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Neoadjuvant chemoradiotherapy plus surgery versus active surveillance for oesophageal cancer: a stepped-wedge cluster randomised trial

Neoadjuvant chemoradiotherapy plus surgery versus active surveillance for oesophageal cancer: a... Background: Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard treatment for locally advanced oesophageal cancer. With this treatment, 29% of patients have a pathologically complete response in the resection specimen. This provides the rationale for investigating an active surveillance approach. The aim of this study is to assess the (cost-)effectiveness of active surveillance vs. standard oesophagectomy after nCRT for oesophageal cancer. Methods: This is a phase-III multi-centre, stepped-wedge cluster randomised controlled trial. A total of 300 patients with clinically complete response (cCR, i.e. no local or disseminated disease proven by histology) after nCRT will be randomised to show non-inferiority of active surveillance to standard oesophagectomy (non-inferiority margin 15%, intra-correlation coefficient 0.02, power 80%, 2-sided α 0.05, 12% drop-out). Patients will undergo a first clinical response evaluation (CRE-I) 4–6 weeks after nCRT, consisting of endoscopy with bite-on-bite biopsies of the primary tumour site and other suspected lesions. Clinically complete responders will undergo a second CRE (CRE-II), 6–8 weeks after CRE-I. CRE-II will include 18F–FDG-PET-CT, followed by endoscopy with bite-on- bite biopsies and ultra-endosonography plus fine needle aspiration of suspected lymph nodes and/or PET- positive lesions. Patients with cCR at CRE-II will be assigned to oesophagectomy (first phase) or active surveillance (second phase of the study). The duration of the first phase is determined randomly over the 12 centres, i.e., stepped- wedge cluster design. Patients in the active surveillance arm will undergo diagnostic evaluations similar to CRE-II at 6/9/ 12/16/20/24/30/36/48 and 60 months after nCRT. In this arm, oesophagectomy will be offered only to patients in whom locoregional regrowth is highly suspected or proven, without distant dissemination. The main study parameter is overall survival; secondary endpoints include percentage of patients who do not undergo surgery, quality of life, clinical irresectability (cT4b) rate, radical resection rate, postoperative complications, progression-free survival, distant dissemination rate, and cost-effectiveness. We hypothesise that active surveillance leads to non-inferior survival, improved quality of life and a reduction in costs, compared to standard oesophagectomy. Discussion: If active surveillance and surgery as needed after nCRT leads to non-inferior survival compared to standard oesophagectomy, this organ-sparing approach can be implemented as a standard of care. Keywords: Oesophageal cancer, Neoadjuvant chemoradiotherapy, Active surveillance, Standard oesophagectomy * Correspondence: b.noordman@erasmusmc.nl Department of Surgery, Erasmus MC – University Medical Centre, Suite Z-839, P.O. Box 2040 3000, CA, Rotterdam, The Netherlands Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Noordman et al. BMC Cancer (2018) 18:142 Page 2 of 12 Background Using two rounds of clinical response evaluations (CREs), Oesophageal cancer is an aggressive disease with poor sensitivity and specificity for differentiation between outcomes after primary surgery [1]. Since the introduc- tumour regression grade (TRG) 3–4 (i.e. > 10% vital cells) tion of neoadjuvant chemo (radio) therapy, survival rates and TRG 1 (i.e. no vital cells) residual tumour using en- have improved substantially [2]. The randomised Che- doscopy with bite-on-bite biopsies and FNA were 90% moRadiotherapy for Oesophageal cancer followed by and 72%, respectively. 18F–FDG PET-CT after nCRT de- Surgery Study (CROSS) showed an absolute 5-year over- tected interval metastases in 10% of patients [14]. all survival benefit of 14% after neoadjuvant chemoradio- The results of the preSANO-trial in combination with therapy (nCRT) plus surgery, compared to surgery alone results in the literature on the clinical outcome of active [3, 4]. Moreover, after nCRT according to CROSS, 29% surveillance justify a phase-III trial, comparing active of all patients (49% for squamous cell carcinoma [SCC] surveillance with standard surgery in patients with a and 23% for adenocarcinoma [AC]) had a pathologically clinically complete response after nCRT. complete response (pCR) in the resection specimen [3]. This high pCR-rate provides the rationale to explore an Objective organ-sparing active surveillance approach after nCRT The aim of this study is to assess the (cost-)effectiveness since, intuitively, an oesophagectomy in patients with no (including non-financial costs and survival) of active viable residual tumour does not improve oncological surveillance after nCRT - as compared to standard sur- outcome. In this organ-sparing treatment strategy, pa- gery - for patients with SCC or AC of the oesophagus or tients will undergo frequent diagnostic evaluations after oesophagogastric junction. nCRT. An oesophagectomy will be performed only in patients with a proven or high suspicion of locoregional Methods regrowth, in the absence of distant metastases. This Study design treatment strategy would have great advantages, espe- TheSANO-trialisaphaseIII multi-centre, stepped-wedge, cially given the perioperative morbidity and mortality, cluster randomised controlled non-inferiority trial. This and the lasting impact on patients’ health-related quality design involves random sequential switch of clusters of par- of life (HRQOL) that is associated with oesophagectomy ticipating institutions from the control arm (standard [3, 5–9]. An active surveillance approach would not only surgery) to the interventional arm (active surveillance). benefit patients who are cured by nCRT alone, but also Randomisation is performed at the institutional level, in- patients with undetectable distant metastases (i.e. micro- stead of the individual level (Figs. 1 and 2)[15]. Twelve metastases) after completion of nCRT. Currently, pa- high-volume centres in the Netherlands are participating in tients with occult distant metastases undergo standard this study (Erasmus Medical Centre, Rotterdam; Catharina oesophagectomy. This theoretically is of no benefit, be- Cancer Institute, Eindhoven; Zuyderland Medical Centre, cause distant metastases, which are the main determi- Heerlen; Radboud University Medical Centre, Nijmegen; nants of long-term survival, are below the detection Elisabeth Tweesteden Hospital, Tilburg; Gelre Hospital, limit at the first clinical evaluation after nCRT. During Apeldoorn; Leiden University Medical Centre, Leiden; active surveillance, these occult metastases might be- Maasstad Hospital, Rotterdam; Zorggroep Twente, Almelo; come clinically manifest, which will prevent patients Netherlands Cancer Institute, Amsterdam; Reinier de Graaf from a non-beneficial oesophagectomy. Group, Delft; Medical Centre Leeuwarden). Based on these At present, active surveillance is applied in selected 12 participating centres, 6 clusters with comparable esti- patients who refuse oesophagectomy or who are finally mated inclusion rates will be formed, each cluster compris- considered unfit for surgery after nCRT [10–13]. Ex- ing 2 participating centres. Based on the expected plorative retrospective studies in these patients show inclusion period of 36 months and the inclusion of promising results, with comparable long-term survival 60 clinically complete responders from the preSANO for active surveillance vs immediate standard surgery trial (see below; Statistical Analysis; Sample Size Cal- and comparable outcomes of postponed oesophagect- culation), every 4.5 months one cluster will switch omy in patients who develop a locoregional regrowth in from the control arm to the interventional arm. Clus- the absence of distant metastases [10–13]. ters will be determined by randomisation, but always In the recently completed diagnostic preSANO-trial, consist of a centre with high expected total inclusion endoscopy with bite-on-bite biopsies and ultra- (≥45) and a centre with a lower (< 30) expected total endosonography with fine needle aspiration (FNA) of inclusion. suspected lymph nodes for detection of locoregional During the first 4.5 months of the trial, all centres will residual disease, combined with 18F–FDG PET-CT for provide standard immediate surgery and will gain ex- detection of interval metastases was adequate for clinical perience in the performance of clinical response (and response evaluation after nCRT for oesophageal cancer. surveillance) evaluations. After 4.5 months, a cluster of 2 Noordman et al. BMC Cancer (2018) 18:142 Page 3 of 12 Fig. 1 Study algorithm. nCRT: neoadjuvant chemoradiotherapy; CRE: clinical response evaluation; cNCR: clinically non-complete response; cCR: clinically complete response. *At this point the patient will be allocated to one of the two treatment arms, dependent on the institution in which the actual treatment takes place. Randomisation will be performed at the institutional level (see §3.1 and §8.2). Patients will know their allocated treatment at the moment of inclusion centres (Erasmus MC and Zuyderland Medical Centre) crossed over into the active surveillance group) cannot with extensive experience in CREs and a large number be included in the trial. These patients will still be of patients included in the preSANO-trial, will start to treated in the same centre, but outside the trial. provide the novel strategy (active surveillance). After the Expected numbers of patients included in both study next 4.5 months, another cluster of 2 participating cen- arms during the different time periods and predefined tres will be randomly assigned by the sponsor using a clusters with comparable expected numbers of inclu- computer-generated number sequence to begin with ac- sions are shown in Fig. 2. Inclusion rate will be closely tive surveillance. This procedure will be repeated after monitored during the trial, and time periods will be 4.5 months until all clusters have crossed over into the adjusted if the number of included patients differ sub- active surveillance arm. The final phase of the trial, with stantially from the expectations. all sites including patients in the active surveillance arm, finishes approximately 9 months after the last cluster of Study population two sites have switched from the control arm to the Operable patients with locally advanced resectable SCC interventional arm (Fig. 2). or AC of the oesophagus or oesophagogastric junction Patients who prefer the treatment that is not offered who are planned to undergo nCRT according to CROSS as study treatment in that particular centre at that time followed by surgical resection are eligible for inclusion (e.g. active surveillance in a centre that has not yet [3]. Patients with language difficulties, dementia or