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Abstract
Objective To analyze the prognostic factors and treatment outcomes in endometrial cancer patients with paraaortic lymph node metastasis.
Methods Data from four centers were collected retrospectively for 92 patients with endometrial cancer treated with combined radiotherapy and chemotherapy or adjuvant radiotherapy alone postoperatively, delivered by either the sandwich or sequential method. Prognostic factors affecting overall survival and progression-free survival were analyzed.
Results The 5-year overall survival and progression-free survival rates were 35 % and 33 %, respectively, after a median follow-up time of 33 months. The 5-year overall survival and progression-free survival rates were significantly higher in patients receiving radiotherapy and chemotherapy postoperatively compared with patients treated with adjuvant radiotherapy alone (P < 0.001 and P < 0.001, respectively). In a subgroup analysis of patients treated with adjuvant combined chemotherapy and radiotherapy, the 5-year overall survival and progression-free survival rates were significantly higher in patients receiving chemotherapy and radiotherapy via the sandwich method compared with patients treated with sequential chemotherapy and radiotherapy (P = 0.02 and P = 0.03, respectively). In the univariate analysis, in addition to treatment strategy, pathology, depth of myometrial invasion, and tumor grade were significant prognostic factors for both overall survival and progression-free survival. In the multivariate analysis, grade III disease, myometrial invasion greater than or equal to 50%, and adjuvant radiotherapy alone were negative predictors for both overall survival and progression-free survival.
Conclusion We demonstrated that adjuvant combined treatment including radiotherapyand chemotherapy significantly increases overall survival and progression-free survival rates compared with postoperative pelvic and paraaortic radiotherapy.
- endometrial cancer
- radiotherapy
- chemotherapy
- lymph node metastasis
- paraaortic lymph node
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The optimal treatment strategy is unknown for stage IIIC2 endometrial cancer.
Outcomes for 92 patients with stage IIIC2 disease were assessed retrospectively.
Adjuvant radiotherapy and chemotherapy increases survival in stage IIIC2 patients.
Introduction
Endometrial cancer is the most common gynecologic malignancy.1 The majority of patients with endometrial cancer are diagnosed with tumors confined to the uterus and have an excellent prognosis. However, 8%–10% of patients have lymph node metastasis at the time of surgery, categorized as stage IIIC.2 3 Patients with stage IIIC disease are divided into those with pelvic lymph node metastasis (stage IIIC1) and those with paraaortic lymph node metastasis with or without pelvic nodal involvement (stage IIIC2). The 5-year survival rates for stage IIIC2 patients range from 36%–75%.3–5 Although some studies suggest a worse prognosis, others do not. Patients with stage IIIC2 disease have a worse prognosis than patients with stage IIIC1 disease: however, other studies found no differences in rates of survival or failure between these two groups.6 7
The role of adjuvant therapy for patients with stage IIIC disease is not well defined, but postoperative adjuvant therapy is preferred to reduce locoregional recurrence and distant metastasis. Adjuvant treatment options include radiation therapy alone, chemotherapy alone, or a combination of radiotherapy and chemotherapy.5 8–12
Although the survival rates of stage IIIC1 and IIIC2 are different, the patients with stage IIIC1 and stage IIIC2 disease are treated in similar fashion. Additionally, the outcomes of stage IIIC1 and IIIC2 endometrial cancer patients have commonly been analyzed together due to the low incidence of paraaortic lymph node metastasis in endometrial cancer patients. However, it is unclear whether such analyzes are valid for endometrial cancer patients with stage IIIC2 disease. Thus, we investigated how tumor characteristics and adjuvant treatments influence survival in stage IIIC2 endometrial cancer patients in a large, multicenter, retrospective study so as to better understand the factors that can help clinicians make treatment decisions.
Methods
Patient selection
Electronically stored clinical data from 259 endometrial cancer patients with lymph node metastasis, treated between 2000 and 2016 at four different university hospitals, were retrospectively reviewed. All patients underwent total hysterectomy, bilateral salphingo-oopherectomy, and bilateral pelvic and paraaortic lymph node dissection. Of the 259 patients with lymph node metastasis, 92 patents (36%) with pelvic and paraaortic metastases were analyzed. The study was approved by the Institutional Review Board before collection of any patient information.
