Surveillance After Resection of Oesophageal aNd Gastric Cancer (SARONG-II) Trial

Study Overview
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Brief Summary
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Cancer of the food pipe (oesophagus) and stomach are increasingly common. Currently, most patients with cancer of the oesophagus and stomach are treated with surgery with or without additional chemotherapy or radiotherapy. In recent years there have been improvements in survival from these two cancers, due to better therapies, less invasive surgery and earlier detection. Despite these improvements, in around half of patients treated with surgery, the cancer will return, usually within the first three years. At present there is very little evidence as to how patients who have been treated for cancer of the oesophagus or stomach should be followed up after surgery and whether different methods of follow-up could improve survival. Currently, national and international guidelines do not provide consistency in their recommendations for follow-up after surgery. The SARONG-II study will investigate if regular radiological scans can lead to earlier detection of a cancer returning, at a stage when it may be more readily treatable. This means that participants who agree to take part will be allocated by chance to either more intensive imaging surveillance (including regular radiological scans and a camera test (endoscopy)) or clinical follow-up. The study aims to recruit at least 952 participants in Europe over a 32-month period. Patients undergoing surgery for oesophageal or stomach cancer will be invited to participate in the study at around 4 to 8 weeks after their surgery. (i) The imaging surveillance group will receive a review in clinic or by telephone with a member of the surgical team, and a radiological scan at 6, 12, 18, 24, 30 and 36 months after randomisation. They will also receive endoscopy at 12 months after randomisation (ii) The clinical surveillance group will receive a review in clinic or by telephone at 6, 12, 18, 24, 30 and 36 months. After this they will be either discharged to their local doctor or receive a review in clinic with a member of the surgical team every year according to local practice The main aim of this study will be to determine whether earlier detection of cancer through more intensive follow-up results in improved survival and better quality of life for patients with oesophagus or stomach cancer. The investigators anticipate the results of the study may have significant practice-changing impact for patients undergoing follow-up after surgery for oesophagus and stomach cancer.

Detailed Description
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It is an encouraging trend that the overall survival rate for oesophagogastric cancer has doubled over the last 20 years. For patients with locally advanced disease treated with curative intent, 5 year survival in the modern era approaches 50%. Relevant factors include earlier diagnosis, improvements in staging, and quality improvements in the standard modalities of surgery, chemotherapy and radiation therapy, increasingly delivered in high volume centers. When local or systemic failure occurs, where therapeutic nihilism may have once prevailed, a menu of therapeutic options can now be considered, such as immunotherapy, salvage locoregional surgery, resection of oligometastatic disease, brachytherapy, radiofrequency ablation (RFA) and stereotactic radiation therapy. In the context of this changing landscape and expanded armamentarium, a key question, as yet unresolved, is how patients treated with curative intent should be optimally followed-up. The options include an intensive imaging surveillance approach using clinical assessment, cross-sectional imaging, and endoscopy, or one purely based on symptomatic follow-up to trigger further investigation. The debate for oesophagogastric cancer is limited by a paucity of evidence. This may reflect both a lack of attention to this topic in research, with no RCTs, and relatively poor quality cohort and observational studies with considerable heterogeneity. The approach to surveillance varies considerably internationally. In Japan, a nationwide survey reported that that high intensity surveillance was common, with endoscopic surveillance utilized in over 80% of patients, in contrast to approximately 6% in Australia and New Zealand. In Europe, the European Registration of Cancer Care (EURECCA) Upper Gastrointestinal group reported a brief summary from 10 Centers, and highlighted substantial differences in elements of surveillance, in particular of cross-sectional imaging, which was sought in just 40% of patients. Guidelines also vary, for instance the European Society for Medical Oncology guidelines currently state, With the exception of endoscopic or operative salvage after initial non-operative management, there is no evidence that regular follow-up has an impact on survival outcomes, while the UK NICE guidelines state, for people without symptoms or evidence of residual disease after treatment for oesophagogastric cancer with curative intent, do not offer routine clinical follow-up or radiological surveillance solely for the detection of recurrent disease. It is clear that research is urgently required on this important topic that will inform everyday practice and future guidelines. In this context, a European collaborative multicenter study was established with the primary objective of assessing the current situation in specialist centers internationally and its impact on survival and quality of life. In this study, the investigators first surveyed 27 European centres, and identified marked variation in surveillance practices, with only 37% of centres providing routine radiologic surveillance for detection of recurrence, and only 19% undertaking routine surveillance endoscopy. The investigators then undertook a European multicentre cohort study, which included 4682 patients. At median follow-up 60 months, 47.5% developed recurrence, oligometastatic in 39%. Intensive surveillance, defined as a computed tomography scan undertaken at least annually for three years after surgery, was associated with reduced symptomatic recurrence and increased tumor-directed therapy. On multivariable analysis, no overall survival benefit was observed among all patients (HR1.01 [0.89-1.13]), but overall survival was improved following intensive surveillance for those who underwent surgery alone and those with lower pathological (y)pT stages. Intensive surveillance was associated with similar overall HRQL. This study established that there is widespread heterogeneity in surveillance protocols in Europe, and the vast majority of centres agreed there is a need for an RCT examining this issue. The SARONG-II study is an international multicentre, open-label, two-arm, parallel design, superiority randomised controlled trial. 952 patients (476 in each of two trial arms) will be recruited from approximately 14 sites in Europe. Participants will be randomised to either imaging surveillance every 6 months for 36 months and an endoscopy at 12 months postrandomisation or clinical follow-up for 36 months. Primary Outcome Measure: All-cause mortality defined as death from any cause. Participants who have not been observed to die during the course of the study will have their survival time censored at their last known follow-up date. Secondary Outcome Measures: a) Disease-specific mortality, defined as known oesophageal or gastric cancer recurrence at the time of death. b) Pattern of tumour recurrence, defined as the incidence of loco-regional or distant recurrence. c) Treatment of tumour recurrence, ie. the requirement for chemotherapy, surgery, immunotherapy, radiotherapy, chemoradiotherapy, best supportive care or other as determined by the clinical team at the treating site. d) Rates of oligometastatic (one site) tumour recurrence. e) Rates of multi-metastatic (several sites) tumour recurrence. HRQoL, including anxiety or depression and worry of cancer returning as measured by the following validated questionnaires: EQ- 5D-5L, EORTC QLQ-C30 and QLQ-OG25 and Cancer Worry Scale (CWS). Incremental cost per quality adjusted life year (QALY)

