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Inspite of these positive developments, RS for liver transplantation has not
attracted wide acceptability as one would have expected. This is due to several
factors:
1. The results of RS have not been shown to be better than the conven-
tional ones.
2. Though technological advances are occurring, their pace is slow and as a
result suitable instruments are still not available (may be a temporary
factor!).
3. There is a long learning curve associated with the art and practice of RS in
general and donor hepatectomy in particular.
4. Applicability of RS for right lobe grafts (which need extensive mobiliza-
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5. Concern with the increased warm ischemia time associated with the
increased operation time of RS is another factor.
Notwithstanding all these one should welcome this new form of surgery
for better management as long as this is done by experienced surgeons
(already gone through the learning curve) in dedicated centres specializing in
this eld.
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147
Chapter 8
Assessment ofTumour Response
toNeoadjuvant Therapy fortheTreatment
ofOesophageal Cancer
CarlosS.Cabalag, JonathanSivakumar, andCuongP.Duong
8.1 Introduction
Multi-modal therapy with neoadjuvant chemotherapy or chemoradiotherapy (CRT)
followed by surgery is the standard of care for resectable locally advanced oesopha-
geal cancer (OC) as it has been shown to improve patient survival when compared
with surgery alone [1]. The potential advantages of neoadjuvant therapy include
downstaging of the primary tumour to facilitate resection with clear margins and to
treat systemic micro-metastatic disease [2].
Assessment of tumour response to neoadjuvant therapy is important. Identifying
patients who develop incurable metastatic disease avoids futile surgery. Conversely,
pre-operative chemotherapy or CRT can induce pathological complete response
(pCR) in 16–23% of oesophageal adenocarcinoma (OAC) and 49% of oesophageal
squamous cell carcinoma (OSCC) [3]. As pCR confers signicant 5-year survival
benet [4], the ability to predict pCR may alter the treatment paradigm to a ‘watch-
and- wait’ approach for the patients with equivocal surgical tness. The current
SANO trial [5] will evaluate whether OC patients who achieved clinical complete
tumour response following CRT can have active surveillance rather than routine
oesophagectomy.
This chapter discusses the efcacy of current available techniques as well as pre-
clinical biomarkers in assessing response following neoadjuvant therapy for OC.
C. S. Cabalag · J. Sivakumar · C. P. Duong (*)
Peter MacCallum Cancer Centre, Melbourne, Australia
e-mail: Cuong.Duong@petermac.org
© The Author(s), under exclusive license to Springer Nature Singapore Pte
Ltd. 2022
P. Sahni, S. Pal (eds.), GI Surgery Annual, GI Surgery Annual 26,
https://doi.org/10.1007/978-981-19-0828-6_8
148
8.2 Current Methods ofAssessing Response
8.2.1 Gastroscopy andEndoscopic Ultrasound
Gastroscopy: Whilst gastroscopy and biopsy is the standard initial method to estab-
lish tissue diagnosis of OC, it has a limited role in assessing tumour response fol-
lowing neoadjuvant therapy. A meta-analysis from Van Rossum etal. evaluated the
role of endoscopic biopsy for determining residual OC after CRT [6]. Based on the
ndings of 12 studies consisting of 1281 patients, where a positive biopsy was con-
sidered ‘ypT+’, endoscopic biopsy was found to have good specicity (91.0%) but
poor sensitivity (34.5%). Whilst the endoscopist’s experience is important,
chemoradiation- induced inammation increases sampling errors and false-negative
biopsy rates [7]. Furthermore, supercial biopsies cannot account for the presence
of deeper residual tumours that are not apparent on the mucosa.