Treatment protocol
Adjuvant therapy was administered at the discretion of the physician. Patients receiving adjuvant therapy were treated with either radiotherapy alone (32 patients, 35%) or combined chemotherapy and radiotherapy (60 patients, 65%). All patients were treated with external beam radiotherapy using a total dose of 50.4 Gy to the pelvis over 5 weeks, with a daily fraction size of 1.8 Gy using 18 or 25 mV photon energies. Radiotherapy was administered via a four-field technique employing a 18 MV linear accelerator with custom multi-leaf collimation blocking. Certain patients underwent intensity-modulated radiotherapy to further spare healthy tissues. The irradiated fields encompassed both pelvic and paraaortic lymphatic chains. The addition of vaginal cuff brachytherapy was left to the discretion of the treating physician. Vaginal cuff brachytherapy delivery consisted of three to four high-dose rate applications, and the prescribed brachytherapy dose was delivered to a plane that was 5 mm deep to the vaginal mucosa.
Patients began the chemotherapy regimen within 2–3 weeks after surgery. The combination of chemotherapy and radiotherapy was delivered in one of two ways: sandwich chemotherapy and radiotherapy, where three cycles of chemotherapy were followed by radiotherapy and three additional cycles of chemotherapy (25 patients, 42%); and sequential chemotherapy and radiotherapy, where all six cycles of chemotherapy were delivered initially, and radiotherapy was given after completion of chemotherapy (35 patients; 58%). The chemotherapy regimen included carboplatin (area under the curve of 5 or 6) and paclitaxel (175 mg/m²) every 21 days.
Clinical follow-up
A radiation oncologist followed all patients during the courses of radiotherapy and, in conjunction with a gynecologic oncologist, monitored patients every 3 months for the first 2 years, every 6 months until year 5, and annually thereafter. Complete physical and gynecologic examinations were periodically performed, as were routine complete blood cell counts, serum biochemical tests, and chest X-rays. Biopsies were reserved for suspicious lesions only.
Treatment toxicities were assessed according to the Common Terminology Criteria for Adverse Events, version 4.0. Radiation-related gastrointestinal system and genitourinary system toxicities and hematologic toxicities were analyzed. Additionally, treatment breaks during radiotherapy delivery were assessed.
Statistical analysis
All statistical analyzes were performed using standard software (SPSS, version 20; SPSS Inc., IBM, Chicago, IL). The primary outcomes of interest were overall survival and progression-free survival. Time to death or progression was calculated as the period from date of diagnosis to date of death or first evidence of disease recurrence. Both overall survival and progression-free survival were evaluated for all patients and also those with endometrioid adenocarcinoma. A separate analysis was not carried out for patients with nonendometrioid histology, because of limited patient numbers (26 patients, 28%). Both overall survival and progression-free survival rates were estimated using the Kaplan–Meier method. Age (<60 years vs. ≥60 years), histology (endometrioid vs nonendometrioid), myometrial invasion rate (<50% vs.≥50%), lymphovascular space invasion (absent vs present), tumor grade (G1 and 2 vs G3), number of metastatic paraaortic lymph nodes, adjuvant treatment (radiotherapy alone vs a combination of radiotherapy and chemotherapy), and vaginal cuff brachytherapy (absent vs present) were analyzed for their association with overall survival and progression-free survival. The Chi-square test or Student’s t test were used to analyze differences in the clinical and pathological factors between the sandwich and sequential delivery arms. Predictions of progression-free survival and overall survival were represented by univariate and multivariate models for all patients. Univariate analyzes were performed via log-rank tests. Multivariate analyzes were performed using the Cox proportional hazards model, using covariates with a P value less than 0.10 based on univariate analyzes. All P values less than 0.05 were statistically significant.
Results
Patient characteristics
As demonstrated in Figure 1, the 5-year overall survival and progression-free survival rates were significantly lower in patients with stage IIIC2 disease than in patients with stage IIIC1 disease (67% vs 35%, P<0.001% and 61% vs 33%, P<0.001, respectively). Characteristics of the 92 patients with paraaortic lymph node metastasis, according to treatment arm, are presented in Table 1. The median age of patients in the entire cohort was 62 years (range, 40–88 years). The predominant histology was endometrioid adenocarcinoma (72%), whereas 28% of patients had a nonendometrioid histology (papillary serous carcinoma (10 patients, 11%), mixed tumor (11 patients, 12%, and clear cell carcinoma (five patients, 5%)). The median number of total dissected pelvic and paraaortic lymph nodes was 41 (range, 10–162), and the median numbers of dissected and metastatic paraaortic lymph nodes were nine (range, 2–61 nodes) and two (range, 1–20 nodes), respectively. The mean primary tumor size was 5.2±2.1 cm.
