Scotti, Vieri MD*; Borghesi, Simona MD†; Meattini, Icro MD*; Saieva, Calogero MD‡; Rossi, Francesca MD§; Petrucci, Alessia MD∥; Galardi, Alessandra MD*; Livi, Lorenzo MD*; Agresti, Benedetta MD*; Fambrini, Massimiliano MD¶; Marchionni, Mauro MD¶; Biti, Giampaolo MD*
Endometrial carcinoma (EC) is the most common malignancy of the female genital tract and represents 6% of all cancers in the women. Postmenopausal women are the most affected, with age of maximal incidence between 50 and 70 years. Its incidence was increasing in the last decades. Endometrial carcinoma is usually diagnosed in an early stage and has a relatively good outcome after multimodality treatment with a combination of surgery and adjuvant radiotherapy (RT).1,2 Total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO) remains the foundation of treatment, whereas the use of a systematic pelvic lymphadenectomy is still debated.3 Most trials showed that postoperative RT reduces the risk of local recurrence (LR), without improving overall survival (OS). Postoperative RT could be important particularly for high-risk women with early-stage disease.4-7
In our study, we retrospectively analyzed 883 patients treated in our institution over a period of 30 years with postoperative RT after surgical approach.
The aim of our study was to analyze the prognostic factors used in the selection of women for postoperative RT, to evaluate the role of pelvic lymphadenectomy, and to demonstrate if postoperative whole pelvic radiotherapy (WPRT) is an effective and safe treatment. We, therefore, retrospectively analyzed 883 patients who were treated at our institution over a period of 32 years (January 1975 to April 2007) with postoperative RT after surgical approach.
MATERIALS AND METHODS
A total of 883 patients with pathological stage I-II EC were surgically treated at Careggi Hospital-University of Florence between January 1975 and April 2007. The median follow-up time was 9 years (range, 1.2-27.6 years). The main patients' characteristics are summarized in Table 1.
Pretreatment evaluation included physical examination, abdominal ultrasound or computed tomographic scan, chest x-ray, and endometrial biopsy. No patients had distant metastases (DMs) at the time of the diagnosis.
The surgical treatment consisted of TAH/BSO or vaginal hysterectomy with BSO in 532 patients (60.2%) and in TAH/BSO with systematic pelvic lymphadenectomy in 351 patients (39.8%).
All patients underwent adjuvant RT. In our institution, adjuvant RT is recommended in patients with more than 50% of myometrial invasion (MI; International Federation of Gynecology and Obstetrics [FIGO] stage IC) and in case of involvement of cervical mucosa (FIGO stage IIA) or cervical stroma (FIGO stage IIB); in patients with less than 50% of MI, RT is prescribed in case of poorly differentiated tumors (grade 3), age of more than 60 years, and nonendometrioid histotype.
Adjuvant RT consisted of WPRT or combined WPRT and vaginal brachytherapy (BT) boost in 747 (84.6%) and 136 patients (15.4%), respectively. Whole-pelvic radiotherapy was delivered by 10 to 25 megavolt linear accelerator from 1985; before 1985, patients were treated with telecobaltotherapy. The median prescribed dose was 50.75 Gy (range, 38-60 Gy) in 1.8- to 2-Gy daily fractions.
The technique of WPRT changed over time: 3-dimensional (3D) conformal radiotherapy (CRT) planning was introduced in 2000, opposing posteroanterior/anteroposterior field technique was used in the beginning, and then 4-field box technique was used. The clinical target volume was defined to include the upper two thirds of the vagina, paravaginal tissues, and regional lymph nodes (common, internal, and external iliac nodes and presacral nodes). The upper border limit was defined at the L5-S1 interspace, the caudal border extended to the inferior limit of the obturator foramen. The lateral border included the widest opening of the bony pelvis with a 1.5-cm margin. For the box technique, the lateral fields extended from the anterior aspect of the pubic symphysis to the S2-S3 interspace. Individual shielding for femoral heads, small bowel, and soft tissue outside the target volume were defined.
