For statistical analysis, SPSS version 13 (SPSS Inc, Chicago, IL) was used for computations.
The time from primary treatment to death or last observation was defined as overall survival. The time from primary treatment to the detection of the first confirmed recurrence was defined as disease-free interval. The interval from the last radical treatment to the detection of recurrence was named time to recurrence. The time from detection of the first recurrence to death or last observation was defined as survival after recurrence. Prognostic variables included FIGO stage, histological type, tumor grade, lymphonodal involvement, myometrial infiltration, positive cytologic examination result, time to recurrence, site of recurrence, number of recurrence sites, symptoms at recurrence, and treatment of recurrence. Survival analyses were performed according to the Kaplan-Meier product-limit method. The log-rank test was used to compare the homogeneity of survival functions across strata defined by categories of prognostic variables. A multiple regression analysis based on the Cox proportional hazard model was used to jointly test the relative importance of variables as predictors of survival times from diagnosis and recurrence disease.
Patients’ characteristics at diagnosis are reported in Table 3. A total of 282 patients with endometrial cancer were enrolled into our retrospective study. The mean age of the study population was 63 years (range, 40–86 years). Patients had a mean follow-up of 49 months (range, 4–237 months), with a median survival time of 59 months (range, 32–85 months). One hundred seventy-four (61.7%) of the 282 patients had a diagnosis of stage I to II endometrial cancer, whereas 108 patients (38.3%) had stage III to stage IV endometrial cancer. In 5 patients (1.8%), clinical stage was unknown. Clinicopathological characteristics of the patients at primary diagnosis are summarized in Table 3.
As far as the symptom at recurrence is concerned, patients were classified as asymptomatic or symptomatic at the time of recurrence detection. One hundred seventeen patients (41.5%) who developed a recurrent disease were symptomatic at the time of detection, whereas 165 patients (58.5%) did not present any symptom.
In Table 4, the distribution of relapses by symptoms at diagnosis is shown in detail.
Regarding the number of relapses, 153 (54.3%) were single and 129 (45.7%) were multiple.
As we stated previously, patients were in addition classified according to the presence of symptoms at the time of recurrence: (a) 80 (28.4%) of the 282 patients were symptomatic and anticipated the scheduled visit, (b) 37 patients (13.1%) reported their symptoms during the follow-up meeting, and (c) 165 (58.5%) were asymptomatic, and the diagnostic path was introduced by a planned visit or examination.
Between the asymptomatic patients, the first procedure advocated to set off the diagnostic procedure was clinical visit alone for 60 (36.4%) of the 165 patients, imaging for 103 patients (62.4%), and cytologic examination for 2 patients (1.2%). Imaging procedures are reported in Table 5.
A Cox proportional hazard logistic regression analysis was performed in univariate and multivariate settings. As shown in Table 6, some factors result to predict survival. Survival hazards from both primary diagnosis and recurrent disease are reported to account for length time bias. Grade (1 + 2 vs 3: median survival time, 33.0 vs 15.0 months, respectively; P = 0.005), myometrial invasion (1 + 2 vs 3: median survival time, 34.0 vs 14.0 months, respectively; P = 0.002), histotype (endometrioid vs others: median survival time, 33.3 months vs 16.0 months, respectively; P = 0.008), risk of recurrences (based on grade and myometrial invasion: low vs high, respectively), number of recurrences (single vs multiple: median survival time, 41.7 vs 10.7 months, respectively; P = 0.016), site of relapse (vaginal vs other sites: median survival time not reached—mean, 119 vs 21.0 months, respectively; P = 0.0001), relapse treatment (surgery alone vs other: median survival time, 82.3 vs 9.2 months, respectively; P = 0.0001) are able to predict survival from recurrent disease.
Symptoms at recurrence are able to predict survival as we can see from Table 6; patients with an asymptomatic recurrence had a median survival time from relapse of 35 months versus 13 months if they had a symptomatic repetition (P = 0.0001; Fig. 1).
