care for all patients undergoing cancer treatment,
not just those on a surgical pathway.
► The translational mechanistic relationships between exercise
and chemotherapy response need to be interrogated further.
Author affiliations
1
Gastrointestinal Medicine and Surgery, Guy’s and St Thomas’ Hospitals NHS Trust,
London, UK
2
School of Sport and Exercise Science, Liverpool John Moores University, Liverpool,
UK
3
Research Institute for Sport and Exercise Science, Liverpool John Moores University,
Liverpool, UK
4
Centre for Health and Human Performance, London, UK
5
School of Cancer and Pharmaceutical Studies, King’s College London, London, UK
6
Clinical Cancer Imaging, King’s College London, London, UK
7
Oncology, Guy’s and St Thomas’ Hospitals NHS Trust, London, UK
8
Oncology, Maidstone and Tunbridge Wells NHS Trust, Maidstone, UK
9
Physiotherapy, Guy’s and St Thomas’ Hospitals NHS Trust, London, UK
10
Pathology, Guy’s and St Thomas’ Hospitals NHS Trust, London, UK
11
Anaesthesia and Intensive Care Medicine, Maidstone and Tunbridge Wells Hospital
NHS Trust, Maidstone, UK
Acknowledgements We wish to thank the members of the PRE-­EMPT and GSTT
Oesophago-­gastric Research Groups for their valuable collaboration with this study:
8 Zylstra J, et al. Br J Sports Med 2022;0:1–9. doi:10.1136/bjsports-2021-104243
Br J Sports Med: first published as 10.1136/bjsports-2021-104243 on 1 February 2022. Downloaded from http://bjsm.bmj.com/ on March 2, 2022 at UFMG - Universidade Federal de Minas
AM Lane, S Ngan, A Qureshi, K Owczarczyk, H Deere, F Chang, U Mahadeva, B
Gill-­Barman, S George, J Dunn, S Zeki, O Hynes, A Coombes, N Griffin, A Jacques,
W Knight, R Bott, A Reyhani, M Hill, M Cominos, T Sevitt, M Barbosa, G Hallward, C
Taylor, T Dixson, R McEwen.
Contributors 1. Conceived and/or designed the work that led to the submission,
acquired data, and/or played an important role in interpreting the results. 2.
Drafted or revised the manuscript. 3. Approved the final version. 4. Agreed to be
accountable for all aspects of the work in ensuring that questions related to the
accuracy or integrity of any part of the work are appropriately investigated and
resolved. JZ, GPW, KB, JP, ASO, LG-­A, NM, JW, GT, JL, MG, MK, CB, MVH, VG, JG, MB,
AD contributed to 1, 2, 3, 4 above. 5. Guarantor, AD. Further contributors are listed
under Acknowledgements.
Funding The work was supported by the Guy’s and St Thomas’ Charity, London
(EFT 150709 to AD); Centre for Health and Human Performance, London.
Competing interests None declared.
Patient consent for publication Consent obtained directly from patient(s).
Ethics approval This study was approved by Research Ethics Committee: South
Central - Oxford C Research Ethics Committee Ref.: REC no.: 16/SC/0438.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. Data
reported may be requested by contacting the corresponding author.
Supplemental material This content has been supplied by the author(s). It
has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have
been peer-­reviewed. Any opinions or recommendations discussed are solely those
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
responsibility arising from any reliance placed on the content. Where the content
includes any translated material, BMJ does not warrant the accuracy and reliability
of the translations (including but not limited to local regulations, clinical guidelines,
terminology, drug names and drug dosages), and is not responsible for any error
Gerais. Protected by copyright.
and/or omissions arising from translation and adaptation or otherwise.
ORCID iD
Janine Zylstra http://orcid.org/0000-0002-9839-7629
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Gerais. Protected by copyright.
9
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Supplementary Information
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Pre-EMPT trial Eligibility Criteria

