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Results from the recent CROSS trial showed that neoadjuvant chemoradiotherapy (nCRT) significantly increased survival as compared to surgery alone in patients with potentially curable esophageal cancer. Furthermore, in the nCRT arm 49% of patients with a squamous cell carcinoma (SCC) and 23% of patients with an adenocarcinoma (AC) had a pathologically complete response in the resection specimen. These results provide a rationale to reconsider and study the timing and necessity of esophagectomy in (all) patients after application of the CROSS regimen.
We propose a “surgery as needed” approach after completion of nCRT. In this approach, patients will undergo active surveillance after completion of nCRT. Surgical resection would be offered only to those patients in whom residual disease or a locoregional recurrence is highly suspected or proven. However, before a surgery as needed approach in oesophageal cancer patients (SANO) can be tested in a randomized controlled trial, we aim to determine the accuracy of detecting the presence or absence of residual disease after nCRT (preSANO trial).
This study is set up as a prospective, single arm, multicenter, diagnostic trial. Operable patients with potentially curable SCC or AC of the esophagus or esophagogastric junction will be included. Approximately 4-6 weeks after completion of nCRT all included patients will undergo a first clinical response evaluation (CRE-I) including endoscopy with (random) conventional mucosal biopsies of the primary tumor site and of any other suspected lesions in the esophagus and radial endo-ultrasonography (EUS) for measurement of tumor thickness and area. Patients in whom no locoregional or disseminated disease can be proven by cytohistology will be offered a postponed surgical resection 6-8 weeks after CRE-I (ie, approximately 12-14 weeks after completion of nCRT). In the week preceding the postponed surgical resection, a second clinical response evaluation (CRE-II) will be planned that will include a whole body PET-CT, followed again by endoscopy with (random) conventional mucosal biopsies of the primary tumor site and any other suspected lesions in the esophagus, radial EUS for measurement of tumor thickness and area, and linear EUS plus fine needle aspiration of PET-positive lesions and/or suspected lymph nodes. The main study parameter is the correlation between the clinical response assessment during CRE-I and CRE-II and the final pathological response in the resection specimen.
The first patient was enrolled on July 23, 2013, and results are expected in January 2016.
If this preSANO trial shows that the presence or absence of residual tumor can be predicted reliably 6 or 12 weeks after completion of nCRT, a randomized trial comparing nCRT plus standard surgery versus chemoradiotherapy plus “surgery as needed” will be conducted (SANO trial).
Netherlands Trial Register: NTR4834; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4834 (archived by Webcite at http://www.webcitation.org/6Ze7mn67B).
Cancer of the esophagus remains a highly lethal malignancy, as reflected by an average overall 5-year survival of 17% [
At present, surgical resection is still considered the cornerstone of curative treatment for patients eligible with stage cT1b-4aN0-3M0 disease. The reported 5-year survival rate for patients who undergo an esophagectomy ranges from 20% to 50%, but rarely exceeds 35% [
During a 5-year period, 366 patients from 5 academic and 2 nonacademic high-volume teaching hospitals in the Netherlands were included in the CROSS trial. Results showed that the addition of nCRT (carboplatin AUC2, paclitaxel 50 mg/m2, and 41.4 Gy of concurrent radiotherapy) to surgery significantly increases long-term survival as compared to surgery alone. Median overall survival of patients who received nCRT plus surgery was 49 months, compared to 24 months for those who received surgery alone, and the 3-year overall survival was superior in the nCRT arm (hazard ratio (HR) = 0.66; 95% confidence interval (CI) 0.50-0.87;
We propose a “surgery as needed” approach after completion of nCRT for carcinoma of the esophagus. In this surgery as needed approach, patients will undergo active surveillance after completion of nCRT. Surgical resection would be offered only to those patients in whom a locoregional recurrence is highly suspected or proven, in the absence of any signs of distant dissemination. Such an organ-preserving strategy would clearly have great advantages. Postoperative mortality and severe morbidity (grade ≥3 according to the Clavien-Dindo classification [
The aim of this present prospective, multicenter, and diagnostic preSANO trial is to determine the accuracy by which we can detect the presence or absence of residual disease after nCRT. The results of this trial will inform us about the percentage of patients with a clinically complete response after nCRT and will help to estimate the number of patients needed for a subsequent randomized controlled trial. The future so-called “SANO trial” will randomize patients into 2 strategy groups: (1) nCRT plus surgery, and (2) nCRT followed by an active surveillance.
