 |
| About Bioline | All Journals | Testimonials | Membership | News |
|
||||||
|
||||||
Indian Journal of Cancer, Vol. 48, No. 2, April-June, 2011, pp. 204-210 Original Article Low risk stage I endometrial carcinoma: Prognostic factors and outcomes A Yoney, C Yildirim, Y Bati, M Unsal Okmeydani Training and Research Hospital, Department of Radiation Oncology, Sisli, Istanbul, Turkey Correspondence Address:A Yoney Okmeydani Training and Research Hospital, Department of Radiation Oncology, Sisli, Istanbul Turkey adnan@yoney.net Code Number: cn11050 DOI: 10.4103/0019-509X.82895 Abstract Objectives: The aim of the study is to evaluate clinical features of patients with low-risk stage I endometrium cancer, who received adjuvant therapy or followed with observation only and to analyse the effects of known prognostic factors in this group of patients.Materials and Methods: A total of 246 patients (median age: 53, range: 31-77) with low-risk stage I endometrial cancer, who were just followed postoperatively (156 patients) or received adjuvant radiotherapy (90 patients) between 1996 and 2007 were reviewed retrospectively. Results: Local recurrence was detected in four patients, distant metastasis occurred in seven patients, and two patients had both local recurrence and distant metastasis. The 83.3% of recurrences were on the vaginal stump. Five- and ten-year local control (LC) and overall survival (OS) rates are 97.6%, 97.6% and 96.4%, 93.5% in the observation and adjuvant therapy groups, respectively, whereas distant control rates are 96.7% and 96.3%. In multivariate analysis, only age and lymphovascular invasion (LVI) were found to affect OS and disease-free survival (DFS). Conclusions: LC and OS rates are high in the low-risk group of patients; however, current adjuvant therapies did not improve the outcomes. Age over 60 years and the presence of LVI have negative effects on outcomes in this group of patients. Keywords: Adjuvant radiotherapy, early stage, endometrial neoplasms, risk factors Introduction Endometrial carcinoma is the most frequent gynecologic malignancy in developed countries. In the majority of cases, tumor is confined to uterus at the time of diagnosis. Abnormal vaginal bleeding is a distinguished symptom in these patients. Because of the postmenopausal predilection of disease, abnormal bleeding attracts attention instantly. Early diagnosis is possible due to relatively slow progression of the disease and early manifestation of symptoms and therefore, survival rates can be high. [1],[2] The primary treatment modality is total abdominal hysterectomy + bilateral salpingo-oophorectomy (TAH + BSO). Type and timing of postoperative adjuvant therapy are still controversial issues. Before 1990s, adjuvant therapy for Stage I patients consisted of intracavitary radiotherapy (ICRT) for cases with myometrial invasion less than ½ or Grade I-II tumors and external radiotherapy (ERT) ± ICRT for cases with myometrial invasion more than ½ or Grade III tumors. Developments in treatment modalities after 1990s brought questions regarding ERT following surgical dissection and surgical staging in pN0. In subsequent years, risk groups were defined and treatment decisions were made accordingly. [2] Cases with Stage IA/IB, Grade I or II, endometrioid histology are considered in the low-risk group. Today, it is widely accepted that there is no need for adjuvant therapy for patients in low-risk group. [3],[4] In this study, low-risk stage I patients presenting to our clinic who underwent adjuvant therapy or were under observation according to evolving treatment protocols were evaluated retrospectively and effects of known prognostic factors and treatment methods upon outcomes were investigated. Material and Methods A total of 674 patients with endometrial carcinoma, who presented to our outpatient clinic from 1996 until 2007, were treated and followed up. Of these, 494 (73.3%) patients had Stage I disease and 246 (49.8%) of them were in the low-risk group. Cases in the low-risk group were investigated retrospectively and general features, treatment modalities, local and distant recurrences, and survival rates were evaluated. Patient records from archives were reviewed in detail for surgery notes, pathology reports, control tests, and physical examination notes. Age, menopausal state, parity, date and type of operation, histopathological diagnosis and stage; size, location and grade of tumor; state of myometrial and lymphovascular invasion (LVI), the presence of nodal involvement; type, duration and dose of therapy; location and occurrence of recurrences and metastases; last follow-up date and present status were recorded. Patient characteristics A total of 246 Stage I (stage IA and IB) cases had Gr I, Gr II or endometroid histology and were considered as low risk group. Median age of these patients was 53, ranging between 31 and 77. There were 58 patients (23.6%) under age of 60, and 188 patients (76.4%) over the age of 60. Demographic characteristics of the patients are shown in [Table - 1]. The majority of patients, i.e., 156 of them (63.4%), were postmenopausal. Median parity was 3 (0-13) with 15 nulliparous (6%), 14 primiparous (5.7%), and 203 multiparous (82.5%) patients. The treatments given and patients outcomes are shown in [Table - 2]. Most of the cases had endometrioid adenocarcinoma histology (227 patients, 92.3%). Fifty-one (61.4%) cases had grade 1 disease. Staging is done according to 1988 FIGO′s endometrial adenocarcinoma staging system. Thirty-five patients had Stage IA (14.2%), 211 patients had Stage IB (85.8%) disease. There were 33 patients (13.4%) who had no myometrial invasion. In 213 (86.6%) patients, myometrial invasion was less than 50%. Of 134 patients who had LVI analyses, 24 were found to be LVI (+) (17.9%) and 110 are LVI (-) (82.1%). Out of 148 patients with reported tumor size, 57 had a tumor size less than 2 cm (%38.5), 91 had a size greater than 2 cm (61.5%). Among patients with reported tumor location, 15% had lower segment involvement and 85% had upper segment involvement. Rest of the patients did not have sufficient information in their pathology reports. Treatment All patients had TAH + BSO. Lymph dissection was performed in 97 patients (39.4%) and the median number of excised lymph nodes was 8 (1-48). Following pathological evaluation of operation materials, pathological stage is determined and decision for adjuvant treatment is based on this result and according to changes in treatment modalities of adjuvant treatment indications within years the different approaches to treatment in those who presented to our clinic after surgical treatment are as follows: 156 patients were observed, 25 had only ICRT, 37 had only ERT, and 28 had both ERT + ICRT. Median time for start of radiotherapy was the postoperative day 41 (range: 11-115). Median time for completion of treatment was 36 days (range: 5-65). There were 3 patients who did not complete treatment. Sixty-five cases underwent pelvic radiation, 12 of them had four field box technique and remaining patients had an anterior and posterior two field radiation. Sixty-five cases had ERT with 180-200 cGy fractions with a median of 50 Gy (10-60). Forty-two cases were treated with Co60, 20 cases with 18 mv beams and 3 cases with 6 mv × beams. Twenty-five cases received ICRT without ERT and 28 cases received both ERT + ICRT. ICRT was applied to the top of the vagina with a median number of 3 (1-5) fractions, median dose of 15 Gys (range:10-30), and completed in a median of 14 days (range:7-33). Cases who received both external and internal treatment completed therapy in a median of 69 days (range:50-99). Statistical methods For analysis of data, qualitative data comparisons were done with Fisher′s Exact x2 -test besides descriptive statistical methods (mean, standard deviation, and frequency). Kaplan-Meier survival analysis was used for survival analyses, Log rank test was used for their comparison and Cox regression test was used for multivariate analysis. Statistical significance was set at P < 0.05 with 95% confidence interval. Results Toxicity Acute Grade I and II gastrointestinal (GI) (RTOG small/large intestine) toxicity occurred in 25 out of 65 patients (38.5%) treated by ERT. Sixteen (24.6%) of these were treated by ERT + ICRT. Grade II dermal toxicity occurred in 3 patients (2.2%). Late Grade III GI toxicity of adhesion or fibrosis has occurred in three patients (4.6%) treated by ERT. Two of these were treated by ERT + ICRT. Grade I-II mucosal atrophy occurred in 2 patients (7.1%) treated by ERT + ICRT, in one patient (3.5%) treated by ERT alone and in one patient (4%) treated by ICRT alone. Grade III atrophy occurred in one patient (3.6%) treated by ERT + ICRT and in one patient (2.7%) treated by ERT alone and again in one patient (4%) treated by ICRT alone. Recurrence and metastasis Four cases had only local recurrence, seven cases had only distant metastasis, and two cases had both recurrence and metastasis. Five- and ten-year local control (LC) rates were 97.6%, distant control rates were 96.7% and 96.3%, respectively. Recurrences were only detected in 156 cases that were under observation for a median period of 25 months (range: 8-55). Sixty-five cases that had ERT, ICRT, or ERT + ICRT did not develop local recurrence. LC rate of patients under observation is 96.2%. LC rate of patients who underwent radiotherapy is 100%. All cases with recurrences were Stage IB and Grade II. No recurrence was detected in Stage IA and Grade I. Additionally, analysis according to age showed two cases were under age of 60 and two cases over age of 60. The 83.3% of recurrences (5/6) developed on the vaginal stump. Pelvic lymph node recurrence was seen in only one case. All cases with recurrence on a vaginal stump and the case with pelvic lymph node recurrence underwent ERT + ICRT. Only one of 4 patients who developed recurrence died 30 months later and 3 of them are still alive and disease free. Two patients who developed both recurrence and metastasis were over 60 years old. One of them died 19 months later and one of them is still alive and disease free since 51 months. Median time for development of metastasis is 34 months. The most frequent location of metastasis was the