(A) Overall and (B) progression-free survival of patients with pelvic lymph node metastasis (stage IIIC1) and patients with paraaortic lymph node metastasis (stage IIIC2).
Patient and tumor characteristics according to the adjuvant treatment protocol
A combination of chemotherapy and radiotherapy was delivered to 60 patients (52%), whereas 32 patients (35%) were treated with adjuvant radiotherapy only. The median total external radiotherapy dose was 50.4 Gy (range, 40–50.4 Gy). The median total brachytherapy and fractional brachytherapy doses for those who received vaginal cuff brachytherapy were 18 Gy (range, 12–28 Gy) and 6 Gy (range, 3–7 Gy), respectively.
In the combination chemotherapy and radiotherapy arm, all patients received the planned radiotherapy doses, but only 50 patients (83%) completed the chemotherapy regimen as planned, whereas 10 patients (17%) received fewer than the planned six cycles of chemotherapy. The median number of adjuvant chemotherapy cycles was six (range, 3–6 cycles). Only two patients (6%) did not complete the radiotherapy as planned, whereas 94% of patients (30 patients) finished the radiotherapy schedule as planned.
Treatment outcomes
The median follow-up times for the entire cohort and those who survived were 33 months (range, 2–189 months) and 63 months (range, 13–189 months), respectively. The 3- and 5-year overall survival were 52% and 35%, and the 3- and 5 year progression-free survival were 48% and 33%, respectively.
Overall, 46 patients (50%) developed disease recurrence, of which 24 patients (52%) were distant, six patients (13%) were locoregional, and 16 patients (35%) were both locoregional and distant metastases at the last visit.
There were no significant differences in recurrence rates between those treated with adjuvant radiotherapy alone and those treated with a combination of chemotherapy and radiotherapy (18 patients (39%) vs 28 patients (61%); P=0.3). Although distant metastasis was predominantly seen as initial recurrence, there were no differences in the incidence of distant metastases between patients receiving adjuvant radiotherapy alone and those receiving a combination of chemotherapy and radiotherapy (54% vs 46%; P=0.2). At the final follow-up, 30 patients (33%) were alive (one (1%) with disease), and 62 patients (67%) had died (45 (49%) of endometrial cancer: 17 (18%) of other causes).
Prognostic factors for overall survival and progression-free survival
The 5-year overall survival rates were significantly higher in patients receiving a combination of radiotherapyand chemotherapy compared with patients treated with adjuvant radiotherapy alone (46% vs 16%; P<0.001) (Figure 2A). Similarly, there was a statistically significant difference between the combination and single treatments for the 5-year progression-free survival rates (44% vs 16%; P<0.001) for the entire cohort (Figure 2B). In the univariate analysis, in addition to treatment strategy, pathology, depth of myometrial invasion, and tumor grade were significant prognostic factors for both overall survival and progression-free survival (Table 2). Vaginal brachytherapy boost after external radiotherapy had no significant impact on either overall survival or progression-free survival.
(A Overall and (B) progression-free survival of patients treated postoperatively with radiotherapy alone or combined radiotherapy and chemotherapy in entire cohort. (C) Overall and (D) progression-free survival of patients treated postoperatively with radiotherapy alone or combined radiotherapy and chemotherapy in patients with an endometrioid histology.
Univariate analysis of prognostic factors for overall survival and progression-free survival
In patients with an endometrioid histology, the 5-year overall survival rates were significantly higher in patients receiving a combination of chemotherapy and radiotherapy compared with patients treated with adjuvant radiotherapy alone (54% vs 20%; P<0.001) (Figure 2C). Similarly, the 5-year progression-free survival rates were 50% in patients receiving adjuvant chemotherapy and radiotherapy, and 20% in patients treated with adjuvant radiotherapy alone (P<0.001) (Figure 2D).
There were no significant difference in age, histology, myometrial invasion rate, lymphovascular space invasion, tumor grade, number of metastatic paraaortic lymph nodes, adjuvant treatment, and vaginal cuff brachytherapy rates between patients treated with the sandwich method and patients receiving sequential treatment. In a subgroup analysis of patients treated with a combination of adjuvant chemotherapy and radiotherapy, the 5-year overall survival rates were significantly higher in patients receiving chemotherapy and radiotherapy via the sandwich method compared with patients receiving chemotherapy and radiotherapy sequentially (62% vs 35%) (Figure 3A). Similarly, patients in the sandwich delivery arm had significantly higher 5-year progression-free survival rates compared with patients in the sequential delivery arm (57% vs 35%; Figure 3B).