The preSANO trial is a prospective, multicenter, diagnostic trial including 120 patients, using a single arm. Five high-volume centers in the Netherlands are currently participating in this study: Erasmus Medical Center, Rotterdam; Academic Medical Center, Amsterdam; University Medical Center, Utrecht; Catharina Cancer Center, Eindhoven; and Atrium Medical Center, Heerlen. The study has been approved by the medical ethics committee (MEC) of the Erasmus Medical Center (MEC2013-211) and has been registered in the Netherlands Trial Register (NTR4834).
We plan to include individuals from a population of operable patients with potentially curable SCC or AC of the esophagus or esophagogastric junction. All patients who are planned to undergo nCRT according to the CROSS regimen [
Study algorithm.
Parameter | Pretreatment | First clinical response evaluation (CRE-I) | Second clinical response evaluation (CRE-II) |
History, physical examination | X | X | X |
Performance status | X | X | X |
Hematologya | X |
|
|
eGFR | X |
|
|
Biochemistryb | X |
|
|
Endoscopy + (random) biopsies | X | X | X |
Radial EUSc | X | X | X |
Linear EUS (+FNA)d | X |
|
X |
CT of neck, thorax, abdomen, and pelvis | X |
|
|
PET-CT | X “partial body” | Xg“whole body” | Xh“whole body” |
Pulmonary function tests | X |
|
|
Bronchoscopye | X |
|
|
ECG | X |
|
|
Toxicityf | Baseline |
|
|
aHematology: CBC, differential
bBiochemistry: serum protein, albumin, magnesium, electrolytes, serum creatinine, bilirubin, alkaline phosphatase, AST, and pregnancy test if indicated at baseline only
cRadial EUS: with measurement of maximum tumor thickness and area
dLinear EUS: with FNA of any suspected lymph nodes
eBronchoscopy: when tumor is located above the carina and when there is suspicion for invasion of the tracheobronchial tree
fToxicity: to be evaluated after each cycle (incidence and grade according to CTC toxicity scale)
gPET-CT: during CRE-I, after EGD and EUS, only for clinically noncomplete responders to exclude disseminated disease
hPET-CT: during CRE-II, prior to EGD and EUS, for all patients (all were clinically complete responders during CRE-I) to guide EGD and EUS in targeting suspected locoregional lesions and to exclude disseminated disease
Study algorithm.
1. During the pretreatment workup, it suffices when a “partial body” F18-FDG PET-CT of the esophagus will be performed (to test for avidity of the primary lesion); if it is preferred to make a “whole-body” PET-CT not only after, but also before the neoadjuvant chemoradiotherapy in order to detect distant metastases at an earlier stage, the indication for performing an external US with FNA of the neck can be limited to those patients who have a suspected lymph node on the PET-CT [
All included patients will receive nCRT according to the CROSS protocol (carboplatin, paclitaxel, and concurrent radiotherapy) [
The first CRE (CRE-I) will be performed 4-6 weeks after completion of chemoradiotherapy (
In the week preceding the planned postponed surgical resection, a second clinical response evaluation (CRE-II) will be scheduled. CRE-II will be performed only in patients who were considered to be clinically complete responders (ie, no viable tumor found) at CRE-I. CRE-II will consist of a PET-CT (standard for all patients at CRE-II and only for tumor-positive patients at CRE-I), an EGD with registration of endoscopic images for future reference, and biopsies of any suspected lesions, including (random) mucosal biopsies at the site of the primary tumor, radial EUS for measurement of maximal tumor thickness and area, and linear EUS plus fine-needle aspiration (FNA) of PET-positive lesions and/or suspected lymph nodes.
An important difference between CRE-I and CRE-II will be that during CRE-I clinically complete responders will be offered a postponed surgical resection, whereas after CRE-II both locoregionally complete and noncomplete responders will be advised to undergo a surgical resection (
If after CRE-II the planned operation is postponed for more than 4 weeks (eg, because the patient has not yet sufficiently recovered from the nCRT), a CRE-III (comparable to CRE-II) will be performed 1 week before the (further) postponed operation.