Brachytherapy boost was generally indicated in stage II patients. Ninety-three stage II patients did not undergo BT for refusal of the women or for logistic reasons. Brachytherapy was delivered with low dose rate (LDR) after-loading using vaginal cylinder with 192Ir source. The median dose given was 24 Gy (range, 15-50 Gy) prescribed at the surface of the vaginal cylinder after WPRT. No patient received whole abdominal RT or para-aortic RT.
After the completion of RT, all patients were followed at our department by a radiation oncologist. Patients were followed in outpatient clinic for a 10-year period; afterward, an annual telephonic follow-up was performed. The follow-up evaluation included physical and gynecological examination; yearly abdominal ultrasound or, for the first 2 years, abdominal computed tomographic scan; yearly or biannual chest x-ray; and yearly vaginal-cuff cytology. Other investigations were performed whenever clinically appropriate. Patients were evaluated every 6 months for the first 5 years, then annually. Recurrences were diagnosed by clinical examination and imaging, and biopsy was performed where required.
For the survival analysis, the date of surgery was used as the start of observation. Disease-free survival (DFS) time was calculated from the date of surgery to the date of LR or metastases occurrence. Survival time was calculated from the date of surgery to the date of last follow-up or date of death. Overall survival was calculated from the date of surgery to the date of last follow-up or death.
The crude probability of survival or relapse/metastasis occurrence was estimated by using the Kaplan-Meier method, and differences between patient groups were assessed by the log rank test. Survival comparisons were carried out using Cox proportional hazard regression models.
Estimated relative risks of death or relapse/metastasis occurrence were expressed as hazard ratios (HR) and corresponding 95% confidence intervals. Univariate models were performed to evaluate the effect of each specific parameter. Multivariate model (with stepwise selection) was performed to identify the major significant predictors of death or relapse/metastasis occurrence.
Statistical results were considered significant at P < 0.05. All statistical tests were performed by the SAS software (SAS, Cary, NC).
The median age at presentation was 62.5 years (range, 26-85 years). The histological type, stage, and grade of tumor are presented in Table 1. The most frequent histological subtype was endometrioid adenocarcinoma and its variants, which was found in 819 patients (97%). Clear cell or papillary serous carcinomas were detected in 25 patients (3%). According to FIGO classification,8 654 (74.1%) women had stage I disease and 229 (25.9%) had stage II disease.
At the time of the analysis, 80.1% of the patients were alive and 6.8% died of EC. Incidence of LR, DM, and vital status at the end of follow-up are shown in Table 2.
Site of Relapse Data
Sites of failure were classified as locoregional and distant (Table 3). Locoregional relapses included vaginal, pelvic, and para-aortic nodal relapses, and ascites, whereas distant relapses were those located elsewhere. Ninety-four patients (10.6%) developed disease recurrence; among these, 47 patients (5.3%) experienced LR, 38 patients (4.3%) experienced DM, and 9 patients (0.1%) experienced both LR and DM (data not shown). In the latter 9 patients, DM appeared within 1 year from the diagnosis of LR.
In Table 4, we report the impact of selected parameters (age, stage, histotype, grading, depth of MI, adjuvant RT technique, and extent of surgery) on OS.
At univariate analysis, the younger patients had a reduced risk of death by EC; the patients older than 70 years had a 9-fold higher risk of death than the younger patients (HR, 9.43; 95% confidence interval [CI], 4.02-22.12); the risk of death increased proportionally with age more than 51 years, and the difference was statistically significant (P < 0.0001).
Survival was significantly associated with the stage (P = 0.04) and the grade (P = 0.02) of the tumor: the stage II patients had a significantly increased risk of death than the stage I patients, and the patients with grade 2 or 3 disease had a significantly increased risk of death compared with the patients with grade 1 disease.