Noordman et al. BMC Cancer (2018) 18:142 Page 4 of 12 Fig. 2 Stepped-wedge cluster design with addition of preSANO cCR-patients and sequential cross-over of 6 clusters comprising 2 centres every 4.5 months altered mental status prohibiting the understanding and be offered immediate surgery (i.e. 6–8 weeks after com- giving of informed consent and patients with non-FDG- pletion of nCRT). Patients who are found to be cCR will avid tumours at baseline will be excluded from participa- undergo a second CRE (CRE-II) 6–8 weeks after CRE-I tion in this study. Patients will have conventional pre- (i.e. 10–14 weeks after completion of nCRT). CRE-II will treatment work-up (including F18-FDG PET-CT to include an 18F–FDG PET-CT, followed by OGD with assess the avidity of the primary tumour). bite-on-bite biopsies of the primary tumour site and any other suspected lesions, radial EUS and in case of PET- Study algorithm (Table 1, Fig. 1, Fig. 3) positive lesions and/or suspected lymph nodes, even if All included patients will undergo nCRT according to these lymph nodes are located directly adjacent to the CROSS (Carboplatin AUC 2 mg/mL per min, Pacli- primary tumour site, linear EUS with FNA. The 18F– taxel 50 mg/m2 of body-surface area and 41.4 Gy of FDG PET-CT during CRE-II must be available to guide concurrent radiotherapy in 23 fractions) [3]. Patients the endoscopist in taking biopsies and FNA during OGD will be re-staged after nCRT during CREs to select and EUS. Patients with (cyto)histological evidence of those who may benefit from active surveillance. CREs locoregional residual disease or highly suspected locore- categorise patients as clinically complete responders gional residual disease on 18F–FDG PET-CT, and with- or clinically incomplete responders. Only patients in out distant metastases during CRE-II will undergo whom no locoregional or disseminated disease is surgery immediately after CRE-II (i.e. 10–14 weeks after proven (cCR) during CREs, will be included in the completion of nCRT). Patients with distant metastases comparative part of this trial. will be referred for palliative care. Patients without (cyto)histological evidence of re- CREs sidual disease during CRE-II (cCR), in the absence of Approximately 4–6 weeks after completion of nCRT all distant metastases, will be assigned to active surveil- included patients will undergo a first clinical response lance (experimental arm) or standard surgery (control evaluation (CRE-I) including oesophagogastroduodeno- arm), according to the randomisation at the institu- scopy (OGD) with at least 8 (random) biopsies, includ- tional level. ing at least 4 bite-on-bite biopsies of the primary tumour site and of any other suspected lesions. Patients Active surveillance with (cyto) histological evidence of locoregional residual Patients in the active surveillance arm will undergo disease during CRE-I will be offered a subsequent 18F– active surveillance by 18F–FDG PET-CT, OGD with at FDG PET-CT to exclude disseminated disease and will least 8 biopsies, including at least 4 bite-on-bite biopsies Noordman et al. BMC Cancer (2018) 18:142 Page 5 of 12 Table 1 Study algorithm Pretreatment CRE-I CRE-II Standard surgery arm Active surveillance arm (4–6 weeks (10–14 weeks (6, 9, 12, 16, 20, 24, 30, 36, 48 (6, 9, 12, 16, 20, 24, 30, 36, 48 after nCRT) after nCRT) and 60 months after nCRT) and 60 months after nCRT) Informed consent X Inclusion X Treatment allocation X ECOG performance status X X X X X Endoscopy with bite-on-bite biopsies X X X X Radial EUS X X X Linear EUS with FNA of suspected lymphXX X nodes a b c b 18F–FDG PET-CT (whole-body) X X X X X d d Quality of Life (EQ-5D, QLQ-C30, QLC-OG25XX X X en Cancer Worry Scale) e f g Oesophagectomy X X All At indication 18F–FDG PET-CT: during CRE-I, after OGD, only for clinically non-complete responders, to exclude disseminated disease 18F–FDG PET-CT: during CRE-II and active surveillance, prior to OGD and EUS, for all patients (all were clinically complete responders during CRE-I) to guide endoscopists in taken biopsies / FNA during OGD and EUS and to exclude disseminated disease PET-CT in the standard surgery arm will be performed at 12 and 24 months after nCRT only, to exclude disseminated disaese Quality of life will be assessed during the first 2 years only Only for patients with locoregional disease After CRE-II: Only for patients with cCR who are allocated to surgery Only for patients in whom a locoregional regrowth is highly suspected or proven, without any signs of distant dissemination CRE: clinical response evaluation; nCRT: neoadjuvant chemoradiotherapy; ECOG: Eastern Cooperative Oncology Group EUS: endo-ultrasonograpy; FNA: fine needle aspiraton. At this point the patient will be allocated to one of the two treatment arms, dependent on the institution. Randomisation has already been performed at the institutional level and will be known to the patient at the moment of inclusion and EUS plus FNA of all suspected lymph nodes at 6, 9, Pathology 12, 16, 20, 24, 30, 36, 48 and 60 months after completion All CRE- and surveillance biopsies will be assessed by ex- of nCRT or when symptoms or results of any diagnostic pert GI pathologists. Initially, all biopsies will be analysed test require shorter assessment intervals. Patients with based on the regular HE-slides (which contains two or (cyto)histological evidence of disseminated disease dur- three levels). If analysis at these levels reveals obvious vital ing active surveillance will be referred for palliative care tumour, the biopsy will be classified (diagnosed) as posi- (Fig. 3). tive. If the assessment of this HE-slide is negative for ma- lignancy (no malignancy), deeper sections will be Surgery performed (two or three additional levels, depending on All patients in the control arm without distant metasta- the amount of tissue on the paraffin block). In case of ses will be offered oesophagectomy after CRE-II, doubt regarding the presence of tumour (cells) after ana- whereas patients in the active surveillance arm will be lysis of a biopsy at the aforementioned additional levels, offered surgery only when locoregional regrowth is extra dPAS and (pan)keratin staining will be performed. highly suspected or proven, also without any signs of In case of an originally diagnosed signet-ring cell carcin- distant dissemination (Fig. 3). oma or a poorly cohesive carcinoma with mucin produc- A transthoracic oesophagectomy or a transhiatal oeso- tion, analysis at three additional (deeper) levels and dPAS phagectomy will be performed, depending on both and keratin staining will be performed consistently. patient characteristics and local expertise and prefer- Only the CRE- and surveillance biopsies with uncer- ence. Open, hybrid and completely minimally invasive tain outcome will be revised at the Department of Path- techniques are allowed. At least 15 lymph nodes should ology of the Erasmus MC following the same strategy. be harvested in every patient. An en-bloc resection of The resection specimens will be assessed using the 7th the primary tumour and the regional lymph nodes edition of the UICC TNM cancer staging. Microscopic- should be carried out including a standard dissection ally radical resection (R0) will be defined as a tumour- of the lymph nodes around the coeliac axis (separ- free resection margin (margin > 1 mm not required). ately collected for nodes along the left gastric, com- Also, prepTNM staging will be estimated as described mon hepatic and splenic artery). In the chest, at least earlier [16]. Tumour regression grade (TRG) will be the right paratracheal, subcarinal and para- determined according to the modified Mandard classifi- oesophageal lymph nodes should be harvested. cation (TRG 1 to 4) [14]. Noordman et al. BMC Cancer (2018) 18:142 Page 6 of 12 Fig. 3 Expected distribution of patients. nCRT: neoadjuvant chemoradiotherapy; CRE: clinical response evaluation; S1: first surveillance evaluation; S2: second surveillance evaluation etc. Treatment allocation*: randomisation will be performed at institutional level and will be known already at the moment of inclusion; immediate surgery arm of randomisation not shown Centralised multidisciplinary tumour board instance the intensity of a hotspot on 18F–FDG PET-CT During CRE-I and CRE-II, positive (cyto)histology is substantially increases over time during surveillance but preferably available when offering a patient surgical positive (cyto)histology cannot be obtained, the MTB resection. However, during active surveillance we do can decide to recommend surgery. allow a centralised multidisciplinary tumour board (MTB, Erasmus MC) to recommend surgical resection Follow-up in selected patients who have a high clinical / diagnostic Follow-up visits of patients in both study arms will occur at suspicion of tumour regrowth, despite repeatedly nega- 6, 9, 12, 16, 20, 24, 30, 36, 48 and 60 months after comple- tive (cyto)histology. This centralised MTB will monitor tion of nCRT. Additional visits will be scheduled if com- and decide on all such suspected patients from all par- plaints will arise before the next visit. In cases of suspected ticipating centres. The reason for offering surgical resec- recurrence, thoraco-abdominal CT, PET-CT and/or upper tion in patients with a (strong) clinical suspicion of gastrointestinal endoscopy will be performed. In order to regrowth, but without positive (cyto)histology is to min- accurately compare distant dissemination rates between imise the risk that a difficulty in confirming regrowth by both treatment arms, 18F–FDG PET-CT scan will be per- histology causes a delay that will permit a tumour re- formed in all patients in the standard surgery arm after 1 growth to expand into an irresectable stage. If for and 2 years of follow-up, after which most (> 80% and > Noordman et al. BMC Cancer (2018) 18:142 Page 7 of 12 90%, resp.) distant metastases will likely have been detected – Postoperative morbidity; postoperative in-hospital [17]. If a patient in the active surveillance will undergo post- mortality in all patients in the active surveillance poned oesophagectomy due to a locoregional regrowth arm, proportion of all patients in the active surveil- without distant metastases, follow-up will be performed ac- lance arm with hospital stay > 60 days or who de- cording to the Dutch Guideline for oesophageal cancer [18]. velop postoperative trachea-neo-oesophageal fistula; – Proportion of all patients in the active surveillance Study parameters/endpoints arm that develop distant dissemination after 1 and 2 The main study parameter in this study is overall sur- years of follow-up. vival of patients with cCR at CRE-II (i.e. 10–14 weeks after completion of nCRT). Secondary study parameters If outcomes of one or more of these parameters in the include: active surveillance arm significantly exceed the outcomes in the standard surgery arm or in the Dutch Upper-GI – The percentage of patients in the active surveillance Cancer Audit (DUCA) data 2016, all participating cen- arm who do not undergo surgery (i.e. patients who tres will be notified immediately and further inclusion are cured by nCRT or who have occult distant will be stopped [24]. Patients who have been already in- metastases during initial staging, which become cluded will be informed and offered the possibility of im- manifest during active surveillance); mediate (high-priority) surgical resection, even in the – HRQOL as measured with EQ-5D [19], QLQ-C30 absence of suspicion of regrowth. Continuation of active [20], QLC-OG25 [21] and Cancer Worry Scale [22] surveillance will also still be offered. questionnaires; – Clinical irresectability (cT4b) rate; R -resection rate Statistical analysis defined as percentage of patients within the entire Sample size calculation randomised population who undergo resection, In the present phase-III study, we plan to randomise at defined as a tumour-free resection margin; institutional level 300 patients with cCR during CRE-II – Postoperative morbidity/complications for all between active surveillance and standard surgical resec- randomised patients with cCR who undergo tion. Simulation of trial outcomes with expected equal resection, as defined by the Esophageal 3-year overall survival rates of 67% in both trial arms Complications Consensus Group [23]; and an intra-correlation coefficient of 0.02 to account – Postoperative mortality for all patients with cCR for between-institution variation (inter-quartile range for who undergo resection, defined as 90 day- and/or 3-year overall survival rates of 63%–71%) indicates a in-hospital mortality; total sample size of 264 patients to show non-inferiority – Progression-free survival, defined as the interval of surveillance to standard surgery with 80% power [25]. between randomisation and the earliest occurrence Non-inferiority is defined as a 3-year survival rate that is of disease progression resulting in primary (or no more than 15 percentage points below the expected peroperative) irresectability of disease, locoregional 67% 3-year survival rate among patients in the standard regrowth (after completion of therapy); surgery arm (data based on the CROSS-trial) [3, 4]. To – Distant dissemination rate; allow for a 12% drop-out (e.g. patients in the active – Cost-effectiveness. surveillance-arm who request immediate surgery in the absence of clinically proven or suspected regrowth) 300 Safety and stopping rules patients are required for randomisation. Based on pre- Delaying surgical resection in patients in the active sur- liminary data from the current preSANO-trial, we veillance arm should neither lead to a significant reduc- expect that 50% of all included patients will have cCR tion in tumour resectability and radical resection rate, during CRE-II, leading to a total required inclusion of nor to a significant increase in postoperative mortality 600 patients. and distant dissemination rate. Therefore, the following To reduce the number of newly included patients and parameters are closely monitored; to optimally use the data from the preSANO-trial, all recently (≥ May 2015) included patients with cCR during – Proportion of all patients in the active surveillance CRE-II from the current preSANO-trial who underwent arm that present with an irresectable or incurable bite-on-bite biopsies during CRE-I and CRE-II will be (T4b or R2) regrowth, in the absence of distant included in the control arm (n = 60 patients). Assuming metastases; a 50% cCR rate, the total number of required patients to – Proportion of all patients in the active surveillance be newly included in the SANO-trial will drop from 600 arm that undergo a microscopically non-radical (R1) to 480 patients. Consequently, patients with cCR are resection; randomised at an institutional level in a 3:5 ratio. Noordman et al. BMC Cancer (2018) 18:142 Page 8 of 12 No interim analyses are planned for survival outcomes. locoregional regrowth, [ad 3] the performance of delayed surgery or [ad 4] the detection of distant metastases). The project leader (JL) is responsible for the study Data analysis design and conduct of the trial, for the preparation of The difference in survival over a 3-year horizon between the protocol and revisions and for preparation of case the control arm and the experimental treatment arm will report forms. Revisions of the study protocol will be be analysed with a mixed-effects Cox regression model. communicated to all local chief investigators. The Clin- Use of a mixed regression model – including an ical Trial Centre (CTC) of the Erasmus MC – Univer- institution-level random effect – is required to capture sity Medical Centre Rotterdam is responsible for the the potential between-institutional variation in survival data master file, data verification and randomisation. [26]. To correct for potential selection bias, the treat- Randomisation will be performed via a computer- ment effect will be estimated with adjustment for prog- generated random numbers sequence. Data will be nostic factors for survival, i.e. age, sex, histologic subtype collected using individual trial case numbers on stan- of tumour, clinical N stage, and WHO performance dardised case report forms collated centrally by the score. We will also use the mixed-effects Cox regression CTC. Patients will not be individually identifiable. The model to study potential differences in treatment effect final dataset will be available to all study investigators between subgroups of patients. Subgroups are prede- but will not be analysed per centre. Authorships will be fined according to age, sex, histologic subtype of tumour, defined following the International Committee of Med- clinical N stage, and WHO performance score. HRQOL ical Journal Editors guidelines [27]. Results will be com- data will be analysed according to the EuroQol, EORTC municated via international conferences, via publications and Cancer Worry Scale scoring manuals [19–22]. Re- and via the NTR. peated measurement analysis will be used to evaluate within and between group differences. Data will be ana- lysed following the intention-to-treat principle, including Discussion protocol deviators. A per protocol analysis will be per- Trials comparing surgical and non-surgical treatment formed as a secondary analysis. modalities often fail due to low accrual if randomisa- tion is at the patient level, which might be explained Ethical and regulatory considerations by patient preferences for an intervention [28–30]. The study has been approved by the medical ethics Therefore, a stepped-wedge cluster design is applied committee of the Erasmus MC (MEC2017–392) and in the present trial [31]. In a stepped-wedge design, has been registered in the Netherlands Trial Register randomisation takes place at the institutional level, (NTR 6803). The study will be conducted according and not at the patient level. Consequently, at the mo- to the principles of the Declaration of Helsinki (10th ment of inclusion patients know which treatment arm version, Fortaleza, 2013) and in accordance with the they will be assigned to, thereby overcoming uncer- Dutch Medical Research Involving Human Subjects tainty about which treatment patients will undergo. Act (WMO) and other applicable guidelines, regula- We expect that this will improve patients’ willingness tions and Acts. In each participating centre, the local to participate. When proven successful, the stepped- coordinating or principal investigator will be respon- wedge design might be used as a new standard for sible for recruitment, data collection, follow-up of comparing surgical with conservative treatments in included patients, completion of case report forms clinical trials. and adherence to the study protocol. The supervising We will include both patients with SCC and pa- physician or any other physician of the multidisciplin- tients with AC, since SCC and AC both respond to ary team will inform subjects about the study and ask nCRT and no statistically significant differential effects for their consent using standard information letters were found in the CROSS-trial. Both patients with and informed consent forms. Both patient information SCC and AC have a substantial pCR rate (49% and letters and informed consent forms are attached as 23% in CROSS respectively) [3]. Moreover, prelimin- separate documents. ary results of the preSANO-trial suggests that residual An independent safety committee will be established disease can be diagnosed with comparable accuracy in to perform on-going safety surveillance and to perform patients with both histological subtypes. interim analyses to assess the safety data and the stop- Furthermore, in combination with the relatively low ping rules as described in “safety and stopping rules”. frequency of toxicity of the CROSS-regimen (91% Each stopping rule will be repeatedly tested when the completed the full nCRT-regimen), the high pCR-rate first 10, 20, 30 and 50 events for that particular stopping supports the use of the relatively low radiation dose rule have occurred (i.e. [ad 1 and 2] detection of of 41.4 Gy [3]. The beneficial effectivity/toxicity ratio Noordman et al. BMC Cancer (2018) 18:142 Page 9 of 12 is the rationale to apply the CROSS-regimen in the Coordinating Investigator SANO-trial, and not a definitive chemoradiotherapy Drs. B.J. Surgery Erasmus MC regimen (≥50 Gy of radiotherapy). The latter could Noordman increase the pCR-rate, but probably at the cost of a Project Leader substantial increase in toxicity and postoperative com- Prof. dr. J.J.B. van Surgery Erasmus MC plications, leading to a less beneficial effectivity/tox- Lanschot icity ratio. It should be noted that postponement of Principal Investigators surgical resection, as will be performed in patients Dr. S.M. Lagarde Surgery Erasmus MC who develop locoregional regrowth in the absence of distant metastases, has been suggested to increase the Dr. B.P.L. Surgery Erasmus MC Wijnhoven incidence of postoperative complications. However, Erasmus MC, Rotterdam this phenomenon has been reported primarily after treatment with high-dose of definitive chemoradio- Dr. K. Biermann Pathology Erasmus MC therapy (so called salvage esophagectomy) in low- Dr. A. van der Medical Oncology Erasmus MC volume centres [32, 33]. The SANO-trial will reveal Gaast whether this also applies to a lower dose of radiother- Dr. E. Ista Implementation Fellow Erasmus MC apy (CROSS regimen) in high-volume centres. Dr. N.C. Krak Radiology Erasmus MC If the SANO-trial shows that active surveillance after Dr. J.J.M.E. Radiotherapy Erasmus MC nCRT for oesophageal cancer leads to non-inferior sur- Nuyttens vival compared to standard oesophagectomy, this organ- Dr. S. Polinder Health Economics Erasmus MC sparing approach could be implemented as a standard of Dr. M.C.W. Gastroenterology Erasmus MC care. Of note, the French ESOSTRATE-trial is also com- Spaander paring active surveillance with standard surgery in Prof. dr. E.W. Public Health Erasmus MC