A recent prospective multicentre study by Noordman etal. (pre-SANO trial) [5]
investigated whether taking two consecutive biopsy samples from the same site,
termed a ‘bite-on-bite’ biopsy, increases the accuracy of detecting residual submu-
cosal disease (Fig.8.1). This was performed in conjunction with a ne-needle aspi-
ration (FNA) of suspicious lymph nodes. When compared with the standard biopsy
technique, the bite-on-bite approach was more accurate with superior sensitivity
(74.0% vs 54.0%) and specicity (77.0% vs 69.0%) and a positive predictive value
of 92.0%. Other smaller studies have also demonstrated improved accuracy of the
‘bite-on-bite’ method [4, 8, 9]. However, given the sub-optimal sensitivity, a nega-
tive endoscopic biopsy result alone cannot exclude residual tumour following neo-
adjuvant therapy.
Endoscopic ultrasound (EUS) and ne-needle aspiration (FNA): EUS utilises a
high-frequency ultrasound transducer to assess tumour thickness and cross- sectional
Residual viable tumour
cluster
abc
Dying tumour cells
Fibrosis ('scar')
Fig. 8.1 ‘Bite on bite biopsy’—(a) In patients who respond to neoadjuvant chemoradiation, the
primary tumour reduces in size. As tumour cells die, a number of tumour cell clusters may still
survive and invade deeper layers such as the submucosa or muscularis propria. (b) A single biopsy
may only obtain a supercial area of brosis and dying tumour cells, possibly missing a deeper
area of viable tumour. (c) By taking a second deeper biopsy at the same site, the probability of
detecting residual disease increases (Image created with Biorender.com)
C. S. Cabalag et al.
149
area, as well as the depth of tumour invasion [10]. Sonographic features suggestive
of a malignant lymph node (rounded shape, clear borders, uniform central hypoecho-
genicity and short-axis diameter >10 mm) can guide FNA sampling to ascertain
tissue diagnosis [11].
While EUS is considered the most accurate method for assessing the initial T
staging (depth of tumour inltration) of OC, it has questionable accuracy following
CRT in predicting cancer regression or remission [12]. Like other structural imag-
ing modality, EUS cannot reliably distinguish inamed oesophageal tissue from
tumour. The meta-analysis from Van Rossum et al. compared post-neoadjuvant
EUS ndings with histopathological result of resected OC specimens [6]. This
included 11 studies (593 patients) reporting on ypT status and ten studies (602
patients) reporting on ypN status. EUS has high sensitivity (96.5%) but very low
specicity (10.9%) in assessing residual primary tumour. It is better at evaluating
malignant lymph nodes (LN) with sensitivity and specicity of 62.0% and 56.7%,
respectively. Vazquez-Sequeiros etal. showed that the addition of FNA to EUS can
improve the accuracy of detecting residual LN metastasis [13].
The utility of EUS is restricted in the setting of tight malignant oesophageal
strictures due to inability to pass the endoscope and the risk of perforation [10].
Another consideration with the use of EUS is that it is operator-dependent and
prone to signicant interobserver variation. Thus, it is recommended for EUS to be
performed by experienced investigators at high-volume institutions [10].
8.2.2 Structural Imaging (CT andMRI)
The Response Evaluation Criteria in Solid Tumours (RECIST) criteria, originally
published in 2000 and later revised in 2009 [14, 15], are widely accepted for assess-
ing the radiological response of CRT. These were developed against the gold-
standard histological assessment of resected tumour and LN specimens. The revised
RECIST guidelines classify treatment status as a complete response, partial
response, progressive disease or stable disease (Table8.1).
Computed tomography (CT): Due to easy accessibility, CT scan is commonly
used for the initial staging of OC and in the assessment of tumour response to neo-
adjuvant therapy. It is most useful for excluding distant metastasis, which would
alter treatment intent and avoid futile surgery. With regard to the primary OC, CT
provides valuable information about tumour morphology, dimension and volume-
try. The accuracy of CT for assessing tumour response in OC patients following
neoadjuvant treatment (NAT) has been analysed in a meta-analysis of eight studies
(471 patients) by de Gouw etal. [16] All studies adopted a volume-based criterion
to dene therapeutic response. The pooled sensitivity and specicity for CT scan in
predicting a complete response in the primary tumour (ypT0) were 68.0% and
96.0% and of draining LN (ypN0) were 79.0% and 45.0%, respectively.