Official Title
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Open Label International Multicentre Randomised Controlled Trial of Intensive Surveillance vs. Standard Postoperative Follow-up in Patients Undergoing Surgical Resection for Oesophageal and Gastric Cancer

Conditions
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Esophageal Cancer, Gastric Cancer

Intervention / Treatment
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* Other: Surveillance protocol


Participation Criteria
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Eligibility Criteria
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A patient will be eligible for inclusion in this study if all of the following criteria apply: Has undergone surgical resection for curatively intended treatment of oesophageal or gastric cancer (adenocarcinoma and squamous cell carcinoma) with or without neoadjuvant/adjuvant chemotherapy or radiotherapy or immunotherapy (or in combination). Aged 18 years or over Willing and able to give informed consent A patient with not be eligible for the trial if any of the following apply: 1. Other cancer(s) undergoing treatment or surveillance

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Imaging surveillance<br>Computed tomography scan every 6 months for 3 years postoperatively. Upper gastrointestinal endoscopy at 12 months postoperatively. | Other: Surveillance protocol<br>* Imaging surveillance will entail a computed tomography scan of the chest, abdomen and pelvis, as well as clinical review, every 6 months for 36 months post surgery along with an endoscopy at 12 months post surgery.<br>|
| No Intervention: Clinical surveillance<br>Clinical review every 6 months for 3 years postoperatively with further investigation according to symptoms. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality | All-cause mortality defined as death from any cause. Participants who have not been observed to die during the course of the study will have their survival time censored at their last known follow-up date. | 36 months post randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-specific mortality | Disease-specific mortality, defined as known oesophageal or gastric cancer recurrence at the time of death. | 36 months post randomisation | 
| Pattern of recurrence | Pattern of tumour recurrence, defined as the incidence of loco-regional or distant recurrence. | 36 months post randomisation | 
| Treatment of recurrence | Treatment of tumour recurrence, ie. the requirement for chemotherapy, surgery, immunotherapy, radiotherapy, chemoradiotherapy, best supportive care or other as determined by the clinical team at the treating site. | 36 months post randomisation | 
| Oligometastatic recurrence as determined using the OligoMetastatic Esophagogastric Cancer (OMEC) classification system | Rates of oligometastatic tumour recurrence | 36 months post randomisation | 
| Multimetastatic recurrence | Rates of multi-metastatic (several sites) tumour recurrence | 36 months post randomisation | 
| Overall quality of life as determined by the global health status using the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire C30 | Using European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire C30, reported as a linear transformed outcome ranging from 0-100. | 36 months post randomisation | 
| Cost effectiveness as determined by incremental cost per quality adjusted life year | Incremental cost per quality adjusted life year (QALY) determined using the 5-level EQ-5D version (EQ-5D-5L) as well as healthcare utilisation costs measured in Euro. | 36 months post randomisation | 
| Fear of cancer recurrence as determined by the cancer worry scale score | Measured from 1-4 | 36 months post randomisation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Surveillance, Cancer recurrence, Quality of life