|GYNAECOLOGY ONCOLOGY SYMPOSIUM: ORIGINAL ARTICLE
|Year : 2014 | Volume
| Issue : 3 | Page : 309-314
Treatment outcome and prognostic factors in intermediate risk stage I endometrial carcinoma
Department of Radiation Oncology, Okmeydani Training and Research Hospital, Istanbul, Turkey
|Date of Web Publication||10-Dec-2014|
Department of Radiation Oncology, Okmeydani Training and Research Hospital, Istanbul
Source of Support: None, Conflict of Interest: None
Introducton: The aim of this study was to evaluate the clinical characteristics, post-surgery adjuvant treatment approach and posttreatment disease course in patients with intermediate risk stage I endometrium cancer and also to assess the effects of known prognostic factors on this group of patients. Patients and Methods: A total of 148 patients followed up postoperatively or after adjuvant treatment between 1996 and 2007 were evaluated retrospectively. Median follow-up duration was 67 months (range: 7-166). Among the study population 14.9% had Ib and 83.1% had stage Ic disease. 72 were treated by external beam radiotherapy (EBRT), 7 by intracavitary radiotherapy (ICRT), 65 by external + intracavitary radiotherapy (EBRT + ICRT), and one by chemoradiotherapy (CRT). Results: Vaginal vault is found to be the most common site of recurrences. Five and 10-year local control (LC) rates were 96.6% and 95.9%, respectively, while 5 and 10-year distant control (DC) rates were 94.6% and 91.9%, respectively. One, 5 and 10-year overall survival rates (OS) were 99.3%, 87.6% and 71.2%, respectively, while 1, 5 and 10-year progression-free survival rates (PFS) were 97.3%, 87.6% and 71.2%, respectively. Univariate analysis has revealed that prognostic factors as age (P = 0.0001), menopausal status (P = 0.049) and EBRT duration (P = 0.003) statistically significantly affected OS; while age (P = 0.0001) and EBRT duration (P = 0.006) affected PFS. Multivariate analysis has revealed that only age (P = 0.001) (P = 0.0001) and ERT duration (P = 0.021) (P = 0.027) affected both OS and PFS. Conclusion: LC and OS rates are high in the intermediate risk group. Age over 60 years and EBRT duration of 35 days and over both have negative effects on outcome in this group.
Keywords: Intermediate risk, stage I, endometrium cancer, adjuvant treatment, 60 years of age, RT duration
|How to cite this article:|
Yoney A. Treatment outcome and prognostic factors in intermediate risk stage I endometrial carcinoma. Indian J Cancer 2014;51:309-14
| » Introduction|| |
Endometrium carcinoma is the most frequent gynecological malignancy in developed countries.  It's primary treatment is total abdominal hysterectomy plus bilateral salpingoophorectomy (TAH + BSO). The timing and nature of postoperative adjuvant treatment are currently still controversial. In previous years, adjuvant treatment in stage I patients included ICRT in patients with <1/2 myometrial invasion or Grade I-II disease while EBRT +/- ICRT in patients with >1/2 myometrial invasion or Grade III disease. Since 1990, following the advances in management, the place of EBRT in pN0 disease determined after lymphatic dissection and surgical staging has become increasingly questioned. After the identification of risk groups, treatment decisions have begun to be made according to this parameter in the following years.  Patients classified as Stage Ia/Ib Grade III and Stage Ic Grade I or II endometrioid histology are considered in the intermediate risk group. Contrary to low risk group for which only follow- up is currently recommended, it has been suggested that adjuvant treatment should be administered in the intermediate risk group. However, due to increased early and late toxicity and no significant outcome difference observed with EBRT compared to ICRT, administration of ICRT as adjuvant treatment is currently considered as sufficient. ,
The aim of this study was to retrospectively evaluate the clinical characteristics, post-surgery adjuvant treatment approach and posttreatment disease course in patients with intermediate risk stage I endometrium cancer and also to assess the effects of known prognostic factors on this group of patients.
| » Materials and Methods|| |
Among 674 patients who have been admitted, treated and followed up in our clinic with the diagnosis of endometrium carcinoma between January1996 and December 2007, only 148 patients in intermediate risk group of stage I disease have been retrospectively evaluated in terms of general features and treatment decisions, local and distant recurrence, and survival.
Patient records, surgical discharge note and reviewed pathology reports, follow-up investigations and examination records were evaluated in detail and information including patient's age, menopausal status, number of pregnancies; type and date of surgery, histopathological diagnosis and stage; tumor diameter, location and grade, presence of myometrial and lymphovascular invasion, presence of lymphatic ganglion involvement, subsequent treatments, duration and doses, locations of recurrence and metastasis and time of detection, date of last visit and patient's condition at last visit were recorded.