patients with cCR after nCRT. The ESOSTRATE-trial Steyerberg aims to include a total of 300 patients with SCC or AC Dr. R. Valkema Nuclear Medicine Erasmus MC with cCR after nCRT https://clinicaltrials.gov/ct2/show/ Almelo NCT02551458. The primary endpoint is overall survival, Dr. A. Agool Nuclear Medicine Zorggroep Twente as in the SANO-trial. Combining results from the Drs. J. van Baarlen Pathology Lab PON ESOSTRATE-trial and the SANO-trial would lead to more certainty. Recently, we have shown that 54% and Drs. E.M. Radiotherapy Medisch Spectrum Twente Hendriksen 61% of all patients are willing to trade-off 15% and 10% overall survival, respectively, to undergo active surveil- Dr. R. Hoekstra Medical Oncology Zorggroep Twente lance instead of standard surgery [34]. Therefore, the Dr. E.A. Surgery Zorggroep Twente statistical power of the SANO-trial is for a non- Kouwenhoven inferiority margin of 15%; combination with the French Drs. A. van der Gastroenterology Zorggroep Twente ESOSTRATE-trial would reduce this margin to 10%. Linde Hence, the future combination of results with the Amsterdam ESOSTRATE-trial is important to further increase our Dr. A. Bartels- Radiology AVL-NKI knowledge of an active surveillance approach beyond Rutten what we will learn from the SANO-trial only. Dr. J. van Dieren Medical Oncology/ AVL-NKI Gastroenterology Abbreviations Dr. J. van Sandick Surgery AVL-NKI AC: AdenoCarcinoma; cCR: Clinically Complete Response; CRE: Clinical Response Evaluation; CROSS: ChemoRadiotherapy for Oesophageal cancer Dr. P. Pathology AVL-NKI followed by Surgery Study [3]; DUCA: Dutch Upper-GI Cancer Audit; Snaebjornsson EUS: Endoscopic UltraSonography; FNA: Fine Needle Aspiration; Gy: Gray; MEC: Medical Ethics Committee; MTB: Multidisciplinary tumour board; Dr. E. Vegt Nuclear Medicine AVL-NKI nCRT: Neoadjuvant ChemoRadioTherapy; NTR: Netherlands Trial Register; Drs. F.E.M. Radiotherapy AVL-NKI OGD: OesophagoGastroDuodenoscopy; pCR: Pathologically Complete Voncken Response; PET-CT: Positron-Emission Tomography - Computed Tomography; SANO: Surgery As Needed approach in Oesophageal cancer patients; Apeldoorn SCC: Squamous Cell Carcinoma; TNM: Tumour Node Metastasis classification Dr. H. Pathology Gelre Ziekenhuis system; TRG: Tumour Regression Grade; UICC: Union for International Cancer Doornewaard Control; WHO: World Health Organization Drs. G.W. Erkelens Gastroenterology Gelre Ziekenhuis Dr. G.S. Medical Oncology Gelre Acknowledgements Madretsma Ziekenhuis Members of the sano-study group. Noordman et al. BMC Cancer (2018) 18:142 Page 10 of 12 (Continued) (Continued) Dr. E.S van der Surgery Gelre Ziekenhuis Dr. K. van der Gastroenterology Medisch Centrum Zaag Linde Leeuwarden To be determined Nuclear Medicine Dr. J. Nieken Pathology Medisch Centrum Leeuwarden To be determined Radiotherapy Drs. V. Oppedijk Radiotherapy Radiotherapeutisch Instituut Delft Friesland Drs. M.R.J. ten Nuclear Medicine Reinier de Graaf Group Prof. dr. J.P.E.N. Surgery Medisch Centrum Broek Pierie Leeuwarden Drs. R.J. Dallinga Radiology Reinier de Graaf Group Drs. R. Wolf Radiology Medisch Centrum Leeuwarden Dr. J.W.T. Dekker Surgery Reinier de Graaf Group Maasstad Ziekenhuis, Rotterdam Dr. V.O. Dezentjé Medical Oncology Reinier de Graaf Group Dr. P.P.L.O. Coene Surgery Maasstad Ziekenhuis Dr. R.R. de Krijger Pathology Reinier de Graaf Group Dr. I. Al Butaihi Nuclear Medicine Maasstad Ziekenhuis Dr. K.J. Neelis Radiotherapy Reinier de Graaf Group Dr. M. Kliffen Pathology Maasstad Ziekenhuis Drs. R. Quispel Gastroenterology Reinier de Graaf Group Dr. E.M.M. Kuiper Gastroenterology Maasstad Ziekenhuis Eindhoven Dr. E.F. Courrech Radiology Maasstad Ziekenhuis Staal Dr. G.J. Creemers Medical Oncology Catharina Cancer Center, Eindhoven Nijmegen Dr. G.A.P. Surgery Catharina Cancer Center, Dr. M.J.R. Janssen Nuclear Medicine Radboudumc Nieuwenhuijzen Eindhoven Drs. M.H. Radiology Radboudumc Dr. M.C. van der Radiotherapy Catharina Cancer Center, Liedenbaum Sangen Eindhoven Drs. C. van der Pathology Radboudumc Dr. E.J. Schoon Gastroenterology Catharina Cancer Center, Post Eindhoven Dr. S.A. Radema Medical Oncology Radboudumc Dr. D.N.J. Nuclear Medicine Catharina Cancer Center, Wyndaele Eindhoven Prof. dr. C. Surgery Radboudumc Rosman Heerlen Drs. H. Rütten Radiotherapy Radboudumc Dr. J. Buijsen Radiotherapy Maastro Clinic Prof. dr. P.D. Gastroenterology Radboudumc Dr. R.G. Riedl Pathology Zuyderland MC Siersema Drs. W.M.J. Nuclear Medicine Zuyderland MC Tilburg Schreurs Dr. L.V. Beerepoot Medical Oncology Elisabeth Tweesteden Dr. M.N. Sosef Surgery Zuyderland MC Ziekenhuis Dr. L.E. Gastroenterology Zuyderland MC Dr. W.L. Hazen Gastroenterology Elisabeth Tweesteden Oostenbrug Ziekenhuis Drs. F.A.R.M. Medical Oncology Zuyderland MC Dr. J. Surgery Elisabeth Tweesteden Warmerdam Heisterkamp Ziekenhuis Leiden Drs. J.C. van Oord Radiology Elisabeth Tweesteden Ziekenhuis Dr. J.J. Boonstra Gastroenterology LUMC Drs. T. Rozema Radiotherapy Instituut Verbeeten Dr. M. Slingerland Medical Oncology LUMC Dr. I.A.C. Nuclear Medicine Instituut Verbeeten Dr. W.O. de Steur Surgery LUMC Vermeltfoort Dr. I.M. Lips Radiotherapy LUMC Dr. A.A.M. van der Pathology Elisabeth Tweesteden, To be Nuclear Medicine Wurff Ziekenhuis determined To be Radiology determined To be Pathology determined Funding Leeuwarden The preSANO trial is funded by the Koningin Wilhelmina Fonds Kankerbestrijding (KWF, Dutch Cancer Foundation) and ZonMw. Both funding bodies have no role Dr. H. Balink Nuclear Medicine Medisch Centrum in the design of the study and collection, analysis, and interpretation of data and Leeuwarden in writing the manuscript. Dr. W.E. Fiets Medical Oncology Medisch Centrum This trial is financially supported by the Dutch Cancer Foundation (KWF Leeuwarden Kankerbestrijding) and ZonMw. Noordman et al. BMC Cancer (2018) 18:142 Page 11 of 12 Availability of data and materials plus surgery versus surgery alone for oesophageal or junctional cancer Not applicable. (CROSS): long-term results of a randomised controlled trial. Lancet Oncol. 2015;16(9):1090–8. Authors’ contributions 5. De Boer AG, Genovesi PI, Sprangers MA, Van Sandick JW, Obertop H, Van BN participated in the study design and drafted the manuscript. JB, PC, JD, Lanschot JJ. Quality of life in long-term survivors after curative transhiatal MD, AG, JH, EK, GN, JP, CR, JS, MJS, MNS, MCS, RV, EZ and ES participated in oesophagectomy for oesophageal carcinoma. Br J Surg. 2000;87(12):1716–21. the study design and critically revised the manuscript. BW and SM initiated 6. Djarv T, Lagergren J, Blazeby JM, Lagergren P. Long-term health-related the trial and critically revised the manuscript. JL initiated the trial and quality of life following surgery for oesophageal cancer. Br J Surg. 2008; supervised the drafting of the manuscript. All authors read and approved the 95(18581441):1121–6. final manuscript and agree to be accountable for all aspects of the work. 7. Scarpa M, Valente S, Alfieri R, Cagol M, Diamantis G, Ancona E, et al. Systematic review of health-related quality of life after esophagectomy for Ethics approval and consent to participate esophageal cancer. World J Gastroenterol. 2011;17(42):4660–74. The study has been approved by the medical ethics committee of the 8. Noordman BJ, Verdam MGE, Lagarde SM, Hulshof MCCM, Van Hagen P, Van Erasmus MC (MEC2017–392). Written, voluntary, informed consent to Berge Henegouwen MI et al. Impact of neoadjuvant chemoradiotherapy on participate in the study will be obtained from participants. Individual patient health related quality of life in esopageal or junctional cancer: results from data will not be made available. the randomized CROSS trial. In press, J Clin Oncol. 2017. 9. Noordman BJ, Verdam MGE, Lagarde SM, Shapiro J, Hulshof MCCM, Van Consent for publication Berge Henegouwen MI et al. Impact of neoadjuvant chemoradiotherapy on Not applicable. health related quality of life in long-term survivors of esophageal or junctional cancer: results from the randomized cross trial. Submitted for Competing interests publication. Ann Oncol. 2017. https://doi.org/10.1093/annonc/mdx726. The authors declare that they have no competing interests. [Epub ahead of print]. 10. Castoro C, Scarpa M, Cagol M, Alfieri R, Ruol A, Cavallin F, et al. Complete clinical response after neoadjuvant chemoradiotherapy for squamous cell Publisher’sNote cancer of the thoracic oesophagus: is surgery always necessary? J Springer Nature remains neutral with regard to jurisdictional claims in Gastrointest Surg. 2013;17(8):1375–81. published maps and institutional affiliations. 11. Taketa T, Correa AM, Suzuki A, Blum MA, Chien P, Lee JH, et al. Outcome of trimodality-eligible esophagogastric cancer patients who declined surgery Author details after preoperative chemoradiation. Oncology. 2012;83(5):300–4. Department of Surgery, Erasmus MC – University Medical Centre, Suite 12. Taketa T, Xiao L, Sudo K, Suzuki A, Wadhwa R, Blum MA, et al. Propensity- Z-839, P.O. Box 2040 3000, CA, Rotterdam, The Netherlands. Department of based matching between esophagogastric cancer patients who had surgery Gastroenterology, Leiden University Medical Centre, Leiden, the Netherlands. and who declined surgery after preoperative chemoradiation. Oncology. Department of Surgery, Maasstad Hospital, Rotterdam, the Netherlands. 2013;85(2):95–9. Department of Surgery, Reinier de Graaf Group, Delft, the Netherlands. 5 13. Furlong H, Bass G, Breathnach O, O'Neill B, Leen E, Walsh TN. Targeting Department of Pathology, Erasmus MC – University Medical Centre, 6 therapy for esophageal cancer in patients aged 70 and over. J Geriatr Rotterdam, the Netherlands. Department of Medical Oncology, Erasmus MC 7 Oncol. 2013;4(2):107–13. – University Medical Centre, Rotterdam, the Netherlands. Department of 14. Chirieac LR, Swisher SG, Ajani JA, Komaki RR, Correa AM, Morris JS, et al. Surgery, Elisabeth Tweesteden Hospital, Tilburg, the Netherlands. 8 Posttherapy pathologic stage predicts survival in patients with esophageal Department of Surgery, Zorggroep Twente, Almelo, the Netherlands. 9 carcinoma receiving preoperative chemoradiation. Cancer. 2005;103(7):1347–55. Department of Surgery, Catharina Hospital, Eindhoven, the Netherlands. 10 15. Hemming K, Haines TP, Chilton PJ, Girling AJ, Lilford RJ. The stepped wedge cluster Department of Surgery, Medical Centre Leeuwarden, Leeuwarden, the 11 randomised trial: rationale, design, analysis, and reporting. BMJ. 2015;350:h391. Netherlands. Department of Surgery, Radboud University Medical Centre, 16. Shapiro J, Biermann K, van Klaveren D, Offerhaus GJ, Ten Kate FJ, Meijer SL, Nijmegen, the Netherlands. Department of Surgery, The Netherlands et al. Prognostic value of pretreatment pathological tumor extent in Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the patients treated with Neoadjuvant Chemoradiotherapy plus surgery for Netherlands. Department of Radiation Oncology, Catharina Hospital, esophageal or Junctional cancer. Ann Surg. 2017;265(2):356–62. Eindhoven, the Netherlands. Department of Surgery, Zuyderland Medical 17. Shiozaki H, Sudo K, Xiao L, Wadhwa R, Elimova E, Hofstetter WL, et al. Centre, Heerlen, the Netherlands. Department of Gastroenterology, Erasmus Distribution and timing of distant metastasis after local therapy in a large MC – University Medical Centre, Rotterdam, the Netherlands. Department cohort of patients with esophageal and esophagogastric junction cancer. of Radiology and Nuclear Medicine, Erasmus MC – University Medical Centre, Oncology. 2014;86(5–6):336–9. Rotterdam, the Netherlands. Department of Surgery, Gelre Hospital, 18. National guideline oesophageal cancer [http://www.oncoline.nl/ Apeldoorn, the Netherlands. Department of Medical Statistics and oesofaguscarcinoom]. Accessed 2 Feb 2018 Bioinformatics, Leiden University Medical Centre, formerly department of 19. Janssen MF, Pickard AS, Golicki D, Gudex C, Niewada M, Scalone L, et al. Public Health, Erasmus MC – University Medical Centre Rotterdam, Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L across Rotterdam, the Netherlands. eight patient groups: a multi-country study. 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Neoadjuvant chemoradiotherapy plus surgery versus active surveillance for oesophageal cancer: a stepped-wedge cluster randomised trial

