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

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:

1. 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. 2. 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). 3. Incremental cost per quality adjusted life year (QALY)

• Disease-specific mortality [Time frame: 36 months post randomisation]
• Pattern of recurrence [Time frame: 36 months post randomisation]
• Treatment of recurrence [Time frame: 36 months post randomisation]
• Oligometastatic recurrence as determined using the OligoMetastatic Esophagogastric Cancer (OMEC) classification system [Time frame: 36 months post randomisation]
• Multimetastatic recurrence [Time frame: 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 [Time frame: 36 months post randomisation]
• Cost effectiveness as determined by incremental cost per quality adjusted life year [Time frame: 36 months post randomisation]
• Fear of cancer recurrence as determined by the cancer worry scale score [Time frame: 36 months post randomisation]