Optimal Surveillance Strategies for Early-Stage Cutaneous Melanoma Post Primary Tumor Excision: An Economic Evaluation

Background. Consensus on standardized active surveillance or follow-up care by clinicians is lacking leading to considerable variation in practice across countries. An important structural modelling consideration is that self-examination by patients and their partners can detect melanoma recurrence outside of active surveillance regimes. Objectives. To identify candidate melanoma surveillance strategies for American Joint Committee on Cancer (AJCC) stage I disease and compare them with the current recommended practice in a cost-utility analysis framework. Methods. In consultation with UK clinical experts, a microsimulation model was built in TreeAge Pro 2019 R1.0 (Williamstown, MA, USA) to evaluate surveillance strategies for AJCC stage IA and IB melanoma patients separately. The model incorporated patient behaviors such as self-detection and emergency visits to examine suspicious lesions. A National Health Service (NHS) perspective was taken. Model input parameters were taken from the literature and where data were not available, local expert opinion was sought. Probabilistic sensitivity analysis, one-way sensitivity analysis on pertinent parameters and value of information was performed. Results. In the base-case probabilistic sensitivity analysis, less intensive surveillance strategies for AJCC stage IA and IB had lower total lifetime costs than the current National Institute for Health and Care Excellence (NICE) recommended strategy with similar effectiveness in terms of quality-adjusted life years and thereby likely to be cost-effective. Many strategies had similar effectiveness due to the relatively low chance of recurrence and the high rate of self-detection. Sensitivity and scenario analyses did not change these findings. Conclusions. Our model findings suggest that less resource intensive surveillance may be cost-effective compared with the current NICE surveillance guidelines. However, to advocate convincingly for changes, better evidence is required.

Spatial Model to Determine Environment-Based Disease: Leptospirosis Vulnerability Zones in Bantul District, Indonesia

Leptospirosis is a zoonosis caused by Leptospira bacteria, transmitted through skin wounds or mucous with water or soil contaminated with leptospires from animal urine especially rodents. This paper aims to map spatially the distribution of leptospirosis and to determine a model of leptospirosis-vulnerability areas based on environment variables using the Geographic Information System. The method used was making a zoning map based on the scoring and weighting of the environmental risk variables of leptospirosis transmission. The spatial distribution of leptospirosis in Bantul District in 2019 is evenly distributed in each sub district, the most cases were in Bantul, Sewon, Kasihan sub districts. Leptospirosis vulnerability zones in the center and northern region of Bantul District. Intensive surveillance, treatment and control of leptospirosis as an early warning system in focus areas.

Clinical Limitations of Tissue Annexin A2 Level as a Predictor of Postoperative Overall Survival in Patients with Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the second common cause of cancer-related death in Taiwan. Tumor recurrence is frequently observed in HCC patients receiving surgical resection, resulting in unsatisfactory overall survival (OS). Therefore, it is pivotal to identify effective prognostic makers, so that intensive surveillance or adjuvant treatments can be applied to predictively unfavorable patients. Previous studies indicated that Annexin A2 (ANXA2) was an effective prognostic marker in several cancers, including HCC. However, the prognostic value of ANXA2 in Taiwanese HCC patients remains unclear, where a great proportion of patients had chronic hepatitis B with liver cirrhosis. Here, ANXA2 was highly expressed in HCC tissues compared with para-neoplastic noncancerous tissues. Furthermore, high ANXA2 expression in HCC tissues independently predicted shorter OS. In subgroup analysis, however, ANXA2 expression could not effectively predict OS in the following subgroups: female, age > 65 years old, Child–Pugh classification B, hepatitis B virus surface antigen negative or anti-hepatitis C antibody positive, alcoholism, tumor number >1, presence of micro- or macrovascular invasion, absence of capsule, non-cirrhosis and high alpha-fetoprotein. In conclusion, ANXA2 expression in HCC tissues could predict postoperative OS. However, the predictive value was limited in patients with specific clinical conditions.