8 Assessment of Tumour Response to Neoadjuvant Therapy for the Treatment…
150
Table 8.1 RECIST criteria
Response
category Criteria
Complete
response
(CR)
Disappearance of all target lesions. Any pathological lymph nodes (whether
target or non-target) must have a reduction in short axis to <10mm
Partial
response (PR)
At least a 30% decrease in the sum of diameters of target lesions, taking as
reference the baseline sum diameters
Progressive
disease (PD)
At least a 20% increase in the sum of diameters of target lesions, taking as
reference the smallest sum on study (this includes the baseline sum if that is the
smallest on study). In addition to the relative increase of 20%, the sum must also
demonstrate an absolute increase of at least 5mm (Note: Appearance of one or
more new lesions is also considered progression)
Stable disease
(SD)
Neither sufcient shrinkage to qualify for PR nor sufcient increase to qualify
for PD, taking as reference the smallest sum diameters while on study
Adapted from: Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, etal. New
Response Evaluation Criteria in Solid Tumours: Revised RECIST Guideline (Version 1.1). Eur J
Cancer (2009) 45(2):228–47
With the move from single-slice scans towards multi-detector scans, the accu-
racy of CT scan to assess tumour response has improved as a result of thin sections
and multiplanar reformation tools [17]. CT can assist in determining resectability of
OC if there is relative preservation of fat planes between the tumour and adjacent
structures of the mediastinum [18]. However, there is limit in CT resolution so that
it cannot differentiate between viable residual tumour and reactive change from
neoadjuvant therapy [11].
Magnetic resonance imaging (MRI): Given its excellent soft tissue contrast and
resolution, MRI has gained increased attention as an advanced imaging technique to
assess treatment response. This imaging modality has been investigated in oncology
primarily as a diffusion-weighted (DW) sequence or dynamic contrast-enhanced
(DCE) sequence. DW-MRI measures the apparent diffusion coefcient (ADC), that
being the diffusion rate of water molecules within a tissue [19]. As diffusion within
a tumour is restricted to cellular membranes and other corresponding structures,
ADC is an indicator of cellularity and subsequently is decreased in the presence of
cancer [20]. As a result, ADC is expected to increase in the setting treatment
response. DCE-MRI is undertaken with fast T1-weighted spoiled gradient echo
sequences and evaluates the movement of gadolinium contrast to calculate tumour
perfusion. This permits assessment of the area under the gadolinium curve or from
calculating the signal intensity through biophysical modelling [11].
De Gouw et al. evaluated three prospective studies on the predictive value of
MRI restaging for histopathological response. These studies dened complete
tumour response as an ADC difference >40.0% in DWI MRI or an AUC difference
>24.6% in DCE MRI.The sensitivity and specicity of MRI for predicting patho-
logical complete response (ypT0) was 80.0% and 83.0%, respectively [16]. Whilst
the results of this analysis are promising, the utility of MRI in assessing treatment
response in OC is not routine due to its limited availability within the community.
C. S. Cabalag et al.
151
8.2.3 Functional Imaging
Position emission tomography (PET): Most OC can be visualised on PET scan as
they have higher avidity to the radiolabelled agent
18
F-uorodeoxyglucose (18F-
FDG) than normal tissue. Hence, PET can assess treatment response by evaluating
the change in metabolic uptake of 18F-FDG using various parameters including
visual assessment of metabolic tumour volume, total lesion glycolysis and stan-
dardised uptake value (SUV) (Fig. 8.2). The PET Response Criteria in Solid
Tumours (PERCIST), adapted from the RECIST criteria, were developed as a stan-
dard for assessing tumour response based on SUV normalised for lean body mass
(SUL) [21, 22]. This categorises patients into one of four groups—complete meta-
bolic response, partial metabolic response, stable metabolic disease and progressive
metabolic disease (Table8.2).