(A) Overall and (B) progression-free survival of patients treated postoperatively with sandwich chemotherapy and radiotherapy or sequential chemotherapy and radiotherapy.
In the multivariate analysis, grade III disease, myometrial invasion of at least 50%, and adjuvant radiotherapy alone were negative predictors for both overall survival and progression-free survival (Table 3). Furthermore, a nonendometrioid histology tended to predict worse overall survival and progression-free survival (P=0.06).
Multivariate analysis of prognostic factors for overall survival and progression-free survival
Toxicity
Acute grade I and II gastrointestinal system and genitourinary system toxicities for the entire group were 46% and 21%, respectively. Grade III gastrointestinal system toxicity was observed in four patients (4%): two patients in the radiotherapy alone arm and two patients in the adjuvant combination chemotherapy and radiotherapy arm. The rate of acute grade I and II gastrointestinal system toxicities was significantly higher in the combination chemotherapy and radiotherapy arm compared with radiotherapy alone (53% vs 31%; P=0.03). However, there were no significant differences in acute grade I and II genitourinary system toxicities in patients treated with either the combination of chemotherapy and radiotherapy or radiotherapy alone (23% vs 16%; P=0.3). Undesired treatment breaks during radiotherapy were observed in 13 patients (14%): 10 patients (11%) in the combination therapy arm and three patients (4%) in the radiotherapy alone arm (P=0.3). The incidence of neutropenia higher than grade II was 14% in patients treated with a combination of chemotherapy and radiotherapy, and 10% in patients treated with adjuvant radiotherapy (P=0.7). There were no significant differences in gastrointestinal system and genitourinary system toxicities between the sandwich and sequential chemotherapy and radiotherapy arms. There were no treatment-related deaths in the entire cohort.
Discussion
In the current study, we demonstrate that the adjuvant combination of radiotherapy and chemotherapy increases overall survival and progression-free survival in endometrial cancer patients with paraaortic lymph node metastasis. Additionally, the sandwich delivery of radiotherapy and chemotherapy significantly increases survival compared with sequential delivery. Although both the single and combination treatments were well-tolerated, combined chemotherapy and radiotherapysignificantly increased grade I and II acute GIS toxicities compared with patients receiving adjuvant radiotherapy alone. These results allow a better understanding of the factors that can help clinicians make treatment decisions.
Lymph node metastasis is the most common prognostic factor for endometrial cancer patients, and survival rates in patients with paraaortic lymph node metastasis is significantly worse than in patients with pelvic lymph node metastasis.13 14 Many researchers believe that systematic lymphadenectomy increases survival in intermediate or high-risk endometrial cancer patients.10 15 The rate of paraaortic lymph node involvement in the presence of pelvic lymph node metastasis is approximately 30%–50%, and higher numbers of dissected lymph nodes are associated with a higher likelihood of lymph node metastasis.16 17 Our data showed that 36% of patients have paraaortic lymph node metastasis in the presence of metastatic pelvic lymph nodes, consistent with reports from the literature.