Surgical resection will be attempted immediately after CRE-I only in those patients who present at CRE-I with histologically proven residual disease after completion of nCRT, without any signs of disseminated disease. All other patients will undergo surgical resection after CRE-II in the absence of distant metastases.
A transthoracic esophageal resection or a transhiatal approach can be performed, depending on both patient characteristics and local expertise and preference. Both open and minimally invasive techniques are allowed.
A wide local excision including the regional lymph nodes is carried out in both techniques, including a standard dissection of the lymph nodes around the coeliac axis. The continuity of the digestive tract will preferably be restored by a gastric tube reconstruction or, if required, by a colonic interposition.
At least 15—but preferably 23 or more—lymph nodes should be aimed to be removed in every patient since it has been shown that long-term survival is maximized with the removal of at least 23 nodes [
All resection specimens will be revised centrally by 2 independent expert pathologists, using a standard protocol. In case of a discordant outcome, the specimens will be reviewed by a third independent expert pathologist. A final diagnosis will be made only if at least 2 pathologists agree. Also, all the CRE-II biopsies of patients who were considered negative at CRE-II, but who had more than 10% residual tumor in their resection specimen will be revised centrally following the same strategy. In these specimens special attention will be given to the effects of the preoperative chemoradiation (ie, tumor reduction and therapy effects). The lymph node dissection should contain at least 15—but preferably 23 or more—nodes derived from both mediastinum and upper abdomen, which are essential for correct ypTNM staging. The resection margins, especially the circumferential margin, will be evaluated with a 1 mm cutoff point for vital tumor. This implies that the tumor-free margin should be larger than 1 mm in order to be classified as R0. If vital tumor is present at 1 mm or less from the surgical resection margin, it is considered microscopically positive (R1).
An interim analysis will be performed by an independent safety committee after a total inclusion of 60 patients in order to carefully monitor serious complications during CRE-I and CRE-II and to assess the achieved radicality of the performed operations.
The main study parameter in this study is the correlation between the clinical response assessment during CRE-I and CRE-II and the final pathological response in the resection specimen as measured by the modified tumor regression grading (TRG) system of Chirieac [
We propose that in this study TRG2 residual tumors may be missed as long as we expect them to be detectable reliably as soon as they have outgrown from TRG2 to TRG3-4 during follow-up. The risk that TRG2 residual tumors will lead to irresectability in the short-term is likely to be small/negligible. However, we do propose that TRG3 and TRG4 residual tumors should be detected without further delay in order to prevent short-term loss of resectability and to minimize the risk of long-term distant disease dissemination. The validity of these assumptions can only be determined in a future SANO trial, in which an active surveillance strategy will be compared with standard surgery in all patients after nCRT.
As was seen in the previous CROSS trial approximately 40% of the included patients will have TRG3 or TRG4 residual tumor in the resection specimen [
We assume that during CRE-I clinically complete responders will comprise patients with TRG1 or TRG2 (as taken from the pathological response data of the CROSS trial), whereas clinically noncomplete responders will be patients with TRG3 or TRG4.
The percentage of patients with SCC and AC with TRG1 or TRG2 in the CROSS trial was 78% and 57%, respectively. This means that approximately 60% of included patients are expected to have negative (cyto)histology at CRE-I.
In a trial by Blom et al [
We assume that approximately 25% of clinically complete responders will refuse to undergo the postponed resection and choose to undergo an active surveillance strategy if no alarming results are found during CRE-II.
These calculations indicate that approximately 60 patients will show a clinically complete response after combined diagnostic investigations during CRE-I and CRE-II (including EUS-FNA with tumor thickness measurements and PET-CT). Of these, approximately 15 patients will refuse to undergo surgery and will undergo active surveillance and approximately 30 patients will have a pCR (TRG1). The 15 remaining patients are expected to have residual disease, of whom approximately 12 patients will have TRG2 residual tumor and approximately 3 patients will have TRG3 or TRG4 residual tumor. As we proposed above, TRG2 residual tumors may be missed. Therefore, we expect that approximately 3 patients with clinically relevant residual disease (TRG3 or TRG4) will be missed.
