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Could Different Follow-Up Modalities Play a Role in the Diagnosis of Asymptomatic Endometrial Cancer Relapses?: An Italian Multicentric Retrospective Analysis

Carrara, Luisa MD*; Gadducci, Angiolo MD; Landoni, Fabio MD; Maggino, Tiziano MD§; Scambia, Giovanni MD; Galletto, Luciano MD; Lissoni, Andrea Alberto MD#; Fuso, Luca MD, PhD**; Zola, Paolo MD**; Sartori, Enrico MD*

International Journal of Gynecological Cancer: July 2012 - Volume 22 - Issue 6 - p 1013–1019
doi: 10.1097/IGC.0b013e31825ad3ee
Uterine Cancer

Objective To determine current practice and to assess the value of routine follow-up procedures for endometrial cancer surveillance. To discuss whether such procedures are feasible and effective to identify asymptomatic recurrences and describe the pattern of relapse detected by procedures.

Methods The records of 282 consecutive women with recurrent endometrial cancer treated from 1986 to 2005 were retrospectively collected in 8 Italian institutions. Primary disease, clinical history, and recurrence features and data were analyzed.

Results Thirty-five (12.4%) of 282 patients had recurrence in vaginal vault, 51 patients (18.0%) had recurrence in central pelvis, 14 patients (4.9%) had recurrence in pelvic wall, and 39 patients (13.8%) had recurrence in lymph nodes. One-hundred twenty-eight patients (45.3%) showed a distant relapse, whereas 15 patients (5.3%) developed both distant relapse and local relapse. The site of relapse influenced survival because the patients with vaginal vault recurrences lived significantly longer than the patients with recurrences in other sites. Eighty (28.4%) of the 282 patients became symptomatic and anticipated the scheduled visit, 37 (13.1 %) of the patients reported their symptoms during the follow-up meeting, and 165 (58.5 %) of the patients were asymptomatic and the diagnostic path was introduced by a planned visit or examination. Among the asymptomatic patients, the first procedure that led to further examinations was clinical visit alone for 60 (36.4%) of 165 patients, imaging for 103 patients (62.4%), and cytologic examination for 2 patients (1.2%). Symptoms at recurrence can 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).

Conclusions Follow-up after endometrial cancer treatment varies in Italy. In this retrospective study, women with asymptomatic recurrence have shown a better clinical outcome compared with those with symptomatic relapse. The optimal approach is actually unknown, and guidelines comparing follow-up protocols have not been established. Prospective cost-effectiveness studies are needed.

*Department of Gynecology and Obstetrics, University of Brescia, Brescia; †Department of Gynecology and Obstetrics, University of Pisa, Pisa; ‡European Institute of Oncology, Milan; §Unit of Gynaecology and Obstetrics, Ospedale “Umberto I°”, Venezia-Mestre; ∥Department of Gynecology and Obstetrics, Catholic University of Rome, Rome; ¶Unit of Gynecology and Obstetrics, Ospedale “Edoardo Agnelli”, Pinerolo, Turin; #Unit of Gynecology and Oncology, Ospedale “San Gerardo”, Monza; and **Department of Gynecology and Obstetrics, University of Turin, Turin, Italy.

Address correspondence and reprint requests to Luisa Carrara, MD, Department of Gynecology and Obstetrics, University of Brescia, Spedali Civili Brescia, P.le Spedali Civili 1, 25123 Brescia, Italy. E-mail:

The authors declare that there are no conflicts of interest.

Received March 16, 2012

Accepted April 17, 2012

Endometrial cancer is the most common cancer in women in Western countries, accounting for 6% to 9% of all cancer types in women.1 Most patients with endometrial cancer have their condition diagnosed at an early stage, without clinical evidence of extrauterine spread (International Federation of Gynecology and Obstetrics [FIGO] stages I and II) and have a 5-year survival of approximately 90%.

Several studies showed that recurrence rate after a completed primary treatment is relatively low (13%; 95% confidence interval, 11%–14%), according to the high rate (70%–80%) of the early-stage disease at initial surgery.2

Surveillance practice protocols in endometrial cancer have been discussed, and a wide variation emerged.3–6 These studies focused on the patterns of recurrences and on the possibility that close follow-up could improve survival. Because no single follow-up test is best for all sites of recurrences, a combination of tests is commonly used. The follow-up tests are directed to areas of potential relapse and conduced at pre-established intervals, more frequently during the first 3 years and infrequently afterward. Postoperative follow-up strategies comprise clinical examination by specialists, Papanicolaou test, and imaging procedures for the patients’ benefit; but there is always a trade-off between quality of care and cost-effectiveness. Actually, follow-up for patients with endometrial cancer varies among countries, and often between institutions within the same country.

Despite intensive follow-up, several researches showed that most recurrences are diagnosed in the interval between routine follow-up visits when patients complain signs and symptoms of disease. There is considerable controversy as to how often patients should be seen, what tests should be performed, and whether these varying strategies have any significant impact on patients’ survival.7,8 There is a lack of consensus among the medical community on effective strategies to address the need and length of follow-up; therefore, its value and the impact on health economics have become increasingly important.

The aim of this study was to compare different follow-up protocols among 8 Italian gynecological cancer centers. We retrospectively reviewed our institutional experience for patients with recurrences of endometrial carcinoma to examine the way recurrences are differently detected, the impact of different procedures of follow-up, and to determine a possible difference in survival between patients who where symptomatic versus asymptomatic at the diagnosis of relapse.

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The records of 282 consecutive women with recurrent endometrial cancer treated from 1986 to 2005 were retrospectively collected from 8 Italian hospitals of gynecology oncology using a common form with standardized items and a common database. Patients’ characteristics at initial diagnosis (date and type of surgery, FIGO stage, histology report, and adjuvant therapy) and at the time of recurrence (date, symptoms, site of relapse, number of localizations, first diagnostic examination of recurrent disease, and recurrence therapy) were reported for each case. Patients were staged retrospectively according to FIGO classification of 1988. The histological classification was performed according to the World Health Organization classification. The architectural grade was defined: grade 1 (G1), less than 5% of nonsquamous or nonmorular growth pattern, and grade 3 (G3), more than 50% of nonsquamous or nonmorular solid growth pattern. Notable nuclear atypia, inappropriate for the architectural grade, raised G1 to G2 tumors by one grade. Myometrial invasion was considered as the distance between the deepest extent of myoinvasive tumor and the overlying endomyometrial junction and was defined as M0, noninvasive; M1, 50% or less myometrial invasion; and M2, more than 50% myometrial invasion. As for the presence or absence of symptoms, patients with recurrent endometrial cancer were classified into 3 categories: (a) symptomatic patients who asked for earlier follow-up visit because of their symptoms, (b) symptomatic patients who did not anticipate follow-up visit and who referred symptoms during the planned follow-up appointment, and (c) asymptomatic patients whose recurrence was detected at the time of the planned follow-up visit.

All the data were reassessed by 2 independent supervisors, and inconsistencies were subsequently solved by a concomitant review.

Surveillance procedures and schedules adopted by each center are listed in Tables 1 and 2. Timing of clinical examination was fairly homogeneous, being performed every 3 months for 2 years, every 6 months from the third year to the fifth year, and yearly afterwards. Conversely, the Papanicolaou test and the diagnostic imaging techniques as the abdominopelvic computed tomographic scan (CT), the magnetic resonance imaging, and the chest x-ray were used at fixed interval times by a few centers and only in the presence of suspicious clinical symptoms by other centers.





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.

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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.

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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.

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Recurrent endometrial cancer; Follow-up; Surveillance procedures; Asymptomatic and symptomatic patients

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