The results of the TOTEM study do not show any improvement in overall survival (OS) and in early detection of relapses for patients surgically treated for endometrial cancer and followed with a 5-year intensive regimen of follow-up, independently from their risk of relapse. Based on findings from this large, randomised, pragmatic, multicentre study, there is no reason to routinely add vaginal cytology, laboratory, or imaging investigations to the minimalist follow-up regimen used in the study. The results add robust evidence to reinforce the existing trend in guideline recommendations to encourage a minimalist follow-up, including scheduled clinical visits and chest, abdomen, and pelvic computed tomography in the first two years in high-risk patients. The findings are published by Dr. Elisa Piovano of the AOU Città della Salute e della Scienza di Torino, Ospedale Sant’Anna in Torino, Italy and the TOTEM Collaborative Group on 20 July 2022 in the Journal of Clinical Oncology.
The authors wrote in background that endometrial cancer is the most common gynaecological cancer in Europe. The population 5-year relative survival is 76%, and the early diagnosis explains this relatively high survival rate. According to current guidelines, after treatment, patients are followed for 5 years with hospital visits every 3-4 months in the first 2 years and every 6-12 months for up to 5 years. However, the follow-up requires a considerable investment of clinical resources, although there is a scarcity of evidence supporting the effectiveness of follow-up in either improving survival or quality-of-life (QoL). Furthermore, adherence to the guidelines is low. Intensive follow-up regimens are widely adopted at least in Southern Europe.
A few randomised controlled studies have been published in this setting, dealing with the reduction of the number of the scheduled visits and with the setting of the follow-up, but never investigating the impact of routine serum, cytological or imaging investigations in improving OS, or QoL. In the absence of clear evidence from randomised studies, the intensity of follow-up regimens after surgical treatment of endometrial cancer is highly variable in clinical practice. To reduce this uncertainty, the study team conducted a randomised study to test whether an intensive versus a minimalist follow-up regimen improves OS in patients undergoing operation for endometrial cancer.
The TOTEM study was conducted in 42 hospitals in Italy and France among surgically treated patients for endometrial cancer, in complete clinical remission, International Federation of Gynecology and Obstetrics stage I-IV. After stratification by centre and risk of relapse (low- or high-), patients were randomly assigned 1:1 to intensive or minimalist hospital-based follow-up regimens. The study was powered to demonstrate an absolute improvement of 5% of the 5-year OS with the intensive regimen.
In total, 1,871 patients were randomly assigned between November 2008 and July 2018, and 1,847 patients (98.7%) were available for the final analysis of whom 60% with low-risk. After a median follow-up of 69 months, the 5-year OS was 90.6% in the intensive and 91.9% in the minimalist arms (hazard ratio [HR] 1.13, 95% confidence interval [CI] 0.86 to 1.50, p = 0.380). No differences in OS were found in subgroup analyses considering age, treatment, risk of relapse, and degree of adherence of the centre to the scheduled follow-up. The probability of detecting a relapse was slightly higher in the intensive arm (HR 1.17, 95% CI, 0.92 to 1.48; p = 0.194).
The authors commented that major strengths of their study are its large sample size with a long follow-up. An important feature of this study is its representativeness of the real population. However, a certain degree of underrepresentation of non-endometrioid histology and misclassification of the risk of relapse cannot be excluded, especially for the possible inclusion in the low-risk group of some patients with mutated p53, an unfavourable prognostic factor not known when the TOTEM study was conceived.
The authors concluded that the TOTEM study clearly showed that intensive follow-up in surgically treated endometrial cancer does not improve OS, even in high-risk patients. These study findings have a high degree of statistical robustness and transferability to clinical practice.
The study was supported by the Regional Oncology Network of Piemonte e Valle d’Aosta.
Zola P, Ciccone G, Piovano E, et al. Effectiveness of Intensive Versus Minimalist Follow-Up Regimen on Survival in Patients With Endometrial Cancer (TOTEM Study): A Randomized, Pragmatic, Parallel Group, Multicenter Trial. JCO; Published Online 20 July 2022. DOI:10.1200/JCO.22.00471