Features of recurrence of endometrioid type endometrial cancer of I stage

Movchan O.M.*1, Svintsitskiy V.S.1, Tsip N.P.1, Nespryadko S.V.1, Bublіieva O.I.1, Iurchenko N.P.2

Summary. The aim of this study was to determine the rates of recurrences of stage I endometrial cancer (EC) and features of their localization depending on the clinical and pathological characteristics of the tumor and methods of patients’ treatment. Patients and Methods: The study included 968 patients with stage I endometrioid EC, who underwent surgical treatment in the Department of Oncogynecology of the National Cancer Institute in 2015–2019. Surveillance of patients lasted from January 2015 to December 2020, with a minimum follow-up period of 1 year from the date of surgery. Adjuvant radiation or chemotherapy was performed depending on the clinical and pathological characteristics of the EC case. Results: During the follow-up period, recurrences were observed in 7.0% of cases and were most often found in stage IC of low differentiation grade. It was found that during surgical treatment without adjuvant therapy relapses occurred in 12–36 months after the start of treatment, with adjuvant radiation therapy — in 6–18 months, and with adjuvant chemotherapy — in 32–60 months. Recurrences most often occurred in patients with EC who underwent surgical treatment in combination with chemotherapy (p < 0.05). The lowest number of recurrences was recorded among patients who underwent surgery as an only treatment. The best 5-year survival rate was observed in the group of patients with surgical treatment (93%), and the worst — in the patients treated with combination of surgery and chemotherapy (57%). In patients without recurrences, the survival rate after treatment was 97%, while in patients diagnosed with relapses, the survival rate was 65%. Conclusion: Despite the predominantly favorable course of EC stage I, some patients develop relapses. The rate and localization of recurrences depend on the histological structure of the tumor and treatment regimens of the EC patients.

DOI: 10.32471/exp-oncology.2312-8852.vol-43-no-4.17052

Submitted: May 10, 2021.
*Correspondence: movchan-89@ukr.net
Abbreviations used: EC — endometrial cancer; GOG — Gynecolo­gic Oncology Group; PORTEC — Post Operative Radiation Therapy for Endometrial Carcinoma.

Endometrial cancer (EC) is the most common cancer of the female reproductive system worldwide and also in Ukraine. In recent decades, there has been observed a trend towards a steady increase in the EC incidence higher than that of cervical cancer. In 2020, in the structure of oncological diseases of the female population of Ukraine, EC occupied the second place (10.9%), second only to breast cancer (23.3%) [1].

The vast majority of EC cases is diagnosed in the early stages (80% — in stage I), with a five-year survival rate of over 95%. However, five-year survival rates are much lower in the case of regional spread or distant metastasis (68 and 17%, respectively) [2].

Indicators for choosing tactics of EC treatment are based on clinical and pathological parameters: age, stage, histological type of tumor, depth of invasion, lymphovascular invasion. These indicators are important factors in predicting the recurrence or metastasis of the disease and patient’s survival [3].

The histological type of 80–90% cases are endometrioid carcinomas [4]. According to various sources, the frequency of recurrences in the early stages of the disease varies from 2 to 26% depending on the differentiation grade of the tumor [5].

In patients with stage I EC of the low-risk group, recurrence may occur in the first three years, which ultimately leads to deterioration of treatment results [6].

To prevent the EC recurrence, adjuvant therapy is used. As a rule, the decision on adjuvant therapy is made accounting clinical and instrumental data on the risk of recurrence. However, there are only a few reports of recurrence risk in patients without use of adjuvant therapy, because postoperative therapy was performed in the conventional way. Retrospective data suggest that the use of radiation therapy is beneficial for the prevention of vaginal recurrence; however, approaches and doses in the literature vary widely. There is currently no established standard for the treatment of relapses. There are only scarce reports in the literature on the results of treatment of patients with EC who did not receive adjuvant therapy after hysterectomy, but who subsequently received treatment for recurrence.

In recent years there have been made the advances in understanding the nature of EC and its treatment, including surgery, adjuvant therapy, combined therapy along with targeted therapy and immunotherapy. All the above indicates the relevance of studying the role of certain factors in the course of the tumor process and the manifestation of the disease in patients with EC. The aim of this study was to determine the rates of recurrences and features of their localization of stage I EC depending on the clinical and pathological characteristics of the tumor and methods of patients’ treatment.