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Springer Journals
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Copyright © The Author(s). 2018
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1471-2407
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10.1186/s12885-018-4034-1
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Abstract

Background: Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard treatment for locally advanced oesophageal cancer. With this treatment, 29% of patients have a pathologically complete response in the resection specimen. This provides the rationale for investigating an active surveillance approach. The aim of this study is to assess the (cost-)effectiveness of active surveillance vs. standard oesophagectomy after nCRT for oesophageal cancer. Methods: This is a phase-III multi-centre, stepped-wedge cluster randomised controlled trial. A total of 300 patients with clinically complete response (cCR, i.e. no local or disseminated disease proven by histology) after nCRT will be randomised to show non-inferiority of active surveillance to standard oesophagectomy (non-inferiority margin 15%, intra-correlation coefficient 0.02, power 80%, 2-sided α 0.05, 12% drop-out). Patients will undergo a first clinical response evaluation (CRE-I) 4–6 weeks after nCRT, consisting of endoscopy with bite-on-bite biopsies of the primary tumour site and other suspected lesions. Clinically complete responders will undergo a second CRE (CRE-II), 6–8 weeks after CRE-I. CRE-II will include 18F–FDG-PET-CT, followed by endoscopy with bite-on- bite biopsies and ultra-endosonography plus fine needle aspiration of suspected lymph nodes and/or PET- positive lesions. Patients with cCR at CRE-II will be assigned to oesophagectomy (first phase) or active surveillance (second phase of the study). The duration of the first phase is determined randomly over the 12 centres, i.e., stepped- wedge cluster design. Patients in the active surveillance arm will undergo diagnostic evaluations similar to CRE-II at 6/9/ 12/16/20/24/30/36/48 and 60 months after nCRT. In this arm, oesophagectomy will be offered only to patients in whom locoregional regrowth is highly suspected or proven, without distant dissemination. The main study parameter is overall survival; secondary endpoints include percentage of patients who do not undergo surgery, quality of life, clinical irresectability (cT4b) rate, radical resection rate, postoperative complications, progression-free survival, distant dissemination rate, and cost-effectiveness. We hypothesise that active surveillance leads to non-inferior survival, improved quality of life and a reduction in costs, compared to standard oesophagectomy. Discussion: If active surveillance and surgery as needed after nCRT leads to non-inferior survival compared to standard oesophagectomy, this organ-sparing approach can be implemented as a standard of care. Keywords: Oesophageal cancer, Neoadjuvant chemoradiotherapy, Active surveillance, Standard oesophagectomy * Correspondence: b.noordman@erasmusmc.nl Department of Surgery, Erasmus MC – University Medical Centre, Suite Z-839, P.O. Box 2040 3000, CA, Rotterdam, The Netherlands Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Noordman et al. BMC Cancer (2018) 18:142 Page 2 of 12 Background Using two rounds of clinical response evaluations (CREs), Oesophageal cancer is an aggressive disease with poor sensitivity and specificity for differentiation between outcomes after primary surgery [1]. Since the introduc- tumour regression grade (TRG) 3–4 (i.e. > 10% vital cells) tion of neoadjuvant chemo (radio) therapy, survival rates and TRG 1 (i.e. no vital cells) residual tumour using en- have improved substantially [2]. The randomised Che- doscopy with bite-on-bite biopsies and FNA were 90% moRadiotherapy for Oesophageal cancer followed by and 72%, respectively. 18F–FDG PET-CT after nCRT de- Surgery Study (CROSS) showed an absolute 5-year over- tected interval metastases in 10% of patients [14]. all survival benefit of 14% after neoadjuvant chemoradio- The results of the preSANO-trial in combination with therapy (nCRT) plus surgery, compared to surgery alone results in the literature on the clinical outcome of active [3, 4]. Moreover, after nCRT according to CROSS, 29% surveillance justify a phase-III trial, comparing active of all patients (49% for squamous cell carcinoma [SCC] surveillance with standard surgery in patients with a and 23% for adenocarcinoma [AC]) had a pathologically clinically complete response after nCRT. complete response (pCR) in the resection specimen [3]. This high pCR-rate provides the rationale to explore an Objective organ-sparing active surveillance approach after nCRT The aim of this study is to assess the (cost-)effectiveness since, intuitively, an oesophagectomy in patients with no (including non-financial costs and survival) of active viable residual tumour does not improve oncological surveillance after nCRT - as compared to standard sur- outcome. In this organ-sparing treatment strategy, pa- gery - for patients with SCC or AC of the oesophagus or tients will undergo frequent diagnostic evaluations after oesophagogastric junction. nCRT. An oesophagectomy will be performed only in patients with a proven or high suspicion of locoregional Methods regrowth, in the absence of distant metastases. This Study design treatment strategy would have great advantages, espe- TheSANO-trialisaphaseIII multi-centre, stepped-wedge, cially given the perioperative morbidity and mortality, cluster randomised controlled non-inferiority trial. This and the lasting impact on patients’ health-related quality design involves random sequential switch of clusters of par- of life (HRQOL) that is associated with oesophagectomy ticipating institutions from the control arm (standard [3, 5–9]. An active surveillance approach would not only surgery) to the interventional arm (active surveillance). benefit patients who are cured by nCRT alone, but also Randomisation is performed at the institutional level, in- patients with undetectable distant metastases (i.e. micro- stead of the individual level (Figs. 1 and 2)[15]. Twelve metastases) after completion of nCRT. Currently, pa- high-volume centres in the Netherlands are participating in tients with occult distant metastases undergo standard this study (Erasmus Medical Centre, Rotterdam; Catharina oesophagectomy. This theoretically is of no benefit, be- Cancer Institute, Eindhoven; Zuyderland Medical Centre, cause distant metastases, which are the main determi- Heerlen; Radboud University Medical Centre, Nijmegen; nants of long-term survival, are below the detection Elisabeth Tweesteden Hospital, Tilburg; Gelre Hospital, limit at the first clinical evaluation after nCRT. During Apeldoorn; Leiden University Medical Centre, Leiden; active surveillance, these occult metastases might be- Maasstad Hospital, Rotterdam; Zorggroep Twente, Almelo; come clinically manifest, which will prevent patients Netherlands Cancer Institute, Amsterdam; Reinier de Graaf from a non-beneficial oesophagectomy. Group, Delft; Medical Centre Leeuwarden). Based on these At present, active surveillance is applied in selected 12 participating centres, 6 clusters with comparable esti- patients who refuse oesophagectomy or who are finally mated inclusion rates will be formed, each cluster compris- considered unfit for surgery after nCRT [10–13]. Ex- ing 2 participating centres. Based on the expected plorative retrospective studies in these patients show inclusion period of 36 months and the inclusion of promising results, with comparable long-term survival 60 clinically complete responders from the preSANO for active surveillance vs immediate standard surgery trial (see below; Statistical Analysis; Sample Size Cal- and comparable outcomes of postponed oesophagect- culation), every 4.5 months one cluster will switch omy in patients who develop a locoregional regrowth in from the control arm to the interventional arm. Clus- the absence of distant metastases [10–13]. ters will be determined by randomisation, but always In the recently completed diagnostic preSANO-trial, consist of a centre with high expected total inclusion endoscopy with bite-on-bite biopsies and ultra- (≥45) and a centre with a lower (< 30) expected total endosonography with fine needle aspiration (FNA) of inclusion. suspected lymph nodes for detection of locoregional During the first 4.5 months of the trial, all centres will residual disease, combined with 18F–FDG PET-CT for provide standard immediate surgery and will gain ex- detection of interval metastases was adequate for clinical perience in the performance of clinical response (and response evaluation after nCRT for oesophageal cancer. surveillance) evaluations. After 4.5 months, a cluster of 2 Noordman et al. BMC Cancer (2018) 18:142 Page 3 of 12 Fig. 1 Study algorithm. nCRT: neoadjuvant chemoradiotherapy; CRE: clinical response evaluation; cNCR: clinically non-complete response; cCR: clinically complete response. *At this point the patient will be allocated to one of the two treatment arms, dependent on the institution in which the actual treatment takes place. Randomisation will be performed at the institutional level (see §3.1 and §8.2). Patients will know their allocated treatment at the moment of inclusion centres (Erasmus MC and Zuyderland Medical Centre) crossed over into the active surveillance group) cannot with extensive experience in CREs and a large number be included in the trial. These patients will still be of patients included in the preSANO-trial, will start to treated in the same centre, but outside the