Abstract
Presenting Author Email: [email protected]
Research question
Does intensive postoperative surveillance after planned curative resection for oesophageal cancer lead to increased detection of oligometastatic disease, facilitating increased use of tumor-directed therapy, hence improving overall survival?
Background and aim
Emerging data demonstrate long-term survival after salvage interventions for local or oligometastatic recurrence following planned curative resection for oesophageal cancer, providing rationale for postoperative surveillance. While meta-analyses confirm the survival benefit of chemotherapy (HR0.81, 0.71-0.92), and HER-2 directed therapy (HR0.75, 0.68-0.84) for patients with recurrent or metastatic oesophageal cancer, the effect of surveillance on oncologic outcome and health-related quality-of-life (HRQL) is unknown.
There is currently no international consensus regarding the utility of surveillance following curative-intent treatment for oesophageal cancer, with divergent guidelines from ESMO, AUGIS and NCCN. A pilot study including 27 European centres (ENSURE-1) demonstrated wide variation in practice, with tumour markers, CT and PET-CT utilised in 4 (14.8%), 10 (37.0%) and 3 (11.1%), respectively.
This multicenter collaborative project aims to determine the independent impact of intensive surveillance on recurrence patterns, oncologic outcome, and HRQL in survivorship, providing the first adequately powered study to address this critical research question.
Patients
A retrospective observational study of patients undergoing treatment with curative intent for oesophageal cancer at participating Centers from June 2009 to June 2015.
Inclusion criteria
1. Age 18 years and above
2. Underwent surgery with curative intent for cTxNxM0 esophageal or esophagogastric junction (Siewert type I, II and III) cancer
3. Salvage surgery after failure of primary endoscopic or oncologic treatment will be included
Exclusion criteria
1. Endoscopic therapy or definitive oncological treatment as sole therapy for esophageal cancer
2. Missing follow-up data
Comparator
Outcomes will be compared among patients managed with intensive surveillance (IS) compared with
standard surveillance. IS will be defined as the routine use of CT/PET-CT for surveillance, at least annually, for at least the first three postoperative years. Each participating centre will be classified as undertaking IS or standard surveillance (SS) according to data submitted in the pilot study (ENSURE-1).
Outcomes
The primary endpoint of this study is:
• Overall survival
The secondary endpoints of this study are:
• Disease-specific survival
• Observed disease-free survival
• HRQL
o Prespecified EORTC QLQ-C30, QLQ-OG25 items
• Recurrence patterns and treatment
o Site of disease at initial recurrence
o Oligometastatic disease at initial recurrence
o Anastomotic disease at initial recurrence
o Palliative chemotherapy, chemoradiation and radiation use
o Treatment for oligometastatic and anastomotic recurrence (surgery, radiation,
chemotherapy only)
Study design
Power calculation and sample size
Power calculations are based on Sisic et al. demonstrating a 5% increase in 5-year overall survival with standardized follow-up in a propensity score matched analysis. Based on an initial feasibility survey of 18 Centers, current estimated number of cases per year for enrolled Centers is 885, therefore it is anticipated that the 5-year study period should capture approximately 4425 patients, of whom 31% undergo high intensity surveillance with cross-sectional imaging, with a minimum postoperative follow-up of 3 years. Using a log-rank analysis to detect a 5% difference in overall survival with sigma of 0.05, with 1371 of 4425 patients in the IS group, the study is powered to 90.4%, while accounting for a potential 20% exclusion rate, the study is powered to 83.1% with current enrolled Centers.
Data collection and study definitions
Where possible, data will be collected from prospectively maintained databases at participating Centers. Collected data will be entered into a standardized data collection spreadsheet “ENSURE Study - Datasheet” (attached). Variables will be coded at source by Co-Investigators according to standardized coding. Briefly, collected data will include:
• Demographics
• Co-morbidities and performance status
• Histologic type
• Tumor location
• Clinical stage and grade
• Pathologic stage, grade, treatment response and margins
• Neoadjuvant therapy details
• Operative details
• Overall postoperative morbidity
• Recurrence and associated treatment
• Survival data
• HRQOL
o ENSURE database will be linked to include relevant HRQL data from a previous study (LASER)
Registration
The study has been registered on ClinicalTrials.gov (NCT03461341).
Statistical Approach
Data will be analyzed using SPSS® (v.23.0) software (SPSS, Chicago, IL, USA). For the multivariable analyses, all clinically relevant variables will be inputted into multivariable linear, logistic or Cox proportional hazards regression models.
Team and infrastructure
An international multidisciplinary collaborative team has been assembled via the Young Investigator Group of the European Society for Diseases of the Esophagus for the conduct of this study, with 27 centres signed up to participate in the pilot study to date. The study will be initiated from St. James's Hospital, Dublin, Ireland; the Karolinska Institute, Stockholm, Sweden; and Imperial College London, London, England.
Steering committee:
Jessie Elliott (Dublin), Fredrik Klevebro (Stockholm), Sheraz Markar (London), Lucas Goense (Utrecht), Melody Ni (London – statistician), Pernilla Lagergran (Stockholm – HRQL researcher)
Supervisory committee:
John V Reynolds (Dublin), Magnus Nilsson (Stockholm), George Hanna (London), Giovanni Zaninotto (Padova).
Infrastructure:
A dedicated biostatistician (Dr Melody Ni, Imperial College London) is a collaborator on the current project and will provide expertise with respect to design and data analysis. A researcher with expertise in HRQL assessment (Professor Pernilla Lagergren, Karolinska Institute) is also a named collaborator on the present project.
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