Abstract
Background:
Patients with grade 3, deeply invasive endometrioid adenocarcinoma are typically managed with primary surgery. The role and type of adjuvant therapy used is controversial. We sought to evaluate the role of adjuvant radiation and/or chemotherapy in women with deeply invasive grade 3 endometrioid tumors.
Methods:
A multi-center retrospective chart review was performed at three large medical institutions in the United States. Patients with grade 3 endometrioid adenocarcinoma invading >50% of the myometrium were included. Medical records were queried to evaluate whether lymph node assessment was performed, the status of the lymph nodes, adjuvant treatment strategy used, and dates of death or recurrence.
Results:
Between 1984 and 2013, 257 patients were identified with a median follow-up of 3.08 years. Most patients (84.7%) had evaluation of pelvic and/or para-aortic lymph nodes and 43% had positive lymph nodes. For node negative patients, there was no difference in overall survival between those who received adjuvant pelvic radiation +/− vaginal brachytherapy (n=52) versus brachytherapy alone (n=46) (5-year probabilities were 0.73 vs. 0.70, p=0.729). Among patients with positive lymph nodes (n=92), the adjuvant treatment strategy utilized impacted overall survival, with women undergoing a combination of chemotherapy and external beam radiation having the best outcomes (p=0.003).
Conclusions:
Among women with grade 3, deeply invasive endometrioid adenocarcinoma, vaginal cuff brachytherapy alone resulted in similar survival when compared to pelvic radiation in node negative patients. The combination of chemotherapy with external beam radiation was associated with improved overall survival for women with positive nodes.
INTRODUCTION
Endometrial cancer is the most common gynecologic malignancy in the United States and in the developed world1. The vast majority of these patients have early stage disease with an excellent overall prognosis. However, certain risk factors, including grade 3 histology and tumor invasion into >50% of the myometrium, significantly increase both the risk of metastatic disease at the time of diagnosis as well as risk for recurrent disease. There is currently no consensus about the optimal adjuvant therapy for early stage endometrial cancer after surgery.
Prior studies have suggested that women with grade 3 endometrioid adenocarcinoma with deep myometrial invasion should be managed postoperatively with adjuvant pelvic radiation. Compared to brachytherapy alone, pelvic radiation was shown to decrease recurrence rates from 19.5% to 4.5% and decrease cancer-related mortality from 27.5% to 18.2%2. Based on these findings, patients with grade 3 deeply invasive disease were excluded from the PORTEC-1 trial as it was felt to be unsafe for patients to be randomized to observation. It is important to note, however, that the women in these studies did not undergo lymph node evaluation at the time of surgery.
When assessment of lymph nodes is included and the nodes are negative, brachytherapy may have equivalent outcomes to pelvic radiation. A sub-analysis of GOG99 included 38 patients with stage I, grade 3, deeply invasive endometrial cancer. Overall survival among women who underwent pelvic radiation was no different than brachytherapy alone (RR=0.65 [0.29, 1.43]) 3. A retrospective review including 5 institutions also found that there was no difference in recurrence rates based on adjuvant treatment strategy used, and rates were highest among women who received pelvic radiation4.
In light of the above studies, the optimal type of adjuvant therapy for women with surgically staged, grade 3, deeply invasive endometrioid adenocarcinoma of the uterus has not yet been established. The NCCN guidelines offer multiple acceptable strategies for stage IB grade 3 disease including vaginal brachytherapy with or without pelvic radiation and/or systemic therapy5. Similarly, for stage IIIC disease, acceptable strategies include systemic therapy (with or without vaginal brachytherapy) or external beam radiation with or without vaginal brachytherapy and with or without systemic therapy5. This reflects the fact that there is no established ideal treatment for patients with deeply invasive grade 3 endometrial cancer. In this retrospective multicenter study, we aim to further characterize the recurrence and survival patterns of patients with deeply invasive grade 3 endometrial adenocarcinoma, and to explore whether one adjuvant treatment strategy is superior to the other.