trial. provide the novel strategy (active surveillance). After the Expected numbers of patients included in both study next 4.5 months, another cluster of 2 participating cen- arms during the different time periods and predefined tres will be randomly assigned by the sponsor using a clusters with comparable expected numbers of inclu- computer-generated number sequence to begin with ac- sions are shown in Fig. 2. Inclusion rate will be closely tive surveillance. This procedure will be repeated after monitored during the trial, and time periods will be 4.5 months until all clusters have crossed over into the adjusted if the number of included patients differ sub- active surveillance arm. The final phase of the trial, with stantially from the expectations. all sites including patients in the active surveillance arm, finishes approximately 9 months after the last cluster of Study population two sites have switched from the control arm to the Operable patients with locally advanced resectable SCC interventional arm (Fig. 2). or AC of the oesophagus or oesophagogastric junction Patients who prefer the treatment that is not offered who are planned to undergo nCRT according to CROSS as study treatment in that particular centre at that time followed by surgical resection are eligible for inclusion (e.g. active surveillance in a centre that has not yet [3]. Patients with language difficulties, dementia or Noordman et al. BMC Cancer (2018) 18:142 Page 4 of 12 Fig. 2 Stepped-wedge cluster design with addition of preSANO cCR-patients and sequential cross-over of 6 clusters comprising 2 centres every 4.5 months altered mental status prohibiting the understanding and be offered immediate surgery (i.e. 6–8 weeks after com- giving of informed consent and patients with non-FDG- pletion of nCRT). Patients who are found to be cCR will avid tumours at baseline will be excluded from participa- undergo a second CRE (CRE-II) 6–8 weeks after CRE-I tion in this study. Patients will have conventional pre- (i.e. 10–14 weeks after completion of nCRT). CRE-II will treatment work-up (including F18-FDG PET-CT to include an 18F–FDG PET-CT, followed by OGD with assess the avidity of the primary tumour). bite-on-bite biopsies of the primary tumour site and any other suspected lesions, radial EUS and in case of PET- Study algorithm (Table 1, Fig. 1, Fig. 3) positive lesions and/or suspected lymph nodes, even if All included patients will undergo nCRT according to these lymph nodes are located directly adjacent to the CROSS (Carboplatin AUC 2 mg/mL per min, Pacli- primary tumour site, linear EUS with FNA. The 18F– taxel 50 mg/m2 of body-surface area and 41.4 Gy of FDG PET-CT during CRE-II must be available to guide concurrent radiotherapy in 23 fractions) [3]. Patients the endoscopist in taking biopsies and FNA during OGD will be re-staged after nCRT during CREs to select and EUS. Patients with (cyto)histological evidence of those who may benefit from active surveillance. CREs locoregional residual disease or highly suspected locore- categorise patients as clinically complete responders gional residual disease on 18F–FDG PET-CT, and with- or clinically incomplete responders. Only patients in out distant metastases during CRE-II will undergo whom no locoregional or disseminated disease is surgery immediately after CRE-II (i.e. 10–14 weeks after proven (cCR) during CREs, will be included in the completion of nCRT). Patients with distant metastases comparative part of this trial. will be referred for palliative care. Patients without (cyto)histological evidence of re- CREs sidual disease during CRE-II (cCR), in the absence of Approximately 4–6 weeks after completion of nCRT all distant metastases, will be assigned to active surveil- included patients will undergo a first clinical response lance (experimental arm) or standard surgery (control evaluation (CRE-I) including oesophagogastroduodeno- arm), according to the randomisation at the institu- scopy (OGD) with at least 8 (random) biopsies, includ- tional level. ing at least 4 bite-on-bite biopsies of the primary tumour site and of any other suspected lesions. Patients Active surveillance with (cyto) histological evidence of locoregional residual Patients in the active surveillance arm will undergo disease during CRE-I will be offered a subsequent 18F– active surveillance by 18F–FDG PET-CT, OGD with at FDG PET-CT to exclude disseminated disease and will least 8 biopsies, including at least 4 bite-on-bite biopsies Noordman et al. BMC Cancer (2018) 18:142 Page 5 of 12 Table 1 Study algorithm Pretreatment CRE-I CRE-II Standard surgery arm Active surveillance arm (4–6 weeks (10–14 weeks (6, 9, 12, 16, 20, 24, 30, 36, 48 (6, 9, 12, 16, 20, 24, 30, 36, 48 after nCRT) after nCRT) and 60 months after nCRT) and 60 months after nCRT) Informed consent X Inclusion X Treatment allocation X ECOG performance status X X X X X Endoscopy with bite-on-bite biopsies X X X X Radial EUS X X X Linear EUS with FNA of suspected lymphXX X nodes a b c b 18F–FDG PET-CT (whole-body) X X X X X d d Quality of Life (EQ-5D, QLQ-C30, QLC-OG25XX X X en Cancer Worry Scale) e f g Oesophagectomy X X All At indication 18F–FDG PET-CT: during CRE-I, after OGD, only for clinically non-complete responders, to exclude disseminated disease 18F–FDG PET-CT: during CRE-II and active surveillance, prior to OGD and EUS, for all patients (all were clinically complete responders during CRE-I) to guide endoscopists in taken biopsies / FNA during OGD and EUS and to exclude disseminated disease PET-CT in the standard surgery arm will be performed at 12 and 24 months after nCRT only, to exclude disseminated disaese Quality of life will be assessed during the first 2 years only Only for patients with locoregional disease After CRE-II: Only for patients with cCR who are allocated to surgery Only for patients in whom a locoregional regrowth is highly suspected or proven, without any signs of distant dissemination CRE: clinical response evaluation; nCRT: neoadjuvant chemoradiotherapy; ECOG: Eastern Cooperative Oncology Group EUS: endo-ultrasonograpy; FNA: fine needle aspiraton. At this point the patient will be allocated to one of the two treatment arms, dependent on the institution. Randomisation has already been performed at the institutional level and will be known to the patient at the moment of inclusion and EUS plus FNA of all suspected lymph nodes at 6, 9, Pathology 12, 16, 20, 24, 30, 36, 48 and 60 months after completion All CRE- and surveillance biopsies will be assessed by ex- of nCRT or when symptoms or results of any diagnostic pert GI pathologists. Initially, all biopsies will be analysed test require shorter assessment intervals. Patients with based on the regular HE-slides (which contains two or (cyto)histological evidence of disseminated disease dur- three levels). If analysis at these levels reveals obvious vital ing active surveillance will be referred for palliative care tumour, the biopsy will be classified (diagnosed) as posi- (Fig. 3). tive. If the assessment of this HE-slide is negative for ma- lignancy (no malignancy), deeper sections will be Surgery performed (two or three additional levels, depending on All patients in the control arm without distant metasta- the amount of tissue on the paraffin block). In case of ses will be offered oesophagectomy after CRE-II, doubt regarding the presence of tumour (cells) after ana- whereas patients in the active surveillance arm will be lysis of a biopsy at the aforementioned additional levels, offered surgery only when locoregional regrowth is extra dPAS and (pan)keratin staining will be performed. highly suspected or proven, also without any signs of In case of an originally diagnosed signet-ring cell carcin- distant dissemination (Fig. 3). oma or a poorly cohesive carcinoma with mucin produc- A transthoracic oesophagectomy or a transhiatal oeso- tion, analysis at three additional (deeper) levels and dPAS phagectomy will be performed, depending on both and keratin staining will be performed consistently. patient characteristics and local expertise and prefer- Only the CRE- and surveillance biopsies with uncer- ence. Open, hybrid and completely minimally invasive tain outcome will be revised at the Department of Path- techniques are allowed. At least 15 lymph nodes should ology of the Erasmus MC following the same strategy. be harvested in every patient. An en-bloc resection of The resection specimens will be assessed using the 7th the primary tumour and the regional lymph nodes edition of the UICC TNM cancer staging. Microscopic- should be carried out including a standard dissection ally radical resection (R0) will be defined as a tumour- of the lymph nodes around the coeliac axis (separ- free resection margin (margin > 1 mm not required). ately collected for nodes along the left gastric, com- Also, prepTNM staging will be estimated as described mon hepatic and splenic artery). In the chest, at least earlier [16]. Tumour regression grade (TRG) will be the right paratracheal, subcarinal and para- determined according to the modified Mandard classifi- oesophageal lymph nodes should be harvested. cation (TRG 1 to 4) [14]. Noordman et al. BMC Cancer (2018) 18:142 Page 6 of 12 Fig. 3 Expected distribution of patients. nCRT: neoadjuvant chemoradiotherapy; CRE: clinical response evaluation; S1: first surveillance evaluation; S2: second surveillance evaluation etc. Treatment allocation*: randomisation will be performed at institutional level and will be known already at the moment of inclusion; immediate surgery arm of randomisation not shown Centralised multidisciplinary tumour board instance the intensity of a hotspot on 18F–FDG PET-CT During CRE-I and CRE-II, positive (cyto)histology is substantially increases over time during surveillance but preferably available when offering a patient surgical positive (cyto)histology cannot be obtained, the MTB resection. However, during active surveillance we do can decide to recommend surgery. allow a centralised multidisciplinary tumour board (MTB, Erasmus MC) to recommend surgical resection Follow-up in selected patients who have a high clinical / diagnostic Follow-up visits of patients in both study arms will occur at suspicion of tumour regrowth, despite repeatedly nega- 6, 9, 12, 16, 20, 24, 30, 36, 48 and 60 months after comple- tive (cyto)histology. This centralised MTB will monitor tion of nCRT. Additional visits will be scheduled if com- and decide on all such suspected patients from all par- plaints will arise before the next visit. In cases of suspected ticipating centres. The reason for offering surgical resec- recurrence, thoraco-abdominal CT, PET-CT and/or upper tion in patients with a (strong) clinical suspicion of gastrointestinal endoscopy will be performed. In order to regrowth, but without positive (cyto)histology is to min- accurately compare distant dissemination rates between imise the risk that a difficulty in confirming regrowth by both treatment arms, 18F–FDG PET-CT scan will