Among 674 endometrial carcinoma patients, 494 patients were noted to have Stage I disease (73.3%). Out of these patients, 148 (30%) who had Stage Ia/Ib Grade III and Stage Ic Grade I or II endometrioid histology were defined as intermediate risk group. Median age was 58 years (range: 34-80). Patient characteristics are presented in [Table 1]. Most of the patients were postmenopausal (n = 132, 89.2%). y. Patients being referred to our clinic from different regions of the country and generally belonging to relatively lower socioeconomic classes, the number of parity in patients admitted to our study showed a diversity as; Median parity being 3 (range: 0-9) and 140 patients (94.6%) had endometrioid adenocarcinoma histology. Most frequent histological grade was grade II. According to FIGO staging system (1988) of endometrium adenocarcinoma, 123 patients were stage Ic (83.1%). The patients were composed of with more than 50% myometrial invasion in 122 cases. There were only 31 (3.4%) positive LVI patients among 90 patients with known LVI status. Also as being undergone surgical operations in different centers and in various regions showing diversity in the pathology reports, we haven't been able to reach fully adequate details in all the cases. Among patients (112 patients) with known tumor location, 16.7% were in the lower segment and 83.3% were in the upper segment. Insufficient information was present in pathology reports of the 36 (24.3%) remaining patients.
TAH + BSO was performed in all patients. As mentioned above the patients being referred to our center from a variaty of surgical clinics causing different types of surgical interventions such as; Lymphatic ganglion dissection (LAD) performed in 56 patients (37.8%) and median number of removed lymphatic ganglions was 8 (range: 1-42). Three patients were followed up without CRT after surgical treatment, 7 were only treated by ICRT, 72 were only treated by EBRT, and 65 were treated by EBRT + ICRT and one was treated by CRT.
Median time until the beginning of radiotherapy was 41 days (range: 11-115), being completed within a median number of 36 days (range: 5-65). We observed that the choise of treatment unit and number of fields depended on the radiation oncologist, pelvic width of the patient as well as the work capasity of the treatment units during such a period of time when no certain treatment protocol was fixed. EBRT was terminated before end of course in 3 patients due to gastrointestinal Gr 2-3 toxicity. Out of 137 patients treated by pelvic irradiation, four-field box technique was used in 52 and anterior-posterior field radiation in the remaining patients. A median dose of 50 Gy (range: 30-60) was administered in 180-200 cGy fractions in 137 patients treated by EBRT Co60 was used in 72, 18 mv in 50, 6 mv x-rays in 15 patients. The ports were to cover a field of to total pelvis including: The upper half of the vagina, paracervical, parametrial and uterosacral tissues, as well as the external iliac and obturator lymph ganglions. The superior border was defined as a line drawn through the L4-L5 interspace, while the inferior border was at the mid-portion of the obturator foramen. The lateral borders were set at 1 cm beyond the lateral margins of the bony pelvic wall at the widest plane of the pelvis. Lateral field borders were the posterior border of the S3 vertebral body and the anterior border of the symphsis pubis. No pelvic organs or structures were to be blocked during the RT.
Those certain years in which patients were treated as depending on dominatingly accepted treatment desicions; ICRT without EBRT was performed in 7 and EBRT + ICRT in 65 patients. Median treatment duration was 69 days (range: 50-99) including both external and internal treatments.
A total of 72 patients received high dose rate (HDR) ICRT. The median total dose was 15 Gy (range: 10-30) delivered in median 3 fractions (range: 1-5) for a median duration of 14 days (range: 7-33).The target volume treated was one half to two-thirds of the length of the vagina. The treatment was delivered using a cylinder connected to an afterloading HDR 192Ir source. The typical dose was prescribed to a depth of 0.5 cm from the vaginal surface. Dose optimization was used in all patients taking ICRT. Such optimization allows the dose distribution to taper down as it gets closer to the introitus and to improve the depth dose distribution by lowering the dose to the vaginal surface in order to obtain the targeted dose at 0.5 cm. The bladder and rectal doses were not calculated.
Cisplatin 50 mg/m 2 + Paclitaxel 175 mg/m 2 was administered three cycles together with EBRT in only one patient.