METHODS
Patient Characteristics
A multicenter retrospective chart review was performed using the endometrial cancer databases maintained at 3 large academic medical centers (MD Anderson Cancer Center, Mayo Clinic, and Memorial Sloan Kettering Cancer Center). The MD Anderson database contained patients who underwent surgery for endometrial cancer at MD Anderson Cancer Center from January 2000 through December 2013. The Mayo Clinic shared 2 databases. One contained patients from 1984–1996 and the second contained patients from 1999–2008. The MSKCC database contained patients from 1999–2008.
We included all women with any stage of grade 3 adenocarcinoma of the endometrium invading more than 50% of the myometrium with clinical information available for reporting. In the pooled database, we had information about demographic data, the type of surgery performed (including whether or not lymph node status was assessed), pathologic features of the tumors, type of adjuvant therapy received, as well as progression free survival (PFS) and overall survival (OS). We had limited data on potential confounding factors due to the combined nature of the database.
Surgical Procedures
All women underwent surgery including hysterectomy; however, lymph node assessment was not performed in all patients. The reason for omitting a lymph node assessment in specific patients was not available for review. For the purposes of the combined study, having lymph node assessment performed included women who underwent pelvic and/or para-aortic lymph node dissection as well as women who underwent sentinel lymph node mapping and biopsy.
Pathology Review
Women were only included if they had grade 3 endometrioid adenocarcinoma of the uterus. Other high grade histologic subtypes and mixed tumor types were excluded. Pathology was reviewed by the institution maintaining each database.
Statistical Analysis
After institutional board review and approval at each institution, data were collected and maintained in a REDCap (Research Electronic Data Capture) database and protected health information was not shared between institutions. Descriptive statistics were used to summarize demographic and clinical characteristics. Progression-free survival was defined as time from date of surgery to recurrence or progression. Those without recurrence or progression were censored at their date of last clinical assessment. Overall survival was defined as the time from date of surgery to death from any cause. Patients alive were censored at the date of last contact. OS and PFS were estimated using Kaplan and Meier product-limit estimator and modeled with Cox proportional hazards regression. A multivariable Cox proportional hazards model was then conducted controlling for age, stage, and BMI, which were the only potential confounding variables available for review.
RESULTS
Patient and Tumor Characteristics
A total of 257 women were included in the analysis, including 34 women from MD Anderson, 126 women from Mayo Clinic, and 97 women from Memorial Sloan Kettering. Clinical and demographic characteristics are summarized in Table 1. At the time of surgery, most patients (215, 84.7%) underwent evaluation of pelvic and/or para-aortic lymph nodes with either sentinel lymph node biopsies or full lymphadenectomy (Table 1). Among women who had lymph node evaluation, 92 (43%) had positive lymph nodes. Most patients had tumors with positive lymph vascular space invasion (157, 61.1%), which is another factor associated with an increased risk of recurrence.
Table 1:
Study sample demographic and clinical characteristics
| Characteristic | N | % |
|---|---|---|
| Age at surgery | ||
| N | 257 | |
| Mean (SD) | 65.7 (12.1) | |
| Min (Med) Max | 28 (66) 95.7 | |
| BMI | ||
| N | 247 | |
| Mean (SD) | 30.0 (7.4) | |
| Min (Med) Max | 15.8 (29.5) 53.5 | |
| Institution | ||
| MDACC | 34 | 13.2 |
| Mayo | 126 | 49.0 |
| MSKCC | 97 | 37.7 |
| Race | ||
| White | 85 | 33.1 |
| Unknown | 172 | 66.9 |
| FIGO Stage | ||
| I | 92 | 36.4 |
| II | 20 | 7.9 |
| III | 96 | 37.9 |
| IV | 45 | 17.8 |
| LVSI | ||
| No | 73 | 28.4 |
| Yes | 157 | 61.1 |
| Unknown | 27 | 10.5 |
| Adjuvant therapy | ||
| No adjuvant therapy | 46 | 17.9 |
| Vaginal brachytherapy | 32 | 12.5 |
| External radiotherapy +/− brachytherapy | 72 | 28.0 |
| Chemotherapy +/− brachytherapy | 52 | 20.2 |
| Chemotherapy and external radiotherapy | 35 | 13.6 |
| Hormonal therapy | 1 | 0.4 |
| Unknown | 19 | 7.4 |
| Progression or recurrence | ||
| No | 138 | 55.7 |
| Yes | 110 | 44.4 |
| Deceased | ||
| No | 129 | 50.6 |
| Yes | 126 | 49.4 |
| Lymph node assessment performed | ||
| No | 39 | 15.4 |
| Yes | 215 | 84.7 |
| Node Status | ||
| Negative | 122 | 57.0 |
| Positive | 92 | 43.0 |
| Unknown | 43* |
1 subject with lymph node assessment performed has unknown node status, 2 subjects with lymph node assessment performed unknown.