peritoneum. Intraabdominal metastasis was detected in seven of nine patients. Second most frequent metastatic site was the lungs with two cases. When metastatic cases were analysed for initial stage one patient is Stage IA and LVI (+), others are Stage IB and LVI (+) except for a single case of LVI (-). The case who was LVI (-) had a tumor size greater than 4.5 cm. Also, all cases were over 60 years old except two. All seven patients with metastasis underwent chemotherapy, two patients with both metastasis and local recurrence underwent chemotherapy and radiotherapy consecutively. Six out of seven patients with metastasis died with a median of 16 months later, only one of them was alive with disease. Survival Kaplan-Meier method of survival analysis showed that all patients in the low-risk group had 1, 5, and 10 year overall survival (OS) rates of 98.8%, 96.4%, and 93.5%, respectively. Disease-free survival (DFS) rates in the same group were 98.8%, 93.5%, and 81.5%, respectively. Twenty patients died (8.1%) while 226 are alive (91.9%). Mean survival was 148.7 ± 3.5 months [Figure - 1]. Univariate analysis showed that age (P = 0.0001), menopausal status (P = 0.009), tumor grade (P = 0.042), and LVI (P = 0.004) had statistically significant influence on OS and age (P = 0.0001), menopausal status (P = 0.009), tumor grade (P = 0.039), and LVI (P = 0.003) had statistically significant influence on DFS. Low-risk patients who were over 60-year-old, postmenopausal, Grade IB, and LVI (+) had lower survival rates than patients who were below 60-year-old, Grade IA, and LVI (-). Coexistence of old age and LVI (+) was associated with worse OS and DFS [Figure - 2]. Histology (P = 0.664), treatment modality (P = 0.270), status of parity (P = 0.216), the presence of lymphatic dissection (P = 0.454), location of tumor (P = 0.963), the presence of myometrial invasion (P = 0.808), commencement time of radiotherapy (P = 0.557), and length of adjuvant therapy (P = 0.180) had no statistically significant influence on OS; likewise, histology (P = 0.670), treatment modality (P = 0.238), status of parity (P = 0.216), the presence of lymphatic dissection (P = 0.477), location of tumor (P = 0.829), the presence of myometrial invasion (P = 0.829), commencement time of radiotherapy (P = 0.559), and length of adjuvant therapy (P = 0.174) had no statistically significant influence on DFS. Evaluation of OS and DFS according to treatment modality shows that patients who were under observation have 1, 5, and 10 year OS rates of 99.4%, 96%, and 93.9%, respectively. Patients who underwent RT (without distinction of ERT, ICRT or ERT + ICRT) have OS rates of 97.8%, 93.6%, and 77.4%. DFS rates for patients under observation are 99.4%, 96%, and 93.9%; DFS rates for patients who underwent RT are 97.8%, 83.5%, and 77.4%. In terms of both OS (P = 0.270) and DFS (P = 0.238) differences were not statistically significant. Similarly, patients who underwent RT (with distinction of ERT, ICRT, and ERT + ICRT) were compared to patients under observation and difference between OS (P = 0.199) and DFS (P = 0.198) rates were not statistically significant [Figure - 3]. Multivariate analysis of Cox Regression test of age, tumor grade, LVI, and menopausal state revealed that age (P = 0.022) and LVI (P = 0.009) had statistically significant influence on OS. Likewise, multivariate analysis for DFS also showed that age (P = 0.021) and LVI (P = 0.011) had statistically significant influence. Discussion Endometrial cancer is generally diagnosed at Stage I due to early symptomatic bleeding in the postmenopausal period. Frequency of Stage I disease is 70% while coexistence of Stage I and II is 85%. [2] In our study, 494 (73%) out of 674 patients with endometrial cancer were found to have Stage I disease. Again the majority of Stage I cases was in the low-risk group with a rate of 49.8%. Studies regarding endometrial cancer have shown the presence of multiple factors, which affect prognosis for all stages of the disease. These can be listed as age, stage, grade, histology, myometrial invasion, LVI, lymph node involvement, size of tumor, cervical invasion, adnexial involvement, and intraperitoneal spread. [5],[6] In studies designed for Stage I disease, prognostic factors have been identified as age, grade, and the presence of LVI. [7],[8],[9] In our study, these factors have been investigated. Age, menopausal state, grade, and the presence of LVI are shown to have a statistically significant influence on OS and DFS in the univariate analysis; age over 60 years old and the presence of LVI are shown to have a statistically significant effect in multivariate analysis. Effectiveness of the presence of both of these factors has been demonstrated in other studies as well. [10],[11] In the presence of both factors together, the rate of local recurrence is as high as 3.9% and OS and DFS decrease. Our study shows that these two factors when present separately do not have a significant influence neither on local recurrence nor on distant metastasis. However, their coexistence has an effect on distant metastasis and these patients have statistically significant