The histological type as well seemed to influence survival (P < 0.0001) in this series: the patients with clear cell or papillary serous carcinomas had a 4-fold higher risk of death than those with endometrioid adenocarcinoma and its common variants (HR, 4.63; 95% CI, 2.34-9.14).
Local recurrence seemed to be significantly related with OS (P < 0.0001; Fig. 1): the patients who developed LR after surgery and adjuvant RT had a 17-fold higher risk of death compared with the patients without LR (17.3; 95% CI, 11.8-25.4).
At the multivariate regression analysis with stepwise selection, age at presentation, histotype, and grading reached the statistical significance (P = 0.0001, P = 0.0001, and P = 0.01, respectively), thus resulting in independent prognostic factors for OS.
The factors associated with poor DFS rates (LR occurrence) at the univariate analysis were stage II disease (P = 0.04; HR, 1.77; 95% CI, 1.02-3.05) and clear cell/papillary serous carcinomas histotype (P = 0.0006; HR, 4.43; 95% CI, 1.76-11.14; Table 5). At the multivariate analysis with stepwise selection, only the histotype emerged as independent relapse predictor (P = 0.0001).
Our results showed a significant association between DM rates and histotype and grading, at univariate (P = 0.002 and P = 0.01, respectively; Table 6) and multivariate regression analyses (P = 0.0001 and P = 0.005, respectively).
We analyzed WPRT-related toxicity according to EORTC toxicity criteria (Table 7). The most common toxicity was gastroenteric: diarrhea was observed in 19.8% of the patients and proctitis was observed in 8.8% of the patients. Cystitis developed in 9.6% of the patients, and vaginitis developed in 1.9% of the patients; in 62 patients (7% of the series), we recorded cutaneous acute skin reaction during treatment. Most of the acute toxicities were grades 1 and 2 (95.2%), and it was well manageable with medications; no grade 4 toxicity was observed. Concerning long-term adverse effects of WPRT, we globally observed 69 events (7.8%), and most events (73.9%) were in grade 1 or 2 toxicity. The remaining 18 events included 2 patients with pelvis bone fracture, 3 patients with chronic subacute small bowel obstruction, 4 patients with painful urination due to reduction of bladder function, 5 patients with dyspareunia after WPRT and BT, 1 case of cutaneous ulcers, and 3 cases of extensive telangectasia in the treatment field.
The role of external beam RT (EBRT) in optimally operated stage I and II EC has been investigated in randomized and retrospective series, and it is still being debated.5-8
Aadlers,5 in a series of 540 patients, showed that EBRT did not influence OS, but in the no-EBRT group, they statistically found more vaginal and pelvic recurrence (6.9% in the no-EBRT group vs 1.9% in the EBRT group; P < 0.01). They suggested EBRT in case of poorly differentiated endometrial carcinoma (G3) and more than 50% of MI.
