Accuracy of detecting residual disease after neoadjuvant chemoradiotherapy for oesophageal cancer (PRESANO trial)

CROSS trial
Results from the recently completed CROSS trial show that the addition of
neoadjuvant chemoradiation (Carboplatin, Paclitaxel and 41.4 Gy of concurrent
radiotherapy) to surgery significantly increases long term survival as compared
to surgery alone. Therefore, neoadjuvant chemoradiation plus surgery is now
considered the therapy of first choice in The Netherlands for potentially
curable oesophageal cancer in patients fit to undergo this treatment.

Pathologically complete response
In subsequent analyses of secondary endpoints of the CROSS trial a striking
finding was made. In the neoadjuvant chemoradiotherapy (nCRT) arm 49% of
patients with a squamous cell carcinoma and 23% of patients with an
adenocarcinoma had a pathologically complete response (pCR) in the resection
specimen. Therefore, these results impose an ethical imperative to reconsider
and study the necessity of standard oesophagectomy in all patients after
application of the CROSS-regimen.

Surgery As Needed for Oesophageal cancer (SANO-)approach
We propose a surgery as needed approach after completion of neoadjuvant
chemoradiotherapy for carcinoma of the oesophagus. In this surgery as needed
approach, patients will undergo close surveillance after completion of
neoadjuvant chemoradiotherapy. Surgical resection would be offered only to
those patients in whom a locoregional recurrence is highly suspected or proven,
without any signs of distant dissemination. Such an organ-preserving strategy
would clearly have great advantages, but only if long term survival would be
comparable to that of the trimodality approach comprising neoadjuvant
chemoradiotherapy followed by standard surgery.

Feasibility of the SANO-approach
Before a surgery as needed approach can be tested in a (randomised) trial, we
aim to determine the feasibility of accurate detection of residual disease
after chemoradiotherapy in a preliminary trial (PRESANO trial). The feasibility
to accurately detect residual or recurrent disease at an early stage will be
essential for the safety of the SANO-approach.

The aim of this present diagnostic study is to determine the accuracy by which
we can detect residual disease after neoadjuvant chemoradiotherapy.

This study is set up as a prospective multi-centre feasibility trial, using a
single arm.

In the current protocol, patients with oesophageal cancer undergo surgical
resection 6-8 weeks after neoadjuvant chemoradiotherapy (nCRT), without
additional diagnostics in the intervening period.
In the context of this study, patients receive a first clinical response
evaluation (CRE-I) 6-8 weeks after the end of nCRT (prior to surgery). This CRE
consists of a complete physical examination, endoscopy with biopsies and a
radial endoscopic ultrasonography. If residual tumour is demonstrated, these
patients are offered immediate surgical resection. These patients will then
have little delay compared to the standard protocol. If during CRE-I no tumour
is found, surgery is postponed for another 6-8 weeks. Prior to this delayed
surgery, patients will undergo a second CRE (CRE-II), which will consist of a
PET-CT, followed by endoscopy with biopsies, radial endoscopic ultrasonography
and endoscopic linear ultrasonography with fine needle biopsies. In principle,
all patients will undergo surgical resection after CRE-II, unless disseminated
disease is found.

The burden for the patient can be summarized as:
CRE-I: endoscopy with biopsies and endoscopic ultrasonography. These studies
are extra as compared with the standard protocol.
There is a very small risk of bleeding, infection and perforation during
endoscopy with biopsies.

CRE-II: again endoscopy with biopsies and endoscopic ultrasonography will be
performed. During endoscopic ultrasonography fine-needle aspirations (FNA) of
suspected lymph nodes is performed. These studies are extra as compared with
the standard protocol.
There is again a very small risk of bleeding, infections and perforations
during endoscopy with biopsies and endoscopic ultrasonography with FNA.
PET-CT: This diagnostic is additional to the standard protocol and has a small
additional burden for patients. In the standard protocol, a PET-CT scan is
already performed pre-treatment. Therefore, in our study protocol a second
(additional) PET-CT scan will be performed.

An additional potential risk is the delay in surgery (12-16 weeks after
completion of nCRT rather than the standard 6-8 weeks). Possible risks include
more (surgical) complications and a lower radical resection rate. However,
previous studies from our group and other international groups have shown that
delaying surgery after pretreatment does not negatively influence outcome (it
might possibly even improve certain outcome parameters). We therefore consider
the risk of delayed surgery after pretreatment to be very small. However, we
did add the rate of radical resections to the list of stopping-rules in this
protocol.