In addition to descriptive statistical methods (Mean, standard deviation, frequency), Fisher's Exact Chi- Square Test was used for the comparison of qualitative variables. Survival analyses were performed by Kaplan Meier Survival Analysis, Log Rank Test was used for comparison and Cox Regression Test was used for multivariate analysis. Statistical significance was considered as P < 0.05 at 95% confidence interval.
| » Results|| |
Acute Grade I and II gastrointestinal (GI) (RTOG small/large intestine) toxicity occurred in 80 out of 137 patients (54%) treated by EBRT. Toxicity has increased up to grade III during RT course in three of these patients and treatment therefore had to be terminated before its course in these cases. Grade II dermal toxicity occurred in 3 patients (2.2%).
Fifty patients (34.5%) had a least one site of late toxicity and the most commonly involved organ was the vagina (15.9%). All late toxicity incidents are recorded in [Table 2]. Note that toxicity was recorded in multiple sites in some patient and therefore the total number of complications exceeds the number of patients effected. The majority of vaginal toxicity was recorded as mild, that is, the patients had no symtoms but had mild vaginal atrophy and telengectasia detected on examination. Grade III atrophy occurred in 2 patients (3%) treated by EBRT + ICRT and again in 2 other patients (2.8%) treated by EBRT alone. All the bladder (4.8%) and skin (6.9%) toxicity was mild. Four patients (2.8%), who had LAD, had bilateral lymphedema. Combined therapy (EBRT + ICRT) was more toxic than either EBRT alone or ICRT alone. It was more toxic for any other toxicity (47.7% compared to 23.6% and 28.6%) or higher grade (Gr 3) of toxicity (4.6% compared to 1.4% and 0%). When compared with those patients who were treated with linear accelerators there was significant increase in all kinds of toxicity in the patients who had been treated by cobalt unit (44.2% compared to 26.2%) and there included also the skin toxicity (9.1% compared to 4.9%).
Recurrence and metastasis
Local recurrence alone occurred in 3, distant metastasis alone in 9, and local recurrence and metastasis in 3 patients. Five and 10-year local control rates were 96.6% and 95.9%, respectively; and distant control rates were 94.6% and 91.9, respectively.
Six patients relapsed at a median time of 24.5 months (range: 12-90). Sites of first relaps according to treatment group are presented in [Table 3]. No recurrence was noted in 3 patients who were followed up without adjuvant treatment, including other one patient treated by CRT. Recurrences occurred 3 (4.2%) out of 72 patients treated by EBRT, 2 (3.1%) out of 65 patients treated by EBRT + ICRT and one out of 7 patients treated by ICRT. Four out of 6 patients with recurrence were stage Ic, while no recurrence was noted in stage Ia patients. Since all the relapsed patients were over sixty years old, the other feature that predicted worse overall locoregional control was age. Patients with local recurrence alone were treated by ICRT as salvage therapy, while those with recurrence and accompanying distant metastasis were treated by CT. Three patients with local recurrence were dead after 14, 28 and 53 months, respectively and 3 patients with both local distant metastases were dead after 13, 14 and 15 months.
Metastases have occurred after a median period of 34 months. Lung was the most frequent site of metastasis. Lung metastasis has occurred in 11 out of 12 patients with metastases. The second most frequent site was bone (n = 2).
When patients developing metastases were evaluated, one out of 9 patients was stage Ib, Gr III, the others were stage Ic, Gr II and all except 2 patients were LVI (+). All except 4 patients were over 60 years old. CT was administered in all of the 9 patients with metastasis only, while CT and RT were administered consecutively in 3 patients with both metastasis and local recurrence. Six out of 9 patients with metastasis only were dead after a mean period of 13 months, while the remaining 3 are still alive with ongoing disease after a mean period of 108 months.
Kaplan Meier survival analysis has revealed that 1, 5 and 10-year OS rates were 99.3%, 87.6% and 71.2%, respectively in all patients in the intermediate risk group. One, 5 and 10-year PFS rates were 97.3%, 87.6% and 71.2%, respectively in the same group. Of these patients, 25 (16.9%) were lost and 123 (83.1%) were still alive. Mean survival period was 137.9 4.7 months [Figure 1].
|Figure 1: Overall survival for intermediate risk Stage I endometrial cancer|
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Univariate analysis has revealed that age (P = 0.0001), menopausal status (P = 0.049) and EBRT duration (P = 0.003) statistically significantly affected OS; while age (P = 0.0001) and EBRT duration (P = 0.006) affected PFS. Multivariate analysis has revealed that only age (P = 0.001 for OS and P = 0.0001 for PFS) and EBRT duration (P = 0.021 for OS and P = 0.027 for PFS) affected both OS and PFS. Among intermediate risk stage I patients, survival in postmenopausal patients over 60 years old with an EBRT duration of greater than 35 days was less than survival in premenopausal patients under 60 years old with an EBRT duration of less than 35 days.