Eligibility criteria:
Inclusion
1. Participants must be diagnosed with operable oesophageal and gastro-oesophageal
adenocarcinoma and scheduled to undergo standard neo-adjuvant chemotherapy and oesophago-
gastric surgery as recommended by the Multidisciplinary Meeting decision.
2. 18+
3. </=79 (patients above this age may be included in studies after the feasibility study has been
completed)
4. Participants must be able to understand and independently consent to participation in the study.
5. Participants must be able to understand and complete the questionnaires.
6. Participants must be willing to undergo all the standard assessments and interventions included in
this study - CPEX testing, blood sampling, questionnaires and exercise intervention where
appropriate.
7. Participants must be willing to wear the Fitbit monitoring device and agree with its use.
8. Participants must be ASA 1-3 and fit for surgical resection.
9. Patients should have a Body Mass Index (BMI) equal to or above 18.5 with less than 10% self-
reported unintentional weight loss at diagnosis.
Exclusion
Participants will be excluded if they:
1. Are not considered medically fit for surgery at diagnosis, as decided by the Multidisciplinary team
2. Will undergo primary or palliative chemotherapy
3. Are recommended to have chemoradiotherapy
4. Are under 18 years old
5. Are over 79 years old
6. Are unable to undergo CPEX testing
7. Do not wish to take part in selected aspects of the study
8. Cannot or do not wish to attend the CHHP for assessment and/or advice on exercise
9. Cannot understand and give informed consent to the study
10. Cannot understand and complete the questionnaires
11. Do not wish to wear a Fitbit monitoring device
12. ASA 4+
13. Patients with BMI of less than 18.5 with self-reported unintentional weight loss of 10% or more
at diagnosis.

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Exercise Prehabilitation Program:
Provided by Centre for Health and Human Performance, London

4 Week, 30 minutes walking programme, with additional Core Strength & Stability, Flexibility and
Band Strength Exercises
Week SESSION 30 minutes moderate walk including; 10 x (30s hard walk with 1min 30s
1 1 easy)
SESSION 30 minutes moderate walk including; 2 x (5 x 1 minute hard walk with 1
2 minute easy) 5 minutes between sets
SESSION 30 minutes moderate walk including; 2 x (10 x 30s hard walk with 1min 30s
3 easy) 5 minutes between sets
SESSION
30 minutes moderate walk
4
SESSION
30 minutes moderate walk
5
Week SESSION 30 minutes moderate walk including; 2 x (6 x 1 minute hard walk with 1
2 1 minute easy) 5 minutes between sets
SESSION 30 minutes moderate walk including; 5 x (2 minutes hard walk with 1
2 minute easy) 5 minutes between sets
SESSION 30 minutes moderate walk including; 10 x (1 minute hard walk with 1
3 minute easy) 5 minutes between sets
SESSION
30 minutes moderate walk
4
SESSION
30 minutes moderate walk
5
Week SESSION 30 minutes moderate walk including; 2 x (10 x 30s hard walk with 1 minute
3 1 30s easy) 15 minutes between sets
SESSION 30 minutes moderate walk including; 5 x (3 minutes hard walk with 2
2 minutes easy) 10 minutes between sets
SESSION 30 minutes moderate walk including; 10 x (1 minute hard walk with 1
3 minute easy) 10 minutes between sets
SESSION
30 minutes moderate walk
4
SESSION
30 minutes moderate walk
5
Week SESSION 30 minutes moderate walk including; 3 x (5 x 30s hard walk with 1 minute
4 1 30s easy) 5 minutes between sets
SESSION 30 minutes moderate walk including; 10 x (2 minutes hard walk with 1
2 minute easy) 10 minutes between sets
SESSION 30 minutes moderate walk including; 15 x (1 minute hard walk with 1
3 minute easy)
SESSION
30 minutes moderate walk
4
SESSION
30 minutes moderate walk
5

N.B. easy = able to hold full conversation; moderate = brisk walking, concentrating to maintain pace; hard = fast/power
walking

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Table 4 Body composition changes

Intervention Group (n=13) Control Group (n=14)

Parameters Median (IQR) Median (IQR) p-value = *

FFM index (kg/m ) 2

Baseline 17.8 (14.4-20.9) 16.3 (11.8-18.5) .225

Post-treatment 18.7 (15.0-20.2) 14.7 (12.3-17.3) .026
FM index (kg/m ) 2

Baseline 9.1 (6.4-9.6) 8.1 (7.1-10.4) .961

Post-treatment 8.2 (6.8-9.2) 8.2 (7.4-10.5) .698
FMR
Baseline 1.08 (0.67-1.75) 1.07 (0.90-1.58) .846
Post-treatment 0.91 (0.59-1.94) 1.11 (0.88-2.16) .409
Visceral fat (cm )
2