627 PL11.02 ENSURE: AN INTERNATIONAL MULTICENTRE STUDY EXPLORING WHETHER SURVEILLANCE AFTER ESOPHAGEAL CANCER SURGERY IMPACTS ONCOLOGICAL AND QUALITY OF LIFE OUTCOMES

Although established and emerging therapies for recurrent esophageal cancer (EC) may impact on survival and health related quality of life (HR-QL), surveillance protocols after the primary curative treatment of EC are varied and inconsistent, reflecting a limited evidence-base to guide an optimum approach. Specifically, whether advantages exist for an intensive surveillance protocol is unknown and was the focus of this study. Methods ENSURE was an international multicentre observational study of consecutive patients undergoing surgery with curative intent for esophageal and junctional cancers (2009–2015) across 20 European and North American centers (NCT03461341). Intensive surveillance (IS) was defined as routine annual CT/PET-CT during the first three postoperative years, and compared with standard surveillance (SS) with investigation as clinically indicated. The primary outcome measure was overall survival (OS), secondary outcomes included treatment, disease-specific survival (DSS), disease-free survival (DFS), recurrence pattern, and HR-QL. Multivariable linear, logistic and Cox proportional hazards regression analyses were performed to determine the independent impact of surveillance on oncologic outcomes and HR-QL. Results 4,682 patients were studied, 45.5% underwent IS. At median follow-up of 60 months, 47.5% developed recurrence; oligometastatic in 39% of cases, with 31% receiving best supportive care, 60% chemotherapy and/or radiation, and 8% surgical resection. IS was associated with reduced symptomatic recurrence (OR0.17 [0.12–0.25]), increased tumor-directed therapy (OR2.09 [1.58–2.77]), and improved OS (HR0.90 [0.82–0.98], 5-year OS 47.9 ± 1.2% versus 43.2 ± 1.1%). On multivariable analysis, significantly improved OS with IS was maintained for patients who underwent surgery alone (HR0.60 [0.47–0.78]) and in those with lower pathological (y)pT stages (Tis-2, HR0.72 [0.58–0.89]). IS was associated with greater anxiety (P = 0.016), but similar overall HR-QL. Conclusion These data suggest that IS may improve oncologic outcomes, particularly in patients with early stage disease at presentation or with a favorable pathological stage post induction therapy. This may be relevant to guideline development and provide a framework and rationale for RCTs. It may also inform shared decision-making with patients at a time where therapeutic options for recurrence are expanding.

546 INTENSIVE SURVEILLANCE AFTER CURATIVE INTENT SURGERY FOR ESOPHAGEAL CANCER: INITIAL RESULTS OF THE ENSURE STUDY

Emerging data demonstrate long-term survival after salvage interventions for local or oligometastatic recurrence after planned curative resection for esophageal cancer, providing rationale for postoperative surveillance. However, the impact of intensive surveillance on oncologic outcome is unknown. This multicenter collaborative study aimed to characterize oncologic surveillance protocols across esophageal cancer centers internationally and determine the independent effect of intensive surveillance on oncologic outcome. Methods The ENSURE international multicenter study included consecutive patients who underwent surgery with curative intent for cTxNxM0 esophageal cancer from June 2009 to June 2015. Intensive surveillance was defined as use of cross-sectional imaging, at least annually, during the first three postoperative years. The estimated sample size of 4425 provided 90% power to detect a 5% increase in 5-year overall survival (OS, primary outcome measure). Secondary outcome measures included disease-free (DFS) and disease-specific survival (DSS), surveillance strategies, incidence of oligometastatic recurrence, treatment strategies, and HRQOL. The study was registered on ClinicalTrials.gov (NCT03461341). Results 4597 patients were included. The participating 27 centres undertook mean(SD) 52.3(17.1) esophageal cancer resections annually between 3.5 ± 1.3 attending surgeons. 37%, 11% and 19% centers utilized postoperative surveillance CT, PET-CT and endoscopy, respectively. Among all patients, intensive surveillance was associated with improved OS (HR0.92 [0.85–0.99]) but not DSS (HR0.93 [0.85–1.01]) or DFS (HR0.97 [0.90–1.04]), and on multivariable analysis, intensive surveillance did not provide oncologic benefit (OS HR1.10 [0.99–1.22], DSS HR1.12 [1.00–1.25]), but reduced observed DFS (HR1.19 [1.08–1.31]). Evaluating surveillance modalities, neither surveillance endoscopy nor laboratory tests improved oncologic outcome, however flexible nasolaryngoscopy was associated with improved OS (HR0.84 [0.69–1.0]). Conclusion ENSURE, the first study powered to assess the impact of postoperative surveillance protocols on oncologic outcome in esophageal cancer, demonstrated no overall survival benefit following intensive imaging surveillance, with reduced observed disease-free survival time. However, routine assessment for secondary aerodigestive malignancies may be of oncologic benefit. The present data do not support the use of intensive imaging surveillance among all patients following esophageal cancer surgery. Further reports detailing subgroup analyses and HRQOL impact are anticipated.