lower OS and DFS rates. As expected, all local recurrences developed in patients who were under observation after surgery. All of these cases were Stage IB and Grade II. Recurrence was not seen in Stage IA and Grade I. Recurrence rate is 2.4% for all patients while it is 3.8% for patients under observation. Our recurrence rate is close to 3.1%, which is the rate reported in a study that standardized observation in this risk group. [12] In the same study, local recurrence in the group who underwent radiotherapy was reported as 1.2% but in our study no recurrence was seen in patients who received radiotherapy. Three of four cases who have the only recurrence and no distant metastasis are still alive. On the other hand, one of two cases who have a local recurrence together with distant metastasis is still alive. In the literature, survival in recurrences is also reported as being over 50%. [13],[14] It is pointed out that grade of tumor and number of local recurrences affect survival. Two patients who died in our study were Grade II. Moreover, one of them had concurrent metastasis. Nine cases in the entire group had distant metastasis. The most common location was peritoneum, followed by the lungs. All patients with metastasis were LVI (+) except one. Moreover, all of them were over 60 years of age except two. All cases with the coexistence of two factors died except one. In the presence of two factors survival was lower. Influence of coexistence of both factors on survival was demonstrated in other studies as well. [10] How and when adjuvant therapy should be initiated in endometrial cancer is still controversial. Until 1990s, adjuvant therapy in Stage I patients consisted of ICRT for cases with myometrial invasion less than ½ or Grade I-II tumors, ERT ± ICRT for cases with myometrial invasion more than ½ or Grade III tumors. Developments after 1990s brought questions regarding the role of ERT after lymphatic dissection and surgical staging in pN0. Randomized GOG-99 and PORTEC 1 studies demonstrated that survival was not better after adjuvant ERT and increased survival could be established with salvage therapy in pelvic (vaginal) recurrences. [15],[16] In the low-risk group (<50% invasion, Grades I-II) recurrences were seen in the vagina. Therefore, the application of only ICRT in this group is preferable. [17] Postoperative radiotherapy not only failed to improve results, but also associated with toxicity. [18] This toxicity can be avoided via ICRT. Studies after 2006 confirmed that in the low-risk group (Stage IA-IB, Grade I-II) addition of ICRT to a TAH + BSO with sampling and cytology did not improve survival but only lowered vaginal recurrence from 3.1% to 1.2%; this fact decreased the frequency of radiotherapy to these patients. [12] A metaanalysis also supported that radiotherapy decreased the likelihood of local recurrence but did not improve survival in the early stage endometrial cancer. RT lowered recurrence rate by 6%. Only in group Stage IC and Grade III there was a tendency to improve survival but results did not reach a statistical significance. [4] Another meta-analysis also showed no need for ERT in low-risk and intermediate-risk groups. Contribution of ERT became evident in the high-risk group. [19] In the retrospective analysis of SEER, adjuvant ERT was shown to significantly increase survival only in Stage IC. [20] In low-risk group application of ICRT only has very favorable results. [21] However, in this risk group recurrence rates were as low as 2%. [22] Depending on the favorable results of therapies in the presence of recurrences, there seems no need for adjuvant therapy in the low-risk group. [10],[12] Our study also supports this approach by showing no remarkable difference that is reflected in survival rates for various treatment modalities within years, while radiation-related complications are increased. Treatment is only recommended in the presence of poor prognostic factors in this group. [23] Deterioration of results in existence of older age and LVI supports this concept. Conclusions In conclusion, there is no need for adjuvant therapy in low-risk Stage I endometrial cancer. There is no contribution of postoperative ERT, ICRT or ERT + ICRT to results. However, cases who are over 60 years old and have LVI (+) have poor prognosis. Especially distant metastases are frequent in cases with above prognostic factors and survival is poor. Additional studies need to be done in such cases with these prognostic factors to further define the need for postoperative adjuvant therapy for patients with these features in the low-risk group. References
Copyright 2011 - Indian Journal of Cancer The following images related to this document are available:Photo images[cn11050t2.jpg] [cn11050f3.jpg] [cn11050f1.jpg] [cn11050t1.jpg] [cn11050f2.jpg] |
| |||||||||
![[Table - 1]](/showimage?cn/photo/cn11050t1.jpg){kind=link}
![[Table - 2]](/showimage?cn/photo/cn11050t2.jpg){kind=link}
![[Figure - 1]](/showimage?cn/photo/cn11050f1.jpg){kind=link}
![[Figure - 2]](/showimage?cn/photo/cn11050f2.jpg){kind=link}
![[Figure - 3]](/showimage?cn/photo/cn11050f3.jpg){kind=link}