This result was confirmed at a multivariate level as shown in Table 6. Risk of recurrences, site of relapse, and symptoms at recurrence retained their value at multivariate analysis being independent predictors of both survival from the first diagnosis and survival after recurrences.
For patients with endometrial cancer treated with curative intent, it is not proven whether intensive follow-up is associated with survival benefit, and it is not clear what constitutes the optimal follow-up regimen. There is a lack of consensus as to how the surveillance methods may be combined to provide a cost-effective follow-up protocol. The intensity and the length of follow-up strategies and how they may change with the progression of time are difficult parameters to agree upon. These follow-up programs include frequent visits and performance of blood CA125, chest x-rays, abdominal and pelvic imaging, and Papanicolaou test. It is not clear which tests or frequency of visits is optimal to maximize the outcomes for these patients.
Testa et al9 prospectively analyzed the role of routine transabdominal and transvaginal sonographic examination in the detection of recurrent disease in gynecological cancer. The analysis of 385 patients documented positive ultrasound (US) examinations in 83 (21.5%) of the 385 patients. These recurrences were all confirmed with positive clinical examination and positive results at CT/magnetic resonance imaging. In the subgroup of patients who had negative clinical examination results and normal tumor marker levels, US showed a positive predictive value of 100% and a negative predictive value of 99.6%. These authors suggested that routine US might play a role in the follow-up of gynecologic malignancies, especially in the group of asymptomatic patients.10
In our study, US examination led to detection of 13.9% of recurrence lesions in asymptomatic patients.
In the group of patients with asymptomatic recurrence, CT scan was the most sensitive method for detecting new lesions (70 cases [43.0%]). Most recurrences were detected by imaging methods.
Different results are presented in the literature: CT scan has been reported to detect 5% to 20.8% of asymptomatic recurrences in patients with endometrial cancer.11,12
About sites of relapses, Morice et al13 in their series showed that distant metastases were more frequent than local recurrences. Aalders et al14 in their retrospective study of 379 patients found local disease in 50% of the patients, distant disease in 28%, and simultaneous local and distant relapse in 21%.
Accordingly, in our study, we observed 40.6% of local endometrial cancer recurrences and 32.5% of distant relapses. This is probably due to different adjuvant treatment among the 8 centers of the study group. About asymptomatic recurrences, physical examination alone led to the detection of 70% of local relapses.
Some authors showed that vault cytology does not contribute to early detection of recurrent disease and, therefore, there is no clinical justification for routine Papanicolaou test in the follow-up of endometrial cancer.4,15 On the other hand, Cooper et al16 and Bristow et al17 reported that Papanicolaou test identified isolated vaginal recurrence in 13.9% and 18.2% of the cases, respectively. In our study, 2 (8.4%) of 24 asymptomatic patients with vaginal recurrence presented a pathological vaginal vault cytology that led to the diagnosis of recurrent disease. Thus, Papanicolaou tests provided clinically useful information only in 1% of all asymptomatic patients.
In the literature, the role of CA125 in posttreatment surveillance for endometrial cancer is discussed, and there is no evidence to support the real benefit of this test in a follow-up program.18 We did not investigate the role of CA125 monitoring because this test was not used by all the centers and also with a significant different frequency.
Imaging of the chest by plain radiographs is usually included in all intensive follow-up programs. Agboola et al4 concluded in a study that the continuation of routine chest radiographic examinations as part of follow-up may be supportable on economic grounds, since the incremental cost per case detected is small. Treatment options of pulmonary recurrence from endometrial cancer comprise surgical resection, chemotherapy, hormonal therapy, and radiotherapy and resulted to be beneficial to the patients.14,19 Even if those studies considered a limited number of cases, patients who underwent pulmonary resection had a longer median survival than those who did not (overall median survival, 25–50 vs <12 months).14,19
In a review presented by Fung-Kee-Fung et al,2 the 77% of recurrences are associated with symptoms. In our series, a total of 117 patients (41.5%) were symptomatic; among this group of patients, 80 (68.4%) of the 117 patients anticipated the scheduled visit because of the symptoms, and 37 patients (31.6%) reported their symptoms during the follow-up visit. Even if in our series most recurrences were detected at scheduled visits (58.6%), a considerable number of recurrences presented out of context from follow-up visits.