Intensive surveillance endoscopy for multiple gastrointestinal tumors in a patient with constitutional mismatch repair deficiency: case report

Background Constitutional mismatch repair deficiency (CMMRD) is an extremely rare autosomal recessive hereditary disease characterized by the absence of mismatch repair gene activity from birth, which results in brain tumors, colonic polyposis, gastrointestinal cancers, and lymphomas later in life. An aggressive approach, including colectomy or proctocolectomy, is recommended for the treatment of colorectal cancer. Additionally, partial colectomy with subsequent endoscopic surveillance may be an alternative strategy due to poor patient’s condition, although there is no evidence of surveillance endoscopy after partial colectomy for CMMRD. Case presentation A 13-year-old male patient with a history of T-lymphoblastic lymphoma underwent total gastrointestinal endoscopy, which revealed rectal cancer, colorectal polyposis, and duodenal adenoma. Differential diagnosis included constitutional mismatch repair deficiency according to its scoring system and microsatellite instability, and subsequent germline mutation testing for mismatch repair genes confirmed the diagnosis of constitutional mismatch repair deficiency based on a homozygous mutation in mutS homolog 6 (MSH6). The patient and his family refused colectomy due to the high risk of malignancies other than colorectal cancer, which could require radical surgery. Therefore, the patient underwent low anterior resection of the rectosigmoid colon for rectal cancer and intensive surveillance endoscopy for the remaining colon polyposis. During the 3-year period after initial surgery, 130 polyps were removed and the number of polyps gradually decreased during 6-months interval surveillance endoscopies, although only one polyp was diagnosed as invasive adenocarcinoma (pT1). Conclusions Our experience of short surveillance endoscopy illustrates that this strategy might be one of options according to patient’s condition.

ENSURE: An international multicenter study exploring whether surveillance after esophageal cancer surgery impacts oncological and quality-of-life outcomes.

4032 Background: Although established and emerging therapies for recurrent esophageal cancer (EC) may impact on survival and health related quality of life (HRQL), surveillance protocols after the primary curative treatment of EC are varied and inconsistent, reflecting a limited evidence-base to guide an optimum approach. Specifically, whether advantages exist for an intensive surveillance protocol is unknown and was the focus of this study. Methods: European iNvestigation of SUrveillance after Resection for Esophageal cancer (ENSURE) is an international multicenter retrospective observational study of consecutive patients undergoing surgery with curative intent for esophageal and gastroesophageal junction cancers (2009 – 2015) across 20 European and North American cancer centers (NCT03461341). Intensive surveillance (IS) was defined as routine annual CT/PET-CT along with clinical assessment during the first three postoperative years, and compared with standard surveillance (SS) with investigation as clinically indicated. The primary outcome measure was overall survival (OS), secondary outcomes included treatment administered, disease-specific survival (DSS), disease-free survival (DFS), recurrence pattern, and HRQL. Multivariable linear, logistic and Cox proportional hazards regression analyses were performed to determine the independent impact of surveillance on oncologic outcomes and HRQL. Results: 4,682 patients were studied (72.6% adenocarcinoma, 69.1% neoadjuvant therapy). 45.5% underwent IS. At a median follow-up of 60 months, 47.5% developed disease recurrence. Oligometastatic recurrence occurred in 39% of cases, with 31% receiving best supportive care, 60% chemotherapy and/or radiation, and 8% surgical resection. IS was associated with reduced symptomatic recurrence (odds ratio [OR] 0.17 [0.12–0.25]), increased tumor-directed therapy (OR 2.09 [1.58–2.77]), and improved OS (HR 0.90 [0.82–0.98], 5-year OS 47.9±1.2% versus 43.2±1.1%). After adjusting for confounders, significantly improved overall survival with IS was maintained for patients who underwent surgery alone as initial therapy (HR 0.60 [0.47–0.78]) and in those with lower pathological (y)pT stages (Tis-2, HR 0.72 [0.58–0.89]). IS was associated with greater anxiety ( P= 0.016), but similar overall HRQL. Conclusions: These data suggest that IS may improve oncologic outcomes, particularly in patients with early stage disease at presentation or with a favorable pathological stage post induction therapy. This may be relevant to guideline development and provide a framework and rationale for RCTs. It may also inform shared decision-making with patients at a time where therapeutic options for recurrence are expanding.