In case of unexpected aberrant distribution of patients in the preSANO trial that leads to decreased TRG3 and TRG4 rates, results of the first 120 patients will be analyzed following the present protocol. If these results are promising but do not reach statistical significance, possibly due to a lack of power, inclusion of extra patients will be considered. If inclusion of extra patients is desirable, the protocol will be amended and assessed by the medical ethics committee.
Expected distribution of patients (based partly on CROSS trial data). All numbers are based on an inclusion of 120 patients. CI: confidence interval; CRE: clinical response evaluation; nCRT: neoadjuvant chemoradiotherapy; N: number of patients; TRG: tumor regression grade, as measured by the modified TRG system of Chirieac. Of the 45 patients who will undergo a postponed resection following CRE-II, 15 patients are expected to have a pathologically incomplete response (at least TRG2).
The clinical response evaluation will consist of different diagnostic modalities. Results of each diagnostic modality will be presented as categorical or continuous data, depending on the outcome measure of each diagnostic modality. These results will be correlated to the (categorical) tumor regression grading in the resection specimen using a Chi-square-based test (categorical-categorical) or a 1-way ANOVA test (continuous-categorical) with post-hoc testing.
The first patient was enrolled on July 23, 2013, and results are expected in January 2016.
The uniqueness of this study lies in the prospective evaluation of a sufficiently large number of patients, using multiple diagnostic modalities on different time points. Although (cyto)histological assessment of biopsies and/or FNAs is the most objective parameter, several studies have shown that the response to nCRT is reflected by tumor size or volume as assessed by EUS [
The reason to include patients with SCC as well as patients with AC in the preSANO trial is that the CROSS regimen has been shown to be effective in both groups of patients. The pCR rates of 49% in patients with SCC and 23% in patients with AC in the CROSS trial provide a rationale for a SANO approach in both histological subtypes. Furthermore, together with the low frequency of toxic effects of the CROSS regimen (91% received the full treatment regimen of nCRT), these high pCR rates advocate the use of the relatively low dose of 41.4 Gy radiotherapy [
Although we have not yet clearly shown that we are able to detect a clinically threatening residual cancer 4-6 weeks after nCRT, there are several arguments why it is not deemed necessary to do so before we delay the planned surgical resection with an additional 6-8 weeks. Recently, it was shown that prolonged time to surgery after nCRT up to at least 12 weeks had no effect on disease-free and overall survival (HR=1.00 and HR=1.06 per additional week,
Postoperative mortality and severe morbidity (grade ≥3 according to the Clavien-Dindo classification [
If the preSANO trial shows that TRG3 and TRG4 residual tumor can be predicted reliably, a randomized trial comparing nCRT plus standard surgery versus chemoradiotherapy plus surgery as needed in oesophageal cancer patients (the SANO trial) will be conducted. Hopefully, this SANO trial will result in an organ-preserving treatment strategy for a selected group of patients and therefore reduce treatment related morbidity and mortality, improve quality of life, and lead to a reduction in health care costs.
The trial is funded by amongst others the Koningin Wilhelmina Fonds Kankerbestrijding (KWF, Dutch Cancer Society) and has been reviewed by external reviewers from the KWF. They assigned the study an A-status, indicating that funding of this project is of the highest priority.
adenocarcinoma
confidence interval
clinical response evaluation
chemoradiotherapy for oesophageal cancer followed by surgery study [
computed tomography
esophagogastroduodenoscopy
endoscopic ultrasonography
fine-needle aspiration
hazard ratio
medical ethics committee
neoadjuvant chemoradiotherapy
Netherlands Trial Register
pathologically complete response
positron-emission tomography
surgery as needed approach in oesophageal cancer patients
squamous cell carcinoma
tumor regression grading
The preSANO trial is funded by the Koningin Wilhelmina Fonds Kankerbestrijding (KWF, Dutch Cancer Society) and Stichting Coolsingel Rotterdam (Coolsingel Rotterdam Foundation).
None declared.
BN participated in the study design and drafted the manuscript. JS, MS, KK, HL, MB, GN, RH, MS, and ES participated in the study design and critically revised the manuscript. BW initiated the trial and critically revised the manuscript. JL initiated the trial and supervised the drafting of the manuscript. All authors read and approved the final manuscript and agree to be accountable for all aspects of the work.