Fig. 8.2 Utility of post-neoadjuvant treatment restaging 18F-FDG PET scan. This patient under-
went CROSS protocol neoadjuvant chemoradiation. Baseline PET scan images on the left com-
pared to restaging PET scan 4weeks following completion of neoadjuvant treatment demonstrates
a complete metabolic response of the tumour
Table 8.2 PERCIST criteria
Response category Criteria
Complete metabolic
response
Visual disappearance of all metabolically active tumour
Partial metabolic
response
>30% decrease in SUL peak (minimum 0.8-unit decrease) in lesion with
greatest uptake (not necessarily in same lesion)
Progressive
metabolic disease
>30% increase in SUL peak (minimum 0.8-unit increase)
>75% increase in total glycolysis
Conrmed new lesions
Stable metabolic
disease
Does not meet other criteria
Adapted from: Wahl R.L., Jacene H., Kasamon Y., Lodge M.A. From RECIST to PERCIST:
Evolving Considerations for PET Response Criteria in Solid Tumors. J.Nucl. Med. 2009;50(Suppl.
1):122S–150S
8 Assessment of Tumour Response to Neoadjuvant Therapy for the Treatment…
152
A systematic review of 13 studies showed 18F-FDG PET to be a good tool for
the assessment of tumour response [23]. However, the denition of PET metabolic
response varied between studies and was largely based on either a 30%–35% reduc-
tion in SUVmax or on an absolute threshold of SUVmax <2.5 on post-treatment
imaging. The reported sensitivity and specicity for predicting pathological
response was 70.3% and 70.1%, respectively. One limitation of PET metabolic
imaging is that radiation-induced oesophagitis has high FDG uptake that may be
indistinguishable from residual tumour [24]. The diagnostic accuracy of 18F-FDG
PET may also be adversely inuenced by factors such as patient size, plasma glu-
cose concentration and respiratory motion artefact [25, 26].
Whilst there is currently no consensus regarding the optimal time period at which
to assess treatment response, the majority of studies in the literature have performed
restaging PET at 4 to 6weeks following the completion of neoadjuvant therapy. As
biochemical changes in a malignancy following NAT precede a change in tumour
size, PET can also be used to detect early treatment response [27]. The identication
of OC patients whose tumours are not responding allows changes in treatment algo-
rithms as demonstrated in the MUNICON I and MUNICON II trials [28, 29]. PET
was performed at 14days after the commencement of neoadjuvant chemotherapy.
Responders who achieved a tumour reduction in SUVmax ≥35% continued with
chemotherapy prior to tumour resection, whilst the nonresponders either proceeded
straight to surgery (MUNICON I) or changed to CRT then surgery (MUNICON II).
The MUNICON trials demonstrate the utility of early PET assessment in tailoring
neoadjuvant treatment, with the nding that the addition of CRT in nonresponders
did not signicantly increase overall survival compared to chemotherapy and sur-
gery. Moreover, the limitations of early PET assessment in the neoadjuvant setting
include the lack of an agreed SUV cut-off value that differentiates a responder from
a nonresponder, and the likelihood of false-positive results in the assessment due to
the local inammatory effects of CRT.For these reasons, early treatment response
assessment with PET is currently not recommended as standard practice.
Another important role of restaging PET is the detection of interval or distant
metastases, which can develop in 8–17% of OC patients undergoing neoadjuvant
therapy [24–26]. PET can also provide prognostic information with a reduction in
tumour SUVmax ≥35% to be predictive for long-term survival [29].