Clinical Outcomes and Lymph Node Assessment
The median follow-up for all patients was 37.0 months and the median follow-up for women who remained alive was 66.5 months, with a range of zero to 236 months. The median progression free survival for all patients with grade 3, deeply invasive disease was 30.0 months (95% CI: 22.2–46.0) and median overall survival was 64.3 months (95% CI: 42.4–87.0).
Women who underwent lymph node assessment had improved progression free and overall survival compared to those who did not undergo lymph node assessment. Median PFS for those who underwent lymph node assessment was 30.6 months compared to 17.0 months in those patients who did not have lymph nodes assessed (p=0.001) and median OS for patients with lymph node assessment was 81.3 months compared to 31.4 months in those without assessment (p<0.001). Unstaged patients tended to be older than those who underwent lymph node assessment (median age 70 versus 64.4, p=0.004) and also had a higher median BMI (32.4 versus 28.9, p=0.043). In a multivariate Cox proportional hazards regression controlling age and BMI, the difference in overall survival remained statistically significant based on stage status with those staged having lower risk of death (HR= 0.57; 95% CI: 0.35 −0.92, p=0.021). Unstaged patients were also less likely to undergo adjuvant therapy, however reasons for omitting adjuvant therapy were not available. 61.5% of patients who did not have evaluation of lymph nodes received any type of adjuvant therapy, compared to 84.7% of patients who did undergo lymph node evaluation (p=0.001). In this small sample, recurrence rates and patterns of recurrence were similar between women who underwent adjuvant treatment and those who did not (Table 2).
Table 2.
Location of first recurrence of unstaged patients based on treatment
| Adjuvant treatment | N | Patients with Recurrent Disease (%) | Location of First | Recurrence |
|---|---|---|---|---|
| Observation alone* | 14 | 6 (42.3) | Local | 1 |
| Distant | 5 | |||
| Local & Distant | 0 | |||
| Vaginal brachytherapy | 0 | NA | Local | NA |
| Distant | NA | |||
| Local & Distant | NA | |||
| External beam RT +/− brachytherapy | 10 | 2 (20.0) | Local | 0 |
| Distant | 1 | |||
| Local & Distant | 1 | |||
| Chemotherapy +/− brachytherapy | 10 | 7 (70.0) | Local | 0 |
| Distant | 6 | |||
| Local & Distant | 1 | |||
| Chemotherapy + External beam RT | 2 | 2 (100.0) | Local | 0 |
| +/− brachytherapy* | Distant | 1 | ||
| Local & Distant | 1 | |||
We do not have location of first recurrence for 1 patient who underwent observation alone, 1 patient who underwent chemotherapy and external beam RT +/− brachytherapy, and 1 patient who underwent hormonal therapy
Adjuvant Treatment of Node Negative Patients
Among women who underwent lymph node evaluation, 122 (57%) were found to have negative lymph nodes. These patients were treated with a variety of adjuvant treatment strategies including observation (14, 12.5%), vaginal brachytherapy (32, 28.6%), external beam RT +/− brachytherapy (43, 38.4%), chemotherapy +/− brachytherapy (14, 12.5%), and chemotherapy + external beam RT +/− brachytherapy (9, 8%). There was no statistically significant difference in PFS (p = 0.493) or OS (p = 0.255) between the treatment strategies.
Among the women who were treated with radiation, 46 women were treated with brachytherapy alone and 52 were treated with pelvic radiation with or without brachytherapy. Compared to brachytherapy alone, pelvic radiation did not improve PFS (HR = 0.85, 95% CI: 0.44–1.63, p = 0.645) or OS (HR = 0.87, 95% CI: 0.41–1.86, p = 0.729), Figure 2a, Figure 2b. Although the sample size was small, the location of first recurrence (local, distant or both) was similar for the different adjuvant therapy groups (Table 3).