MATERIALS AND METHODS

In the study, 968 patients with endometrioid type EC of stage I (according to International Federation of Gynecology and Obstetrics, 1988), who underwent surgical treatment in the Research Scientific Department of Oncogynecology of the National Cancer Institute in the period from January 2015 to December 2019, were enrolled. Surveillance of patients lasted from January 2015 to December 2020, with a minimum follow-up period of 1 year from the date of surgery. Every 3 months during the observation period, patients underwent the following examinations: cytological analysis of smears from the vaginal stump, ultrasound diagnosis of the pelvic organs and abdominal cavity. Patients underwent computed tomography every 6 months (or if recurrence was suspected).

The study was carried out in line with fundamental ethical principles — complete confidentiality of information about participants’ personal data and the amount of treatment provided; the results were used only for research purposes. The research program was approved by the Commission on Bioethics of the National Cancer Institute of the Ministry of Health of Ukraine, and the work was agreed with the local ethics committee, with a conclusion on compliance with moral and ethical standards of bioethics Council of Europe Convention on Human Rights and Biomedicine (1997), as well as current legislation of Ukraine.

All patients with EC of stage IA, regardless of the EC differentiation grade, as well patients with EC of stage IB with highly differentiated tumors, received only surgical treatment in the volume of extirpation of the uterus with adnexa. Patients with stage IB who had moderately or poorly differentiated tumors and patients with stage IC regardless of the EC differentiation grade in addition to surgery received radiation therapy or chemotherapy. Pelvic region was irradiated (40–46 Gy) with/without brachytherapy, also radiation was given to the vaginal mucosa (35–50 Gy). The patient received chemotherapy in a case of contraindications to radiation therapy, namely: obesity of degree IV and higher, extragenital pathology, violation of the terms of radiation therapy initiation (more than 2 months after surgery). First-line chemotherapy was performed via the paclitaxel + carboplatin/cisplatin regimen. Adjuvant therapy was applied in 2 months after surgery.

The presence of metastases was confirmed by morphological, radiological, echoscopic and clinical methods of examination.

Statistical analysis of the results was performed using the STATISTICA 6.0 software (StatSoft, Inc.). Analysis of differences between groups was performed using the χ2 test. Patient’s survival was analyzed by the Kaplan — Meier method, the reliability of the difference between the survival curves — by log-rank test. The level of statistical significance was established as p < 0.05.

RESULTS

During the follow-up period, recurrences were detected in 68 EC patients that comprises 7.0% of all patients included in the study.

The analysis of age categories of the patients with stage I EC was carried out and the frequency of recurrences depending on age was estimated (Table 1). The age of the patients ranged from 25 to 85 years and averaged 57.9 ± 7.6 years, those with recurrence — 59.6 ± 7.5 years. It was found that the highest recurrence rate (2.7%) was observed in the age group of 55–59 years. In the age categories of 25–34 years and older than 80 years, EC was quite rare, and recurrences of the disease in such patients were not registered.

Table 1. Recurrence rate in patients with stage I EC of different age groups
Age (years) 25–29 30–34 35–39 40–44 45–49 50–54 55–59 60–64 65–70 70–74 75–80 80 and older
Number of patients, n (%) 2 (0.2) 9 (0.9) 27 (2.8) 51 (5.3) 99 (10.2) 139 (14.4) 212 (21.9) 181 (18.7) 136 (14.1) 70 (7.2) 33 (3.4) 9 (0.9)
Number of cases with recurrence, n (%) - - 1 (0.1) 3 (0.3) 5 (0.5) 4 (0.4) 26 (2.7) 15 (1.6) 8 (0.9) 5 (0.5) 1 (0.1) -

When analyzing the frequency of recurrences in patients with EC depending on the spread of the tumor process, it was found that among patients with stage IA recurrences were observed in the lowest numbers (Table 2). However, in patients with stage IC, the relapses occurred almost twice more often as compared to stages IA and IB.

Table 2. The recurrence rate in patients with stage I EC depending on the characteristics of the tumor process and the type of adjuvant treatment
Index Without recurrence, n = 900 (%) Recurrence, n = 68 (%) P value
Average age, years 58.5 ± 6.9 59.6 ± 8.0
Stage:


353 (96.7)
476 (93.3)
71 (76.3)
12 (3.3)
34 (6.7)
22 (23.7)
0.001
Differentiation grade:
High — G1
Moderate — G2
Low/Undifferentiated — G3
219 (94.4)
566 (95.1)
115 (81.6)
13 (5.6)
29 (4.9)
26 (18.4)
0.002
Treatment:
Surgical
Surgical + radiation therapy
Surgical + chemotherapy
576 (96.5)
188 (91.7)
136 (81.9)
21 (3.5)
17 (8.3)
30 (18.1)
0.002

Notes: The difference between the groups of the EC patients without and with recurrences is significant.