Baseline 204 (41-256) 206 (141-274) .698

Post-treatment 154 (104-228) 214 (163-249) .207
Subcutaneous fat (cm ) 2

Baseline 153 (109-214) 165 (112-183) .808

Post-treatment 147 (111-227) 158 (129-190) .771
VA/SA ratio
Baseline 0.83 (0.61-1.51) 1.24 (0.84-1.50) .308
Post-treatment 0.83 (0.59-1.39) 1.22 (0.99-1.41) .357
Weight (kg)
Baseline 80.1 (64.3-84.3) 87.5 (68.7-94.5) .052
Post-treatment 76.4 (69.2-79.9) 88.2 (74.0-95.6) .053
* p-values derived from Wilcoxon-signed rank test

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Table 5 Immunity Markers - Baseline versus Post-NAC

Intervention Group Control Group

p-
Mean (SD) Range Mean (SD) Range
value =
CD3
1474.38 964.94
Baseline (683-2793) (582-1587)
(649.65) (350.45)
1681.2 981.08
Post-NAC (733-2861) (516-1686)
(504.36) (349.75)

Participant change Baseline 34.26 (-16.78- (-23.00-

4.53 (25.67) .034
Post-NAC (%) (36.58) 111.57) 63.41)

CD4
960.60 550.88
Baseline (292-2031) (337-971)
(403.63) (172.49)
1117.73 584.92
Post-NAC (471-1625) (327-1231)
(323.09) (249.27)

Participant change Baseline 42.08 (-22.45- (-26.30-

9.36 (37.90) .095
Post-NAC (%) (51.40) 179.45) 112.17)

CD8
548.50 376.75
Baseline (174-1678) (134-877)
(394.68) (227.63)
551.47 363.33
Post-NAC (182-1267) (120-675)
(297.64) (179.24)

Participant change Baseline 29.41 (2.82- (-23.03-

0.98 (19.69) .033
Post-NAC (%) (31.19) 89.66) 50.89)

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Table 6 Inflammatory Markers - Baseline versus Post-NAC

Intervention Group Control Group

p-
Mean (SD) Range Mean (SD) Range
value =
IL-6

Baseline 2.68 (3.76) (0.16-16.1) 1.13 (0.65) (0.41-3.03)

Post-NAC 3.20 (4.63) (0.6-19.5) 2.31 (1.56) (0.86-6.73)

Participant change Baseline +27.93 (-55.94- +126.41 (-53.14-

.041
Post-NAC (%) (97.02) 275.00) (107.59) 282.39)

VEGF
12.61 (2.66-
Baseline 7.79 (3.43) (2.92-15.5)
(11.98) 53.51)
(3.64-
Post-NAC 9.79 (5.13) 9.21 (4.16) (5.1-17.35)
21.26)

Participant change Baseline -10.51 (-60.27- +51.79 (-67.10-

.274
Post-NAC (%) (62.09) 149.58) (99.54) 300.34)

INF-y

Baseline 0.34 (0.38) (0.1-1.34) 0.15 (0.17) (0.01-0.7)

Post-NAC 0.39 (0.59) (0.1-2.29) 0.23 (0.22) (0.07-0.9)

Participant change Baseline +57.24 (-80.60- +223.64

(-50-1900) .364
Post-NAC (%) (140.13) 300) (562.36)

TNFa

Baseline 1.53 (3.92) (0.21-16.2) 0.58 (0.18) (0.36-0.88)

Post-NAC 1.76 (4.77) (0.3-18.99) 0.74 (0.31) (0.41-1.5)

Participant change Baseline -1.77 (-53.03- +28.31 (-30.99-

.245
Post-NAC (%) (33.23) 45.45) (74.51) 233.33)

MCP-1

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54.14 (12.73- 39.98

Baseline (4.24-95.7)
(32.62) 136.33) (27.82)
60.94 (16.8- 63.37 (24.68-
Post-NAC
(21.18) 97.63) (33.18) 137.2)

Participant change Baseline +52.11 (-34.01- +163.69 (-45.56-

.093
Post-NAC (%) (58.18) 174.16) (193.53) 482.08)

EGF

Baseline 2.71 (3.13) (0.34-12.4) 6.96 (7.32) (0.5-24.5)

Post-NAC 3.38 (6.25) (0.4-25.2) 2.87 (3.30) (0.6-12.5)

Participant change Baseline +20.06 (-62.72- -8.23 (-95.21-

.607
Post-NAC (%) (80.48) 176.47) (152.86) 440.00)

Zylstra J, et al. Br J Sports Med 2022;0:1–9. doi: 10.1136/bjsports-2021-104243