Figure 2:
Progression free survival (2a) and overall survival (2b) in pelvic radiation versus brachytherapy alone among staged women with node negative disease
Table 3.
Location of first recurrence of staged, node negative patients based on treatment.
| Adjuvant treatment | N | Patients with Recurrent Disease (%) | Location of First | Recurrence |
|---|---|---|---|---|
| Observation alone | 14 | 5 (35.7) | Local | 2 |
| Distant | 3 | |||
| Local & Distant | 0 | |||
| Vaginal brachytherapy | 32 | 9 (28.1) | Local | 5 |
| Distant | 4 | |||
| Local & Distant | 0 | |||
| External beam RT +/− brachytherapy | 43 | 11 (25.6) | Local | 1 |
| Distant | 9 | |||
| Local & Distant | 1 | |||
| Chemotherapy +/− brachytherapy | 14 | 5 (35.7) | Local | 0 |
| Distant | 2 | |||
| Local & Distant | 2 | |||
| Unknown | 1 | |||
| Chemotherapy + External beam RT | 9 | 1 (11.1) | Local | 0 |
| +/− brachytherapy | Distant | 0 | ||
| Local & Distant | 1 | |||
Adjuvant Treatment of Node Positive Patients
There were a total of 92 patients with node positive disease, and information about the adjuvant treatment strategy utilized was available for 81 women. Various adjuvant treatment strategies were used, as outlined in Figure 3a. Overall survival was significantly impacted by the type of adjuvant treatment used, and the patients who underwent multimodal treatment with a combination of chemotherapy and external beam radiation (+/− brachytherapy) had the best outcomes (p=0.003), Figure 3a, Figure 3b. When directly comparing women who underwent chemotherapy alone (+/− brachytherapy) with those who underwent chemotherapy and external beam radiation (+/− brachytherapy), those who underwent chemotherapy and external beam radiation therapy had improved overall survival (p=0.009), Figure 3c. This difference remained statistically significant after controlling for age, stage, and BMI (p=0.021). Chemotherapy and external beam radiation therapy (+/− brachytherapy) was not found to be superior to external beam radiation alone (+/− brachytherapy), however, but this comparison is limited by small sample sizes in each group (p=0.304), Figure 3c. The location of the first recurrence of staged, node positive patients was similar between groups, see Figure 3d.
Figure 3:
Adjuvant treatment strategies employed in staged, node positive patients with hazard ratios (HR) for overall survival (3a) and Kaplan Meier curve for overall survival based on treatment (3b). Comparison of overall survival based on adjuvant treatment regimen used (3c) and location of first recurrence based on adjuvant treatment regimen used (3d).
DISCUSSION
In this large, multi-institutional study, we found that lymph node assessment (with either sentinel lymph node biopsy or lymphadenectomy) was associated with better progression free and overall survival in women with grade 3, deeply invasive endometrioid adenocarcinoma of the uterus. Among patients with negative nodes, there was no difference in survival between patients treated with adjuvant brachytherapy versus whole pelvic radiation. Among women with positive lymph nodes, women who underwent multimodal therapy with a combination of chemotherapy and external beam radiation (+/− brachytherapy) had the best overall survival.
The assessment of lymph node status appears to be important among grade 3 endometrioid tumors with deep myometrial invasion, as it was able to identify that 43% of patients had positive nodal disease. Although in our study, it was also associated with improved progression free and overall survival,this is likely, in part, due to the fact that patients who underwent lymph node assessment were more likely to undergo adjuvant therapy, possibly due to medical comorbidities. Previous randomized controlled trials have demonstrated no survival benefit associated with lymph node dissection6, 7. In these trials, women had clinically stage 1 tumors but all histologies were included. Whether women with grade 3, deeply invasive tumors represent a distinct population that may benefit from the use of lymph node assessment to guide further treatment is still unclear. Some retrospective studies support a survival benefit among women with intermediate or high risk tumor types8, 9. This warrants further investigation among deeply invasive grade 3 cancers, especially knowing that the rate of positive lymph nodes is so high. Finally, further studies on sentinel lymph node assessment may help determine if this potential survival benefit results from the downstream impact on use of adjuvant treatment strategies.