Consistent with other studies, the 5-year overall survival for the study cohort was 35%, comparable to overall survival rates for patients with endometrial cancer stages IIIC1 and 2.2 6 12 13 18 19 We also found that the most common site of initial recurrence was distant, similar to Turan et al's study.20 We demonstrated that histologic grade and depth of myometrial invasion were independent predictors of overall survival and progression-free survival. Additionally, we found that patients with nonendometrioid node-positive endometrial cancer had worse clinical outcomes than did those with endometrioid carcinoma.4 21
Data from current studies of stage IIIC endometrial cancer in which patients have been surgically staged are limited. Since local recurrence and distant metastases are higher in patients with stage IIIC disease, many efforts have been made to improve their prognosis. However, there is no consensus on the optimal adjuvant treatment strategy for such patents.22–24
Adjuvant radiotherapy is a common approach for patients with locally advanced endometrial cancer.18 25 Recently, 5-year survival rates of 46% were reported in 50 patients treated for paraaortic lymph node metastases.19 High rates of distant recurrences has led to concerns about the insufficiency of radiotherapy alone for the postoperative treatment of stage IIIC endometrial cancer patients: thus, there are few articles dealing with long-term survival in patients with systematic lymphadenectomy followed by postoperative adjuvant chemotherapy.12 19 26 Both 5- and 10-year overall survival rates for 21 patients with paraaortic lymph node metastasis treated with systematic lymphadenectomy and postoperative chemotherapy were 72% and 62%, respectively.12 Since chemotherapy reduces the risk of distant metastasis, the combination of chemotherapy and radiotherapy may improve both local control and distant metastasis. Recent prospective studies exploring the efficacy of concurrent chemotherapy and radiotherapy in advanced endometrial cancer have reported improved survival with acceptable toxicity profiles.27–30 Pooled data of two randomized clinical trials (NSGO-endometrial cancer-9501/EORTC-55991 and MaNGO ILIADE-III) were conducted to investigate whether adjuvant chemotherapy and radiotherapy would improve outcomes in women with FIGO stage I–III endometrial cancer with high-risk features.27 The authors reported that sequential chemoradiotherapy resulted in a statistically significant improvement in cancer-specific survival (P=0.01) and a trend toward an overall survival benefit (P=0.07). Recently, Lee et al4 evaluated the treatment outcomes of 61 stage IIIC2 endometrial cancer patients treated with different adjuvant therapies (40 patients received chemotherapy and radiotherapy, 17 patients received chemotherapy alone, and four patients received radiotherapy alone). The authors concluded that the type of adjuvant treatment modality has no significant impact on survival. Although studies demonstrating the efficacy of combined chemotherapy and radiotherapy are based mainly on patients with locally advanced endometrial cancer or those with high-risk features, there are no clear data demonstrating the efficacy of combined chemotherapy and radiotherapy in stage IIIC2 endometrial cancer patients. Additionally, studies have evaluated the survival and prognostic factors in locally advanced endometrial cancer consisting of different histological types that were treated with different modalities. We found that adjuvant combined chemotherapy and radiotherapy after systematic pelvic and paraaortic lymph node dissection significantly improved overall survival and progression-free survival for the entire cohort and patients with an endometrioid histology.
Considering the significant rate of distant metastasis as the first site of recurrence in this current study cohort, optimization of systemic therapy is clearly a high priority in patients with stage IIIC2 endometrial cancer. Although adjuvant carboplatin and paclitaxel is a commonly used chemotherapy regimen for advanced stage endometrial cancer that has demonstrated both efficacy and manageable toxicity, the optimal sequencing of chemotherapy and radiotherapy still remains unanswered. A series of studies have supported the sandwich method for the treatment of stage III endometrial cancer and reported 3-year progression-free survival rates of 53%–80% and 3year overall survival rates of 52%–90%.31–33 In this current study, all patients received adjuvant paclitaxel and carboplatin either in the sequential arm (58%) or in a ‘sandwich’ protocol (42%). We demonstrated that a sandwich combined modality significantly increases overall survival and progression-free survival compared with sequential chemotherapy and radiotherapy without any difference in GIS and GUS toxicity rates.
Our study is not without inherent limitations due to its retrospective nature and associated selection biases. Additionally, we could not perform survival analyzes of patients treated with adjuvant chemotherapy alone, since the treatment policy for stage IIIC endometrial cancer at our centers is postoperative adjuvant radiotherapy with or without chemotherapy. Since our data was retrospectively collected, we could not assemble some factors that may potentially affect the survival, including cervical invasion, performance score, and comorbidities. Lastly, determination of overall toxicity was performed from patient charts retrospectively. We could only analyze acute toxicities that occurred during chemotherapy and radiotherapy delivery, whereas neurotoxicities caused by systemic chemotherapy were not analyzed. Despite these limitations, our findings are important in demonstrating the efficacy of combined chemotherapy and radiotherapy to treat stage IIIC2 endometrial cancer patients.
Conclusions
Despite the efficacy of combined modality that was demonstrated compared with radiotherapy alone, higher rates of distant metastasis still remains a major problem calling for further optimization of effective systemic therapy. Since the survival rates were low in patients with stage IIIC2 endometrial cancer, patients with grade III disease and more than 50% myometrial invasion had worse overall survival and progression-free survival rates. Additionally, if adjuvant chemotherapy is delivered together with radiotherapy, sandwich modality significantly increases the survival compared with sequential chemotherapy and radiotherapy delivery.
References
Footnotes
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent Not required.
Provenance and peer review Not commissioned; externally peer reviewed.