be per- histology causes a delay that will permit a tumour re- formed in all patients in the standard surgery arm after 1 growth to expand into an irresectable stage. If for and 2 years of follow-up, after which most (> 80% and > Noordman et al. BMC Cancer (2018) 18:142 Page 7 of 12 90%, resp.) distant metastases will likely have been detected – Postoperative morbidity; postoperative in-hospital [17]. If a patient in the active surveillance will undergo post- mortality in all patients in the active surveillance poned oesophagectomy due to a locoregional regrowth arm, proportion of all patients in the active surveil- without distant metastases, follow-up will be performed ac- lance arm with hospital stay > 60 days or who de- cording to the Dutch Guideline for oesophageal cancer [18]. velop postoperative trachea-neo-oesophageal fistula; – Proportion of all patients in the active surveillance Study parameters/endpoints arm that develop distant dissemination after 1 and 2 The main study parameter in this study is overall sur- years of follow-up. vival of patients with cCR at CRE-II (i.e. 10–14 weeks after completion of nCRT). Secondary study parameters If outcomes of one or more of these parameters in the include: active surveillance arm significantly exceed the outcomes in the standard surgery arm or in the Dutch Upper-GI – The percentage of patients in the active surveillance Cancer Audit (DUCA) data 2016, all participating cen- arm who do not undergo surgery (i.e. patients who tres will be notified immediately and further inclusion are cured by nCRT or who have occult distant will be stopped [24]. Patients who have been already in- metastases during initial staging, which become cluded will be informed and offered the possibility of im- manifest during active surveillance); mediate (high-priority) surgical resection, even in the – HRQOL as measured with EQ-5D [19], QLQ-C30 absence of suspicion of regrowth. Continuation of active [20], QLC-OG25 [21] and Cancer Worry Scale [22] surveillance will also still be offered. questionnaires; – Clinical irresectability (cT4b) rate; R -resection rate Statistical analysis defined as percentage of patients within the entire Sample size calculation randomised population who undergo resection, In the present phase-III study, we plan to randomise at defined as a tumour-free resection margin; institutional level 300 patients with cCR during CRE-II – Postoperative morbidity/complications for all between active surveillance and standard surgical resec- randomised patients with cCR who undergo tion. Simulation of trial outcomes with expected equal resection, as defined by the Esophageal 3-year overall survival rates of 67% in both trial arms Complications Consensus Group [23]; and an intra-correlation coefficient of 0.02 to account – Postoperative mortality for all patients with cCR for between-institution variation (inter-quartile range for who undergo resection, defined as 90 day- and/or 3-year overall survival rates of 63%–71%) indicates a in-hospital mortality; total sample size of 264 patients to show non-inferiority – Progression-free survival, defined as the interval of surveillance to standard surgery with 80% power [25]. between randomisation and the earliest occurrence Non-inferiority is defined as a 3-year survival rate that is of disease progression resulting in primary (or no more than 15 percentage points below the expected peroperative) irresectability of disease, locoregional 67% 3-year survival rate among patients in the standard regrowth (after completion of therapy); surgery arm (data based on the CROSS-trial) [3, 4]. To – Distant dissemination rate; allow for a 12% drop-out (e.g. patients in the active – Cost-effectiveness. surveillance-arm who request immediate surgery in the absence of clinically proven or suspected regrowth) 300 Safety and stopping rules patients are required for randomisation. Based on pre- Delaying surgical resection in patients in the active sur- liminary data from the current preSANO-trial, we veillance arm should neither lead to a significant reduc- expect that 50% of all included patients will have cCR tion in tumour resectability and radical resection rate, during CRE-II, leading to a total required inclusion of nor to a significant increase in postoperative mortality 600 patients. and distant dissemination rate. Therefore, the following To reduce the number of newly included patients and parameters are closely monitored; to optimally use the data from the preSANO-trial, all recently (≥ May 2015) included patients with cCR during – Proportion of all patients in the active surveillance CRE-II from the current preSANO-trial who underwent arm that present with an irresectable or incurable bite-on-bite biopsies during CRE-I and CRE-II will be (T4b or R2) regrowth, in the absence of distant included in the control arm (n = 60 patients). Assuming metastases; a 50% cCR rate, the total number of required patients to – Proportion of all patients in the active surveillance be newly included in the SANO-trial will drop from 600 arm that undergo a microscopically non-radical (R1) to 480 patients. Consequently, patients with cCR are resection; randomised at an institutional level in a 3:5 ratio. Noordman et al. BMC Cancer (2018) 18:142 Page 8 of 12 No interim analyses are planned for survival outcomes. locoregional regrowth, [ad 3] the performance of delayed surgery or [ad 4] the detection of distant metastases). The project leader (JL) is responsible for the study Data analysis design and conduct of the trial, for the preparation of The difference in survival over a 3-year horizon between the protocol and revisions and for preparation of case the control arm and the experimental treatment arm will report forms. Revisions of the study protocol will be be analysed with a mixed-effects Cox regression model. communicated to all local chief investigators. The Clin- Use of a mixed regression model – including an ical Trial Centre (CTC) of the Erasmus MC – Univer- institution-level random effect – is required to capture sity Medical Centre Rotterdam is responsible for the the potential between-institutional variation in survival data master file, data verification and randomisation. [26]. To correct for potential selection bias, the treat- Randomisation will be performed via a computer- ment effect will be estimated with adjustment for prog- generated random numbers sequence. Data will be nostic factors for survival, i.e. age, sex, histologic subtype collected using individual trial case numbers on stan- of tumour, clinical N stage, and WHO performance dardised case report forms collated centrally by the score. We will also use the mixed-effects Cox regression CTC. Patients will not be individually identifiable. The model to study potential differences in treatment effect final dataset will be available to all study investigators between subgroups of patients. Subgroups are prede- but will not be analysed per centre. Authorships will be fined according to age, sex, histologic subtype of tumour, defined following the International Committee of Med- clinical N stage, and WHO performance score. HRQOL ical Journal Editors guidelines [27]. Results will be com- data will be analysed according to the EuroQol, EORTC municated via international conferences, via publications and Cancer Worry Scale scoring manuals [19–22]. Re- and via the NTR. peated measurement analysis will be used to evaluate within and between group differences. Data will be ana- lysed following the intention-to-treat principle, including Discussion protocol deviators. A per protocol analysis will be per- Trials comparing surgical and non-surgical treatment formed as a secondary analysis. modalities often fail due to low accrual if randomisa- tion is at the patient level, which might be explained Ethical and regulatory considerations by patient preferences for an intervention [28–30]. The study has been approved by the medical ethics Therefore, a stepped-wedge cluster design is applied committee of the Erasmus MC (MEC2017–392) and in the present trial [31]. In a stepped-wedge design, has been registered in the Netherlands Trial Register randomisation takes place at the institutional level, (NTR 6803). The study will be conducted according and not at the patient level. Consequently, at the mo- to the principles of the Declaration of Helsinki (10th ment of inclusion patients know which treatment arm version, Fortaleza, 2013) and in accordance with the they will be assigned to, thereby overcoming uncer- Dutch Medical Research Involving Human Subjects tainty about which treatment patients will undergo. Act (WMO) and other applicable guidelines, regula- We expect that this will improve patients’ willingness tions and Acts. In each participating centre, the local to participate. When proven successful, the stepped- coordinating or principal investigator will be respon- wedge design might be used as a new standard for sible for recruitment, data collection, follow-up of comparing surgical with conservative treatments in included patients, completion of case report forms clinical trials. and adherence to the study protocol. The supervising We will include both patients with SCC and pa- physician or any other physician of the multidisciplin- tients with AC, since SCC and AC both respond to ary team will inform subjects about the study and ask nCRT and no statistically significant differential effects for their consent using standard information letters were found in the CROSS-trial. Both patients with and informed consent forms. Both patient information SCC and AC have a substantial pCR rate (49% and letters and informed consent forms are attached as 23% in CROSS respectively) [3]. Moreover, prelimin- separate documents. ary results of the preSANO-trial suggests that residual An independent safety committee will be established disease can be diagnosed with comparable accuracy in to perform on-going safety surveillance and to perform patients with both histological subtypes. interim analyses to assess the safety data and the stop- Furthermore, in combination with the relatively low ping rules as described in “safety and stopping rules”. frequency of toxicity of the CROSS-regimen (91% Each stopping rule will be repeatedly tested when the completed the full nCRT-regimen), the high pCR-rate first 10, 20, 30 and 50 events for that particular stopping supports the use of the relatively low radiation dose rule have occurred (i.e. [ad 1 and 2] detection of of 41.4 Gy [3]. The beneficial effectivity/toxicity ratio Noordman et al. BMC Cancer (2018) 18:142 Page 9 of 12 is the rationale to apply the CROSS-regimen in the Coordinating Investigator SANO-trial, and not a definitive chemoradiotherapy Drs. B.J. Surgery Erasmus MC regimen (≥50 Gy of radiotherapy). The latter could Noordman increase the pCR-rate, but probably at the cost of a Project Leader substantial increase in toxicity and postoperative com- Prof. dr. J.J.B. van Surgery Erasmus MC plications, leading