No statistically significant effect on OS and PFS was found for histology (P = 0.605 and P = 0.572, respectively), treatment type (P = 0.347 and P = 0.366, respectively), parity status (P = 0.297 and P = 0.367, respectively), presence of lymphatic ganglion dissection (P = 0.452 and P = 0.575, respectively), tumor diameter (P = 0.494 and P = 0.437, respectively), presence of myometrial invasion (P = 0.543 and P = 0.541, respectively), presence of LVI (P = 0.358 and P = 0.355, respectively), grade (P = 0.526 and P = 0.560, respectively), stage P = 0.325 and P = 0.327, respectively), time between surgery and initiation of adjuvant treatment (P = 0.539 and P = 0.486, respectively) and total RT dose (P = 0.480 and P = 0.419, respectively). When the effects of type of adjuvant treatment on OS and PFS was evaluated; 1, 5 and 10- year OS were 98.6%, 89.7% and 57.4%, respectively in patients treated by EBRT; 98.5%, 87.1% and 71.6%, respectively in patients treated by EBRT + ICRT; and 85.7%, 71.4% and 71.4%, respectively in patients treated by ICRT alone [Figure 2]. One, 5 and 10-year PFS were 98.6%, 89.7% and 57.4%, respectively by PRT; 96.9%, 87.1% and 71.6%, respectively by EBRT + ICRT; and 71.4%, 71.4% and 71.4%, respectively by ICRT. No statistically significant differences in survival rates were noted between treatment modalities (P = 0.475 for OS and P = 0.646 for PFS).
|Figure 2: Overall survival for Intermediate risk Stage I according to adjuvant therapies (P: 0.475)|
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When age, menopausal status and EBRT duration were placed in multivariate analysis by Cox Regression, it was found that age (P = 0.001 for OS and P = 0.0001 for PFS) and EBRT duration (P = 0.021 for OS and P = 0.027 for PFS) statistically significantly affected both OS and PFS.
| » Discussion|| |
Since endometrium cancer manifests early by bleeding in the postmenopausal period, it is often diagnosed at Stage I. Frequency of Stage I is 70% and simultaneous Stage I and II occurs in 85%. 2 Among 674 patients with endometrium cancer in our study, 494 (73%) were Stage I. Most of the Stage I patients have low risk, intermediate risk group is the second most common risk group. Among our study population, 49.8% of the patients were in low risk group and 30% were in intermediate risk group.
Surgery is recommended as the primary treatment of endometrium cancer. Surgical approach also allows pathological staging. Surgical goals include TAH + BSO, dissection of pelvic and paraaortic lymphatic ganglions, cytological evaluation by peritoneal irrigation and examination of intraabdominal organs and tissues such as liver, intestines, diaphragmatic surfaces and omentum, through inspection and palpation.  Following pathological evaluation of these materials, pathological stage is determined and decision for adjuvant treatment is based on this result. If lymphatic dissection is not included in surgery, sufficient pathological staging cannot be performed. Follow- up only and EBRT have been compared in studies evaluating adjuvant treatment indications in patients who had lymphatic dissection, and it has been found that LC is increased by EBRT, while radiation related complications are also increased.  It has been found in GOG 99 study that recurrence is reduced from 12% to 3% by EBRT without any positive contribution to OS.  In studies comparing EBRT and ICRT, no significant difference has been found between low and intermediate risk groups, complications were increased in EBRT and ICRT provided sufficient LC with minimal morbidity.  It has been suggested that EBRT is not necessary in this risk group. , ICRT alone has been recommended to reduce the complications associated with EBRT.  In the PORTEC2 study, vaginal recurrence was noted in 1.8% by ICRT and in 1.6% by EBRT (P = 0.74). Locoregional recurrence was 5.1% by ICRT and 2.1% by EBRT (P = 0.17); isolated pelvic recurrence was 1.5% by ICRT and 0.5% by EBRT (P = 0.30); and rate of extensive metastasis was 8.3% by ICRT and 5.7% by EBRT (P = 0.46), which were all similar. OS and DFS results were also similar. In contrast, acute GI Grade I-II toxicity rates was lower in those treated by ICRT (12.6%) compared to those treated by EBRT (53.8%). Due to comparable treatment outcome despite lower toxicity, ICRT has been recommended as adjuvant treatment alternative in this group.  Since having a patient population referred from different regions of the countary having undergone different surgical procedures lymphoid dissection rate was 38% in our study. Since EBRT was used in 93% of our patients due to low lymphoid dissection rate and ICRT was used in only 4.7% and comparison of outcome between these two treatment alternatives could not be made in our study.