When assessing the frequency of recurrence taking into account the morphological features of EC, it was found that in patients with moderately differentiated (G2) tumors recurrences were observed in the least number of treated patients (Table 2). Almost the same number of relapses was found in patients with highly differentiated endometrial neoplasms (G1), while in patients with poorly differentiated tumors (G3) their frequency was significantly (three to four times) higher.

Analysis of the recurrence rate depending on the method of adjuvant treatment showed their highest rate in the EC patients who underwent surgical treatment in combination with chemotherapy (Table 2) (p < 0.05). It was found that the lowest recurrence rate was registered among patients who underwent surgery as an independent method of treatment.

When assessing the frequency and localization of recurrence, taking into account the EC differentiation grade, in patients with poorly differentiated endometrial tumors, the recurrences were found most frequently in pelvis and pelvic lymph nodes (Table 3). In cases of moderate differentiation, lymph nodes (pelvic + paraaortic) were also the most common recurrence sites. Moreover, in patients with moderately differentiated tumors who received postoperative radiation therapy, distant metastases to the liver and omentum were detected.

Table 3. Localization of recurrences depending on EC differentiation grade
Localization of the recurrence G1, n (%) G2, n (%) G3, n (%)
Total number, n = 68 13 (19.1) 29 (42.6) 26 (38.2)
Lymph nodes (pelvic and paraaortal) 4 (5.9) 10 (14.7) 13 (19.1)
Omentum 4 (5.9) 5 (7.4) -
Pelvis 3 (4.4) 2 (3.0) 19 (26.9)
Vaginal stump - 2 (3.0) 6 (8.8)
Lungs 1 (1.5) 2 (3.0) 4 (5.9)
Liver 1 (1.5) 6 (8.8) -
Brain - 1 (1.5) -
Bones - 1 (1.5) 2 (3.0)

When studying the timing of relapses in patients, it was determined that in a case of surgical treatment without adjuvant therapy relapses occurred in 12–36 months after the start of treatment, with adjuvant radiation therapy — in 6–18 months, and with adjuvant chemotherapy — in 32–60 months. The main number of relapses in stage I EC occurred in the first three years after completion of treatment, which indicates the need for closer monitoring of patients during this period.

The overall five-year survival of all patients with EC stage I (n = 968) achieved 94%. A statistically significant difference between the patients who received only surgery, surgery in combination with radiation therapy and surgery in combination with chemotherapy was revealed. The highest five-year survival was observed in patients with stage I EC who received only surgical treatment, and yielded 93.0%, compared with patients who underwent combined therapy (surgical + radiation therapy), whose survival rate decreased to 84.0% (log-rank test; test statistic = 3.209200, p = 0.00133). The lowest survival rates were observed in the group of patients who received surgical treatment and chemotherapy — 57.0% (log-rank test; test statistic = 4.439520; p = 0.00001) (Figure).

 Features of recurrence of endometrioid type endometrial cancer of I stage
Figure. Overall 5-year survival of patients with EC stage I depending on the method of treatment

The study of the survival of the EC patients treated for local recurrences compared with non-relapsed patients has revealed that the overall 5-year survival rate of patients who relapsed was significantly lower than that of the patients without recurrence (65% vs 97%, respectively). During the observation period, the survival of patients in these groups differed: after 36 months from the beginning of treatment, the survival of patients without recurrence was 98%, while in patients with recurrence — 85%. The median of this index in the group of patients with relapses was 26.8 months.

DISCUSSION

In recent years, the number of the EC patients of young and middle age has increased, in almost 7% of cases EC is diagnosed before the age of 44 years, which, of course, affects the demographic situation [7]. According to some reports, in 20% of patients with stage I EC, tumor relapses could develop in 6 months to 3 years after treatment [8].

Currently, the surgical method is the most common in the treatment of patients with EC of the initial stages, both alone and in combination with other methods [9]. The results of our study showed that the most effective independent method of treatment of patients with early-stage EC remains surgical. Patients with this treatment have a favorable prognosis without any adjuvant therapy. The tactics of adjuvant therapy in patients with stage I EC depend on the extent of surgery performed. Indications for distant adjuvant radiation therapy are determined primarily by risk factors for lymphogenic EC metastases, which are completely eliminated when performing adequate lymphadenectomy. Adjuvant treatment of stage I–II EC should be performed according to the recommendations of the European Society of Gynaecological Oncology — European Society for Medical Oncology — European Society for Radiotherapy and Oncology consensus [3, 10].

Our study found that in the group of patients receiving adjuvant treatment for stage I EC after surgery, recurrences occurred, both loco-regional and distant. At the same time, patients with stage I EC who did not receive adjuvant treatment after hysterectomy had a fairly low recurrence rate. However, in general, approximately 30% of patients have a relatively higher risk of recurrence without adjuvant therapy. These are older patients with EC of low differentiation grade, and deeper invasion [3, 5].