to a less beneficial effectivity/tox- Lanschot icity ratio. It should be noted that postponement of Principal Investigators surgical resection, as will be performed in patients Dr. S.M. Lagarde Surgery Erasmus MC who develop locoregional regrowth in the absence of distant metastases, has been suggested to increase the Dr. B.P.L. Surgery Erasmus MC Wijnhoven incidence of postoperative complications. However, Erasmus MC, Rotterdam this phenomenon has been reported primarily after treatment with high-dose of definitive chemoradio- Dr. K. Biermann Pathology Erasmus MC therapy (so called salvage esophagectomy) in low- Dr. A. van der Medical Oncology Erasmus MC volume centres [32, 33]. The SANO-trial will reveal Gaast whether this also applies to a lower dose of radiother- Dr. E. Ista Implementation Fellow Erasmus MC apy (CROSS regimen) in high-volume centres. Dr. N.C. Krak Radiology Erasmus MC If the SANO-trial shows that active surveillance after Dr. J.J.M.E. Radiotherapy Erasmus MC nCRT for oesophageal cancer leads to non-inferior sur- Nuyttens vival compared to standard oesophagectomy, this organ- Dr. S. Polinder Health Economics Erasmus MC sparing approach could be implemented as a standard of Dr. M.C.W. Gastroenterology Erasmus MC care. Of note, the French ESOSTRATE-trial is also com- Spaander paring active surveillance with standard surgery in Prof. dr. E.W. Public Health Erasmus MC patients with cCR after nCRT. The ESOSTRATE-trial Steyerberg aims to include a total of 300 patients with SCC or AC Dr. R. Valkema Nuclear Medicine Erasmus MC with cCR after nCRT https://clinicaltrials.gov/ct2/show/ Almelo NCT02551458. The primary endpoint is overall survival, Dr. A. Agool Nuclear Medicine Zorggroep Twente as in the SANO-trial. Combining results from the Drs. J. van Baarlen Pathology Lab PON ESOSTRATE-trial and the SANO-trial would lead to more certainty. Recently, we have shown that 54% and Drs. E.M. Radiotherapy Medisch Spectrum Twente Hendriksen 61% of all patients are willing to trade-off 15% and 10% overall survival, respectively, to undergo active surveil- Dr. R. Hoekstra Medical Oncology Zorggroep Twente lance instead of standard surgery [34]. Therefore, the Dr. E.A. Surgery Zorggroep Twente statistical power of the SANO-trial is for a non- Kouwenhoven inferiority margin of 15%; combination with the French Drs. A. van der Gastroenterology Zorggroep Twente ESOSTRATE-trial would reduce this margin to 10%. Linde Hence, the future combination of results with the Amsterdam ESOSTRATE-trial is important to further increase our Dr. A. Bartels- Radiology AVL-NKI knowledge of an active surveillance approach beyond Rutten what we will learn from the SANO-trial only. Dr. J. van Dieren Medical Oncology/ AVL-NKI Gastroenterology Abbreviations Dr. J. van Sandick Surgery AVL-NKI AC: AdenoCarcinoma; cCR: Clinically Complete Response; CRE: Clinical Response Evaluation; CROSS: ChemoRadiotherapy for Oesophageal cancer Dr. P. Pathology AVL-NKI followed by Surgery Study [3]; DUCA: Dutch Upper-GI Cancer Audit; Snaebjornsson EUS: Endoscopic UltraSonography; FNA: Fine Needle Aspiration; Gy: Gray; MEC: Medical Ethics Committee; MTB: Multidisciplinary tumour board; Dr. E. Vegt Nuclear Medicine AVL-NKI nCRT: Neoadjuvant ChemoRadioTherapy; NTR: Netherlands Trial Register; Drs. F.E.M. Radiotherapy AVL-NKI OGD: OesophagoGastroDuodenoscopy; pCR: Pathologically Complete Voncken Response; PET-CT: Positron-Emission Tomography - Computed Tomography; SANO: Surgery As Needed approach in Oesophageal cancer patients; Apeldoorn SCC: Squamous Cell Carcinoma; TNM: Tumour Node Metastasis classification Dr. H. Pathology Gelre Ziekenhuis system; TRG: Tumour Regression Grade; UICC: Union for International Cancer Doornewaard Control; WHO: World Health Organization Drs. G.W. Erkelens Gastroenterology Gelre Ziekenhuis Dr. G.S. Medical Oncology Gelre Acknowledgements Madretsma Ziekenhuis Members of the sano-study group. Noordman et al. BMC Cancer (2018) 18:142 Page 10 of 12 (Continued) (Continued) Dr. E.S van der Surgery Gelre Ziekenhuis Dr. K. van der Gastroenterology Medisch Centrum Zaag Linde Leeuwarden To be determined Nuclear Medicine Dr. J. Nieken Pathology Medisch Centrum Leeuwarden To be determined Radiotherapy Drs. V. Oppedijk Radiotherapy Radiotherapeutisch Instituut Delft Friesland Drs. M.R.J. ten Nuclear Medicine Reinier de Graaf Group Prof. dr. J.P.E.N. Surgery Medisch Centrum Broek Pierie Leeuwarden Drs. R.J. Dallinga Radiology Reinier de Graaf Group Drs. R. Wolf Radiology Medisch Centrum Leeuwarden Dr. J.W.T. Dekker Surgery Reinier de Graaf Group Maasstad Ziekenhuis, Rotterdam Dr. V.O. Dezentjé Medical Oncology Reinier de Graaf Group Dr. P.P.L.O. Coene Surgery Maasstad Ziekenhuis Dr. R.R. de Krijger Pathology Reinier de Graaf Group Dr. I. Al Butaihi Nuclear Medicine Maasstad Ziekenhuis Dr. K.J. Neelis Radiotherapy Reinier de Graaf Group Dr. M. Kliffen Pathology Maasstad Ziekenhuis Drs. R. Quispel Gastroenterology Reinier de Graaf Group Dr. E.M.M. Kuiper Gastroenterology Maasstad Ziekenhuis Eindhoven Dr. E.F. Courrech Radiology Maasstad Ziekenhuis Staal Dr. G.J. Creemers Medical Oncology Catharina Cancer Center, Eindhoven Nijmegen Dr. G.A.P. Surgery Catharina Cancer Center, Dr. M.J.R. Janssen Nuclear Medicine Radboudumc Nieuwenhuijzen Eindhoven Drs. M.H. Radiology Radboudumc Dr. M.C. van der Radiotherapy Catharina Cancer Center, Liedenbaum Sangen Eindhoven Drs. C. van der Pathology Radboudumc Dr. E.J. Schoon Gastroenterology Catharina Cancer Center, Post Eindhoven Dr. S.A. Radema Medical Oncology Radboudumc Dr. D.N.J. Nuclear Medicine Catharina Cancer Center, Wyndaele Eindhoven Prof. dr. C. Surgery Radboudumc Rosman Heerlen Drs. H. Rütten Radiotherapy Radboudumc Dr. J. Buijsen Radiotherapy Maastro Clinic Prof. dr. P.D. Gastroenterology Radboudumc Dr. R.G. Riedl Pathology Zuyderland MC Siersema Drs. W.M.J. Nuclear Medicine Zuyderland MC Tilburg Schreurs Dr. L.V. Beerepoot Medical Oncology Elisabeth Tweesteden Dr. M.N. Sosef Surgery Zuyderland MC Ziekenhuis Dr. L.E. Gastroenterology Zuyderland MC Dr. W.L. Hazen Gastroenterology Elisabeth Tweesteden Oostenbrug Ziekenhuis Drs. F.A.R.M. Medical Oncology Zuyderland MC Dr. J. Surgery Elisabeth Tweesteden Warmerdam Heisterkamp Ziekenhuis Leiden Drs. J.C. van Oord Radiology Elisabeth Tweesteden Ziekenhuis Dr. J.J. Boonstra Gastroenterology LUMC Drs. T. Rozema Radiotherapy Instituut Verbeeten Dr. M. Slingerland Medical Oncology LUMC Dr. I.A.C. Nuclear Medicine Instituut Verbeeten Dr. W.O. de Steur Surgery LUMC Vermeltfoort Dr. I.M. Lips Radiotherapy LUMC Dr. A.A.M. van der Pathology Elisabeth Tweesteden, To be Nuclear Medicine Wurff Ziekenhuis determined To be Radiology determined To be Pathology determined Funding Leeuwarden The preSANO trial is funded by the Koningin Wilhelmina Fonds Kankerbestrijding (KWF, Dutch Cancer Foundation) and ZonMw. Both funding bodies have no role Dr. H. Balink Nuclear Medicine Medisch Centrum in the design of the study and collection, analysis, and interpretation of data and Leeuwarden in writing the manuscript. Dr. W.E. Fiets Medical Oncology Medisch Centrum This trial is financially supported by the Dutch Cancer Foundation (KWF Leeuwarden Kankerbestrijding) and ZonMw. Noordman et al. BMC Cancer (2018) 18:142 Page 11 of 12 Availability of data and materials plus surgery versus surgery alone for oesophageal or junctional cancer Not applicable. (CROSS): long-term results of a randomised controlled trial. Lancet Oncol. 2015;16(9):1090–8. Authors’ contributions 5. De Boer AG, Genovesi PI, Sprangers MA, Van Sandick JW, Obertop H, Van BN participated in the study design and drafted the manuscript. JB, PC, JD, Lanschot JJ. Quality of life in long-term survivors after curative transhiatal MD, AG, JH, EK, GN, JP, CR, JS, MJS, MNS, MCS, RV, EZ and ES participated in oesophagectomy for oesophageal carcinoma. Br J Surg. 2000;87(12):1716–21. the study design and critically revised the manuscript. BW and SM initiated 6. Djarv T, Lagergren J, Blazeby JM, Lagergren P. Long-term health-related the trial and critically revised the manuscript. JL initiated the trial and quality of life following surgery for oesophageal cancer. Br J Surg. 2008; supervised the drafting of the manuscript. All authors read and approved the 95(18581441):1121–6. final manuscript and agree to be accountable for all aspects of the work. 7. Scarpa M, Valente S, Alfieri R, Cagol M, Diamantis G, Ancona E, et al. Systematic review of health-related quality of life after esophagectomy for Ethics approval and consent to participate esophageal cancer. World J Gastroenterol. 2011;17(42):4660–74. The study has been approved by the medical ethics committee of the 8. Noordman BJ, Verdam MGE, Lagarde SM, Hulshof MCCM, Van Hagen P, Van Erasmus MC (MEC2017–392). Written, voluntary, informed consent to Berge Henegouwen MI et al. Impact of neoadjuvant chemoradiotherapy on participate in the study will be obtained from participants. Individual patient health related quality of life in esopageal or junctional cancer: results from data will not be made available. the randomized CROSS trial. In press, J Clin Oncol. 2017. 9. Noordman BJ, Verdam MGE, Lagarde SM, Shapiro J, Hulshof MCCM, Van Consent for publication Berge Henegouwen MI et al. Impact of neoadjuvant chemoradiotherapy on Not applicable. health related quality of life in long-term survivors of esophageal or junctional cancer: results from the randomized cross trial. Submitted for Competing interests publication. Ann Oncol. 2017. https://doi.org/10.1093/annonc/mdx726. The authors declare that they have no competing interests. [Epub ahead of print]. 10. Castoro C, Scarpa M, Cagol M, Alfieri R, Ruol A, Cavallin F, et al. Complete clinical response after neoadjuvant chemoradiotherapy for squamous cell Publisher’sNote cancer of the thoracic oesophagus: is surgery always necessary? J Springer Nature remains neutral with regard to jurisdictional claims in Gastrointest Surg. 2013;17(8):1375–81. published maps and institutional affiliations. 11. Taketa T, Correa AM, Suzuki A, Blum MA, Chien P, Lee JH, et al. Outcome of trimodality-eligible esophagogastric cancer patients who declined surgery Author details after preoperative chemoradiation. Oncology. 2012;83(5):300–4. Department of Surgery, Erasmus MC – University Medical Centre, Suite 12. Taketa T, Xiao L, Sudo K, Suzuki A, Wadhwa R, Blum MA, et al. Propensity- Z-839, P.O. Box 2040 3000, CA, Rotterdam, The Netherlands. Department of based matching between esophagogastric cancer patients who had surgery Gastroenterology, Leiden University Medical Centre, Leiden, the Netherlands. and who declined surgery after preoperative chemoradiation. Oncology. Department of Surgery, Maasstad Hospital, Rotterdam, the Netherlands. 2013;85(2):95–9. Department of Surgery, Reinier de Graaf Group, Delft, the Netherlands. 5 13. 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BMC Cancer – Springer Journals

Published: Feb 6, 2018

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