Postoperative radiotherapy endometrial cancer-1 is a large, international, randomized trial of 715 patients treated with TAH/BSO. It considered all moderately differentiated (G2) EC, patients with well-differentiated (G1) EC with more than 50% of MI and G3 EC with less than 50% of MI. In view of the significant locoregional control benefit (5% of LR in RT group vs 14% in no-RT group), WPRT was indicated in selected patients, with high-risk features of LR (ie, age >60, G1-G2 with >50% of MI, all G3).6,7
A phase III trial published in 2004 by the Gynecologic Oncology Study Group (GOG) is usually reported as GOG 99 trial. In this series, 392 intermediate-risk EC patients (defined as all women found to have any degree of MI, with adenocarcinoma of any grade, and no-evidence of lymph node involvement) were treated with TAH/BSO plus pelvic and para-aortic lymphadenectomy and randomly assigned to 50.4 Gy to pelvis versus no-EBRT. From GOG 99 analysis, a subgroup of high intermediate-risk EC emerged: (a) G2-G3 tumors, with lymphovascular invasion and outer third MI, (b) age 50 years or more with any 2 risk factors listed above, or (c) age of at least 70 years with any risk factor listed above. They demonstrated that EBRT significantly reduced the risk of recurrence in intermediate-risk EC, but WPRT should be limited to patients whose risk factors fit a high intermediate-risk definition.8
A recent pooled trial was published by the ASTEC/EN.5 Study Group about 905 intermediate- or high-risk, early-stage EC treated with TAH/BSO or TAH/BSO plus pelvic and/or para-aortic lymphadenectomy. The authors showed that the use of BT could reduce the isolated recurrence rate at 5 years to 6.1%, whereas the local effect of EBRT is therefore only modest. They concluded that EBRT cannot be recommended as part of routine treatment to improve survival for women with early EC at intermediate- or high-risk recurrence, and BT might be preferred for local control.4
Most recent randomized data from the PORTEC-2 trial, undertaken in 19 Dutch radiation oncology centers, evaluated 427 patients with stage I or IIA EC of high intermediate risk: they were randomly assigned to EBRT versus vaginal BT. In this relevant study, BT was effective in ensuring vaginal control, with fewer gastrointestinal toxic effects than EBRT. The authors confirmed that BT should be the adjuvant treatment of choice for patients with endometrial carcinoma of high intermediate risk.9,10
Kong et al,11 in a recent systematic review and meta-analysis (Cochrane meta-analysis) of 4 completed randomized trials, presented data for 1770 women and showed that adjuvant RT reduces the risk of pelvic recurrence with no evidence that it improves OS.
A benefit in OS for patients with stage IC/grade 1 (P < 0.001) and stage IC/grades 3 and 4 (P < 0.001) disease was demonstrated by Lee in 2006 in the largest population analysis of adjuvant RT. The series reported data of more than 21,000 patients and revealed a statistically significant association between improved overall and relative survival and WPRT in stage IC disease.12
Our results in LR and DM are consistent with several retrospective series, which showed relapse rates of 15% to 20%, of which 4% to 7% are LR and 7% to 17% are DM.13
Over the past few decades, several studies have demonstrated the prognostic importance of different parameters including lymph node status, histological type of carcinoma (serous carcinoma and clear cell carcinomas are poor prognostic types), histological grade, stage of disease, depth of MI, lymphovascular space involvement, and cervical involvement. In agreement with the major studies of the literature,10,13-15 in our series, stage and grading emerged as significant prognostic factors at univariate and multivariate analyses.
On the contrary, in our experience, depth of MI did not show a significant impact on OS and on DFS; this is probably because of the paucity of patients with less than 50 % of MI: it can be a bias of our nonrandomized series.
Brachytherapy was suggested to all stage II patients, but only 136 of 229 underwent treatment after WPRT. In our study, however, the omission of BT was not correlated with a higher incidence of vaginal relapse. Analyzing the dose distribution to the vaginal vault in the WPRT treatment plans, we found an excellent coverage of the target with at least 95% of the prescribed dose, and this can probably explain the low rate of vaginal recurrence in stage II patients treated with WPRT only.
Younger age has been associated with worse outcome in EC patients; older women have a significantly decreased OS, cause-specific survival, and a greater risk of recurrence after postoperative RT.16 In our series, the risk of death increased proportionally in the patients older than 51 years, and the patients older than 70 years had a 9-fold higher risk of death than the younger ones.
Several studies demonstrated the prognostic importance of various key surgical and pathological parameters, including histological type. Clear cell and papillary serous carcinomas account for only 15% to 20% of the cases and show an aggressive behavior and a poor prognosis.17 In our study, the patients with clear cell and papillary serous carcinomas had a 4-fold higher risk of death than those with endometrioid adenocarcinoma and its common variants (P < 0.0001). Moreover, the histotype emerged as an independent relapse predictor (P = 0.0001), and it is significantly associated to a higher risk of DM at univariate and multivariate regression analyses.