Symptomatic Metastases have Poorer Prognosis in Breast Cancer Patients Under Intensive Surveillance

Purpose The purpose of this study was to investigate risk factors for post-metastasis overall survival (PMOS), and to analyze the effect of early detection of distant metastases before symptoms occur on survival in breast cancer patients under intensive surveillance.Methods A total of 7,840 patients underwent surgery for breast cancer from January 2010 to December 2014 at Samsung Medical Center; of these, we retrospectively studied 316 metastatic breast cancer patients. The patients were divided into two groups based on method of metastases detection, routine surveillance without symptoms (asymptomatic group) or follow-up for new-onset symptoms (symptomatic group).Results Multivariate analysis of PMOS showed that the patients with multiple metastases had a 1.872 fold risk of PMOS (p = 0.011) compared to the patients with bone metastasis only. The hazard ratio for the symptomatic group was higher than that for the asymptomatic group (p < 0.001). When patients were stratified by tumor subtype, patients who were HR-positive and asymptomatic on diagnosis of distant metastasis had a better prognosis than those who were HR-positive and symptomatic on diagnosis. However, patients who were HER2-positive showed no significant survival difference between two groups.Conclusion Breast cancer patients who were diagnosed with distant metastasis after symptoms occurred had a poorer prognosis than patients who were diagnosed before symptoms had developed. It is important to follow up patients regularly for symptoms related to distant metastases. Our findings validate the need for intensive surveillance, suggesting reconsideration of the guidelines for metastases screening in breast cancer patients.

Intensity of metastasis screening and survival outcomes in patients with breast cancer

Previous randomized trials, performed decades ago, showed no survival benefit of intensive screening for distant metastasis in breast cancer. However, recent improvements in targeted therapies and diagnostic accuracy of imaging have again raised the question of the clinical benefit of screening for distant metastasis. Therefore, we investigated the association between the use of modern imaging and survival of patients with breast cancer who eventually developed distant metastasis. We retrospectively reviewed data of 398 patients who developed distant metastasis after their initial curative treatment between January 2000 and December 2015. Patients in the less-intensive surveillance group (LSG) had significantly longer relapse-free survival than did patients in the intensive surveillance group (ISG) (8.7 vs. 22.8 months; p = 0.002). While the ISG showed worse overall survival than the LSG did (50.2 vs. 59.9 months; p = 0.015), the difference was insignificant after adjusting for other prognostic factors. Among the 225 asymptomatic patients whose metastases were detected on imaging, the intensity of screening did not affect overall survival. A small subgroup of patients showed poor survival outcomes when they underwent intensive screening. Patients with HR-/HER2 + tumors and patients who developed lung metastasis in the LSG had better overall survival than those in the ISG did. Highly intensive screening for distant metastasis in disease-free patients with breast cancer was not associated with significant survival benefits, despite the recent improvements in therapeutic options and diagnostic techniques.