Our results are consistent with those of randomized trials, including Post Operative Radiation Therapy for Endometrial Carcinoma (PORTEC-1), which show a 15% local regional recurrence rate after 8 years of follow-up (10% vaginal stump, 5% pelvic region) [11]. It should be noted that the three-year survival of the EC patients with pelvic or distant recurrence is only 8 and 14%, respectively [11].

Several randomized clinical trials have been conducted to determine the effectiveness of adjuvant therapy [11–15]. Patients benefited significantly from distant radiation therapy: the 5-year risk of loco-regional recurrence decreased from 23% to 5% [3].

There is a debate about whether adjuvant vaginal brachytherapy is as effective as distant pelvic radiation therapy in reducing vaginal recurrence [12]. The results of a five-year PORTEC-2 study showed equally low vaginal recurrence rates (1.8% for vaginal brachytherapy vs 1.6% for distant pelvic radiation therapy) in both treatment groups. However, the researchers found no differences between the groups in terms of survival without signs of disease recurrence and overall survival [12]. Similar results were found in a Swedish study comparing pelvic brachytherapy with vaginal brachytherapy. Based on these results, adjuvant vaginal brachytherapy has become the standard of care for patients with EC, providing maximum control for early recurrence [16].

Among patients who received postoperative radiation therapy after hysterectomy and were treated for isolated vaginal recurrence using remote pelvic radiation therapy and vaginal brachytherapy, complete remission was observed in 89% cases. The 3- and 5-year survival rates of such patients were 73% and 65%, respectively. These data were confirmed in the analysis of long-term treatment outcomes [13]. According to PORTEC-1 and PORTEC-2, brachytherapy remains indicated as adjuvant therapy in only 15% of EC patients.

It should be noted that after brachytherapy and chemotherapy pelvic and paraaortic recurrences were much more common [17]. However, there is debate among physicians as to whether a combined chemotherapy regimen should be preferred to chemotherapy alone, given the similar recurrence-free survival rates in the Gynecologic Oncology Group (GOG)-258 study and concerns about the expected higher toxicity. However, significantly more cases of recurrence of vaginal, pelvic and paraaortic nodes were reported only in the chemotherapy group and it is not reported how many patients in the radiation therapy group received chemotherapy during relapse [18].

Chemotherapy has been shown to be superior to radiation therapy in the treatment of locally advanced cancer, and has thus become part of the standard of care [19]. Instead, if chemotherapy is administered alone, the incidence of loco-regional recurrence approaches 20%, predicting further distant metastasis and death [19].

The optimal sequence of chemotherapy and radiation therapy courses is a matter of debate. Many research centers prefer sequential treatment, prescribing chemotherapy first, which is often based on logistical reasons and the principle that chemotherapy should be started early to treat latent distant metastases. In the combined Mario Negri Gynecologic Oncology group/Iliade trials, which used any sequence of therapy (most patients initially receiving chemotherapy), there was no difference in outcomes between the patients firstly treated with chemotherapy vs those firstly treated with radiotherapy [15]. However, published results of the last two major promising randomized trials have shown the safety and efficacy of combined chemotherapy and radiation therapy based on the Phase II Radiation Therapy Quality Assurance study. This option has the advantage that both adjuvant treatments begin immediately after surgery, and the total duration of treatment is shorter than in the case of sequential therapy.

Recently, the results of three important studies evaluating combined radiation and chemotherapy aimed at reducing the incidence of both local and distant recurrences were presented: PORTEC-3, GOG-249, GOG-258 [15, 17, 18]. The role of chemotherapy in stage I EC of low differentiation grade is currently being investigated [19]. Concomitant use of cisplatin with radiation therapy for women with pelvic and/or vaginal recurrences (Clinical-Trials.gov Identifier NCT00492778) is currently ongoing.

Thus, despite early detection of EC, high survival rates and effective adjuvant therapy, 7.0% of the patients experience relapses observed mainly in the period from 6 months to three years after treatment. Today, the effectiveness of treatment of patients with EC varies, even in the cases of the same histological structure, the tumor differentiation grade and the spread of neoplastic process, which may be associated with molecular heterogeneity of EC. At present, there are no effective methods to prevent recurrence of stage I EC, and life expectancy is reduced by almost half in the case of recurrence. Today, the main focus is on molecular genetic markers to create a better classification of EC to develop personalized treatment, and combined therapy to prevent recurrence and metastasis. The results of these trials are likely to have a significant impact on treatment recommendations in the coming years.

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