Our Department's policy to treat with WPRT the early-stage EC patients has not been changed despite the increasing attitude of gynecologic oncologists to perform a systematic pelvic and/or para-aortic lymphadenectomy. However, neither the incidence of LRs nor the long-term treatment-related consequences of multimodality treatments seem to be different in patients treated with WPRT after TAH/BSO with or without lymphadenectomy (P = 0.19). It should be of some interest to compare patients with early EC treated with lymphadenectomy (without EBRT) and patients treated with EBRT (without lymphadenectomy), but this comparison is outside the scope of the present study and will be the subject of further studies.
Our data on patients treated with or without pelvic lymphadenectomy recall Benedetti Panici's randomized trial and MRC ASTEC Trial, which did not identify significant differences in OS and DFS between the 2 groups.3,18,19
According to accepted guidelines, we think that TAH/BSO should be considered the standard approach for fit patients. Despite that the FIGO classification of the stages of endometrial cancer has required a full systematic pelvic and para-aortic lymphadenectomy, future analysis are advocated to clarify the role of systematic lymphadenectomy in endometrial cancer and if a systematic pelvic and para-aortic lymphadenectomy can avoid WPRT in early-stage EC.20,21 Intraoperative analysis by frozen section of histopathological risk factors performed by experienced gynecopathologists22,23 represents a validated and applicable tool in estimating the risk of lymph nodes involvement allowing an optimized use of lymphadenectomy and consequently allowing oncologists to tailor adjuvant treatment on a complete pathological staging (ie, to recognize patients who can benefit from an association of EBRT and chemotherapy).24
On the other hand, vaginal hysterectomy with BSO can be considered a valid surgical approach in early-stage EC without reducing the final opportunity of the definitive cure of the patients. Our experience showed that patients treated with vaginal hysterectomy with BSO followed by WPRT did not have a worse course in outcome than those treated with abdominal surgery. As previously reported in retrospective series comparing vaginal and abdominal surgery for early-stage EC, vaginal surgery can be considered a valid surgical option for early-stage EC in nonfit patients.25,26
The morbidity of pelvic RT should not be underestimated. Whereas the rate of serious complications is low, a number of patients report long-term symptoms, which influence quality of life.27,28 Therefore, it is necessary to weigh serious complications of adjuvant radiation against the expected benefit of treatment.
In the PORTEC-1, the 5-year actuarial rates of late complications (all grades) were 26% in the WPRT group and 4% in the control group (P < 0.0001). Most patients experienced mild symptoms, although 3% of the treated patients had severe complications.7 In a GOG study,8 most of the treated patients also experienced mild symptoms (63% grades 1-2 and 5% grades 3-4 gastrointestinal adverse effects). Six women in the RT arm experienced grade 3 or 4 small bowel obstruction versus one in the control group. Two women in the RT arm died from complications involving intestinal injury thought to be radiation related. Our data showed that WPRT might yield a good local disease control with an acceptable toxicity profile consistent with other series from the literature.29,30 Concerning long-term adverse effects of WPRT, we globally observed 69 events (7.8%), and most (73.9%) were grade 1 or 2 toxicity. In our experience, toxicity profile has not significantly changed because we routinely use 3D CRT technique. However, the number of patients treated after 2000 is widely inferior to the number of patients treated before 2000, and probably a more sophisticated technique (ie, intensity modulated radiation therapy) will provide further better results in toxicity.31
Optimizing management of women with early-stage disease requires a careful recurrent-disease risk evaluation. Our analysis showed that patients with early-stage EC have a good outcome in OS and DFS. Patients with clear cell carcinoma or papillary serous carcinoma histotype have a worse prognosis and should probably be considered separately in future analysis. Pelvic lymphadenectomy in early-stage EC did not affect LR nor increase long-term adverse effects. Whole pelvic RT with or without BT had an acceptable toxicity profile.
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