There is a suggestion that efficacy of routine visits and examinations is questionable and it is needed to outline an adequate strategy because improved survival is due to diagnosis of recurrence at an early and asymptomatic stage, which allows for more curative resection of recurrence.
Several authors failed to detect any difference in survival between patients with asymptomatic relapse and those with symptomatic recurrences. Shumsky et al15 showed that there was no statistical difference in survival between the group detected on routine follow-up and those who were detected when they developed symptoms. Both Agboola et al4 and Berchuk et al5 show no difference in survival between patients who present with and without symptoms. With the limits of a retrospective study and the small (17) recurrence analyzed, also Owen and Duncan20 did not find any difference in the survival between cases with symptomatic and asymptomatic recurrences. In our study, we found that symptoms at recurrence are able to predict survival: patients with an asymptomatic recurrence had a median survival time from relapse of 35 months versus 13 months if they had a symptomatic repetition (P = 0.0001; Fig. 1). The diagnostic anticipation allowed by a scheduled follow-up protocol seems to improve the clinical outcome of patients with recurrent disease. However, no firm conclusion can be drawn because of the retrospective design of this study and the differences in surveillance protocols adopted by different centers. We also have to consider the lead-time bias, that is, the diagnostic anticipation simply prolongs the survival time during which the patient is aware of the disease, and the length time bias, that is, patients with slowly progressive disease, are more suitable to be detected by screening tests.
The quality of life and attitudes of patients participating in follow-up programs were investigated in a study by Shumsky et al,15 and results indicated that regular contact with a physician reassured patients and that visits and tests caused only slight anticipatory anxiety and other minor inconveniences. In our retrospective study, quality of life could not be investigated, but it still remains one of the important aims for a future prospective trial.
In summary, there is a lack of evidence on which to create a recommendation for specific follow-up tests and frequency of visits.
In light of the uncertainty of the schedule of visits and tests to be recommended and based on the rate of recurrent disease and on current practices, we suggest the following for the patients who are at high risk of relapse (stage I disease with deep myometrial invasion and poorly differentiation and patients with more advanced stage): prompt assessment for symptoms of potential disease relapse, clinical assessment at least every 4 months for 3 years, and then annually for 3 more years; during those visits, patients may have visit, blood CA125, chest x-rays, and abdominopelvic ultrasound or CT. When recurrences of disease are detected, patients should be assessed by a multidisciplinary oncology team including surgical, radiation, and medical oncologists to determine the best treatment options.
Only prospective randomized trials may assess the real effectiveness of formal guidelines for the follow-up of patients with endometrial cancer after primary treatment.
Patients should be encouraged to participate in clinical trials investigating screening tests added on to their clinical assessment. New prospective studies are needed to asses the best surveillance protocol and to evaluate the potential cost savings associated with eliminating ineffective testing.
Actually, in Italy, the first multicenter randomized trial on endometrial cancer follow-up is open (TOTEM study). The general aim of this study is to compare the effect of 2 follow-up regimens (intensive vs minimalist) on 5-year overall survival and to value the impact of follow-up procedures on the clinical management of patients with endometrial cancer.
1. Jemal A, Siegel R, Ward E, et al.. Cancer statistics, 2009. CA Cancer J Clin. 2009; 59: 225–249.
2. Fung-Kee-Fung M, Dodge J, Elit L, et al.. Follow-up
after primary therapy for endometrial cancer: a systematic review [research support, non–US government review]. Gynecol Oncol. 2006; 101: 520–529.