The advent of hybrid PET-CT has integrated the higher-resolution anatomical
detail into PET imaging, to improve the diagnostic accuracy and interpretation of
many lesions. Like PET imaging, PET-CT carries an important role for identifying
interval metastases on restaging scans [30], although there is a paucity of literature
to compare these tools following chemotherapy [31]. Particularly in the detection of
liver metastases, PET-CT has been found to be superior in the early detection of
liver lesions compared with PET alone [32, 33]. Furthermore, trials have demon-
strated that the adoption of PET-CT has altered management in 20%–30% of cases
[34–36]. In light of its superior accuracy in this setting, mounting evidence supports
the central role of PET-CT as the preferred functional imaging in the assessment of
treatment response.
C. S. Cabalag et al.
153
8.3 Pathological Assessment ofResected Tumour
Post- Neoadjuvant Treatment (yp Staging)
Tumour regression grading (TRG) systems were created to categorically character-
ise the amount of residual tumour from bro-inammatory tissue (scar) induced by
NAT.The standard in reporting histopathological response to neoadjuvant therapy
in OC, termed ‘yp’ staging, was established by Mandard etal. [37]. The Mandard
TRG is a categorical 5-point grading system whereby TRG 1 represents a complete
pathological response and TRG 5 signies no histological evidence of tumour
response to CRT (Fig.8.3). This study of 93 resected specimens (83% OSCC) was
conducted to determine if tumour regression post-neoadjuvant CRT was associated
with disease-free survival. On multivariate analysis, only TRG (TRG 1–3 versus
TRG 4–5) was a signicant independent prognostic factor of disease-free survival.
More recent work by Noble etal. conrmed these ndings by Mandard in a multi-
centre cohort study, as well as the nding that LN downstaging from neoadjuvant
chemotherapy was associated with improved overall survival [38]. Although the
TRG grading systems have no impact on altering the course of treatment pre-
operatively, numerous studies have shown a role in its ability to prognosticate.
Despite a number of studies suggesting that TRG is an independent prognostic
factor, it has its limitations. Firstly, histopathological examination is prone to inter
and intra-observer variability. Moreover, this potential variability is reected in the
fact that there is no single, widely accepted TRG classication system for OC, with
nine different systems of grading internationally [39]. Most importantly, the current
TRG classication systems do not account for the status of nodal metastases post
NAT termed ‘ypN’. To illustrate the signicance of nodal metastases, the main nd-
ings from a large worldwide series of neoadjuvant pathological staging data reveal
that persistence of nodal metastatic disease post-NAT portends poor survival irre-
spective of ‘ypT’ status [40]. Another problem in the assessment of tumour regres-
sion is the lack of standardisation in sampling surgical specimens, which is
especially important for categorising a response as pCR—ideally the entire tumour
site should be histologically examined.
8.4 Novel Methods ofAssessment
Pre-existing methods to assess the response to NAT have largely been imaging
based and are limited by the nature of the technology used as well as inter-operator
variability. More sensitive and objective methods in the areas of molecular-based
biomarkers, circulating tumour cells and circulating tumour DNA are currently in
development. The improvement in overall survival for OC not only depends upon
the development of novel therapeutic strategies but is also incumbent upon sensitive
and accurate noninvasive methods to assess for treatment response in the pursuit of
optimising patient management.
8 Assessment of Tumour Response to Neoadjuvant Therapy for the Treatment…
154
TRG 1
No residual cancer
Fibrosis
Tumor cel
l
TRG 2
Rare residual cancer cells
TRG 4
Residual cancer
outgrowing fibrosis
TRG 3
Fibrosis outgrowing
residual cancer
TRG 5
No response to treatment
Fig. 8.3 Tumour
regression grade (TRG) for
post-neoadjuvant treated
oesophageal cancer
according to Mandard etal.
Each tumour grade is
depicted by a cross section
of the oesophagus that is a
representation of the
histological features. In
TRG 5, an absence of
brosis with tumour
growth indicates no
response to treatment
(Image created with
Biorender.com)
C. S. Cabalag et al.