Even if, the study had to be conducted retrospectively which leads to relatively inhomogeneous population, we stil had the chance oppurtunity to rely on a high population of patients and highly great selection of prognostic factor assessment.
Many factors affecting prognosis have been defined in patients diagnosed as endometrial cancer of all stages in several studies. These include age, stage, grade, histology, myometrial invasion, lymphovascular invasion, lymphatic ganglion involvement, tumor size, cervical invasion, adnexial involvement and intraperitoneal spread. , Prognostic factors in studies conducted in stage I patients include age, grade, the presence of LVIJ , These factors have been evaluated in our study and univariate analysis has revealed that age, menopausal status and treatment duration significantly affected OS and PFS, while it has been noted in multivariate analysis that age over 60 years and longer treatment duration statistically significantly affected OS and PFS. Age has been noted as a significant factor in all studies. Prolongation of EBRT duration also negatively influences both OS and PFS. Occurrence of acute toxicity during EBRT leads to prolongation of treatment duration and undesired early termination of treatment in some patients. Three patients could not continued treatment due to Grade II-III diarrhea and cystitis in our study. Occurrence of late toxicity by EBRT is also more than that observed by ICRT. The fact that there is no statistically significant difference between these treatments in terms of OS and PFS suggests that EBRT is not required in this risk group. Randomized studies have also produced similar results and therefore EBRT is not recommended in intermediate risk group as adjuvant treatment.  In a meta-analysis, RT has been found to reduce local recurrence in early stage endometrium cancer without any further contribution to survival. It has been reported that there was a tendency of increase in survival that did not reach a statistically significant level, only in the intermediate risk group of stage Ic and Grade III patients.  In another meta-analysis, it has been concluded that EBRT is not necessary in low risk and intermediate risk groups, and the contribution of EBRT becomes significant only in the high risk group.  In SEER retrospective analysis, it has been found that adjuvant EBRT significantly increased survival only in stage Ic.  This effect could not be analyzed because there were only 5 stage Ic patients in our study
Direct comparison between RT and CT has been made in a randomized study by JGOG.  CT with a combination of cyclophosphamid + doxorubicin + cisplatin and EBRT were compared. No significant difference was found in terms of local recurrence rate, site of recurrence and 5-year PFS and OS results. Thus, it has been suggested that CT with Cisplatin might be an effective alternative for RT in intermediate risk endometrium cancer adjuvant treatment.
All the local recurrences occurred in Gr III or stage Ic patients, as expected. No recurrences occurred in stage Ia patients. Recurrence rate for all patients was 3.4%. As probably caused by understaged cases due to incomplete staging surgery in the study population our recurrence rate was slightly higher than the rate (2.1%) found in the study which suggested ICRT as standard treatment in this risk group.  Three patients with local recurrence and all 3 patients with both local recurrence and distant metastasis were lost after a median period of 13 months. Contrastingly, it has been reported in several studies that survival is over 50% in recurrences. , It has been reported that grade and number of recurrences affected survival in patients with local recurrence. All patients who were lost were stage Ib Gr III or stage Ic in our study. No recurrences occurred in stage Ia patients.
Distant metastasis was noted in 12 patients in the whole group. Most frequent distant metastasis site was the lungs and the second most frequent site was bone. All but 2 patients with metastasis were LVI (+). Moreover, all but 4 patients were over 60 years old. All patients bearing both of the factors were lost for median 3 months (range: 1-5). Survival becomes poor in the presence of these two factors above. The negative effect of the presence of these two factors on survival has been noted also in several other studies. 
In conclusion, EBRT is not required as adjuvant treatment in intermediate risk stage I endometrium cancer. Results with ICRT are not inferior to the results obtained by the addition of EBRT. Morever, EBRT adds a toxicity load on the patients. The need for early termination of treatment or prolongation of treatment duration due to toxicity, together with age over 60 years negatively affects the outcome. Distant metastases are especially more frequent inpatients with these prognostic factors as well as Gr III histology and LVI; and survival is poor in this subgroup.
Further studies involving patients with these prognostic factors are needed in order to determine the most appropriate post-surgical adjuvant treatment approach in intermediate risk group patients bearing these characteristics.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]