3. Wylie J, Irwin C, Pintilie M, et al.. Results of radical radiotherapy for recurrent endometrial cancer
[research support, non-US government]. Gynecol Oncol. 2000; 77: 66–72.
4. Agboola OO, Grunfeld E, Coyle D, et al.. Costs and benefits of routine follow-up
after curative treatment for endometrial cancer. CMAJ. 1997; 157: 879–886.
5. Berchuck A, Anspach C, Evans AC, et al.. Postsurgical surveillance of patients with FIGO stage I/II endometrial adenocarcinoma [clinical trial]. Gynecol Oncol. 1995; 59: 20–24.
6. Salvesen HB, Akslen LA, Iversen T, et al.. Recurrence of endometrial carcinoma and the value of routine follow up [research support, non-US government]. Br J Obstet Gynaecol. 1997; 104: 1302–1307.
7. Gordon AF, Owen P, Chien PF, et al.. A critical evaluation of follow-up
of women treated for endometrial adenocarcinoma. J Obstet Gynaecol. 1997; 17: 386–389.
8. Tjalma WA, van Dam PA, Makar AP, et al.. The clinical value and the cost-effectiveness of follow-up
in endometrial cancer patients [review]. Int J Gynecol Cancer. 2004; 14: 931–937.
9. Testa AC, Fruscella E, Ludovisi M, et al.. The role of sonographic examination in the follow-up
of gynecological neoplasms. Gynecol Oncol. 2005; 99: 696–703.
10. Savelli L, Testa AC, Ferrandina G, et al.. Pelvic relapses of uterine neoplasms: transvaginal sonographic and Doppler features. Gynecol Oncol. 2004; 93: 441–445.
11. Gadducci A, Cosio S, Fanucchi A, et al.. An intensive follow-up
does not change survival of patients with clinical stage I endometrial cancer. Anticancer Res. 2000; 20: 1977–1984.
12. Reddoch JM, Burke TW, Morris M, et al.. Surveillance for recurrent endometrial carcinoma: development of a follow-up
scheme. Gynecol Oncol. 1995; 59: 221–225.
13. Morice P, Levy-Piedbois C, Ajaj S, et al.. Value and cost evaluation of routine follow-up
for patients with clinical stage I/II endometrial cancer. Eur J Cancer. 2001; 37: 985–990.
14. Aalders JG, Abeler V, Kolstad P. Recurrent adenocarcinoma of the endometrium: a clinical and histopathological study of 379 patients. Gynecol Oncol. 1984; 17: 85–103.
15. Shumsky AG, Stuart GC, Brasher PM, et al.. An evaluation of routine follow-up
of patients treated for endometrial carcinoma. Gynecol Oncol. 1994; 55: 229–233.
16. Cooper AL, Dornfeld-Finke JM, Banks HW, et al.. Is cytologic screening an effective surveillance method for detection of vaginal recurrence of uterine cancer? [comparative study research support, non-US government]. Obstet Gynecol. 2006; 107: 71–76.
17. Bristow RE, Purinton SC, Santillan A, et al.. Cost-effectiveness of routine vaginal cytology for endometrial cancer surveillance. Gynecol Oncol. 2006; 103: 709–713.
18. Price FV, Chambers SK, Carcangiu ML, et al.. CA 125 may not reflect disease status in patients with uterine serous carcinoma. Cancer. 1998; 82: 1720–1725.
19. Sohaib SA, Houghton SL, Meroni R, et al.. Recurrent endometrial cancer
: patterns of recurrent disease and assessment of prognosis. Clin Radiol. 2007; 62: 28–34; discussion 5–6.
20. Owen P, Duncan ID. Is there any value in the long-term follow-up
of women treated for endometrial cancer? Br J Obstet Gynaecol. 1996; 103: 710–713.
Keywords:Copyright © 2012 by IGCS and ESGO
Recurrent endometrial cancer; Follow-up; Surveillance procedures; Asymptomatic and symptomatic patients