In regard to adjuvant therapy, among women who were staged in this study and were found to have negative lymph nodes, pelvic radiation did not improve PFS or OS over brachytherapy alone. These findings are similar to that which was reported in previous studies. In a sub-analysis of the 38 patents in GOG99 with grade 3 deeply invasive disease, pelvic radiation had a trend towards improved overall survival compared to brachytherapy with a relative risk of 0.65, but this trend was not statistically significant3. Similar to our study, Rasool et al performed a multi-institutional retrospective review including 5 institutions4. They had a total of 54 patients with stage I, grade 3 deeply invasive disease. Recurrence rates ranged from 8–17% and no one adjuvant treatment strategy was superior to the others. In fact, the group that received pelvic radiation had the worst outcomes. Overall, these findings suggest that pelvic radiation may not be superior to brachytherapy in this group. This should be interpreted with caution, however, as the sample size was small, and the study was not powered to detect a clinically significant difference.
For women with node positive disease, we found that treatment with a combination of chemotherapy and external beam radiation (+/− brachytherapy) was associated with improved overall survival. When directly comparing chemotherapy alone (+/− brachytherapy) with chemotherapy and external beam radiation (+/− brachytherapy), the addition of external beam radiation to chemotherapy was associated with an improvement in OS. Interestingly, however, we found that rates of local recurrence were similar in the two groups, making it difficult to ascertain why the addition of radiation may have had this impact. Nonetheless, these findings are similar to those described by Klopp et al in their retrospective review of 71 women with stage IIIC endometrial adenocarcinoma. Although the study included all grades, it specifically identified grade 3 disease as having a worse prognosis. The 5 year disease specific and overall survival was significantly better for women who received pelvic radiation compared to those who received chemotherapy10. The recently published results of GOG 258, however, showed that the combination of chemotherapy with tumor volume-directed radiation followed by 4 cycles of carboplatin and paclitaxel was associated with similar recurrence free survival rates when compared to chemotherapy alone (HR 0.9, 95% CI [0.74, 1.1]11. This included women with optimally debulked stage III and IVA endometrial carcinoma and only approximately 17% of patients in the study had grade 3 endometrioid tumors. Perhaps the patients with grade 3 deeply invasive tumor represent a subgroup that benefits from multimodal therapy.
To our knowledge, this is the largest study evaluating deeply invasive grade 3 endometrioid adenocarcinoma of the uterus. We are also the only group to specifically evaluate a subset of node positive grade 3 endometrioid adenocarcinoma with deep myometrial invasion. The long term follow up and multi-institutional collaboration are also strengths of our study.
The study was limited in the data available for review by the retrospective nature of the study. For example, we did not collect data on chemotherapy regimen used. There were many potential confounders that may have influenced the reasons why adjuvant strategies were selected for patients that are not accounted for in the analysis due to lack of availability of this data in our combined databases. Also, the overall study period is long, and it likely includes practice patterns that have changed over time. Although the number of patients studied was relatively large compared to other studies, the number of patients undergoing each adjuvant treatment strategy was small, therefore it is difficult to draw strong conclusions from the results.
Overall, our findings support lymph node evaluation in women who have grade 3, deeply invasive tumors. For node negative patients, pelvic radiation may not be superior to vaginal brachytherapy. For node positive patients, multimodal therapy combining chemotherapy with external beam radiation is associated with improved overall survival.
Figure 1:
Progression free survival (1a) and overall survival (1b) based on lymph node assessment
Acknowledgments
FUNDING
This work was presented as a poster at the Society of Gynecologic Oncology Annual Meeting in 2015 in San Diego, California and as an oral presentation at the Western Association of Gynecologic Oncologists Annual Meeting in 2017 in Rancho Mirage, California.
This work was supported in part by Cancer Center Support Grant (NCI Grant P30 CA016672), the NCI SPORE in Uterine Cancer (2P50 CA098258–06), and a T32 training grant for gynecologic oncology (CA101642). Drs. Leitao and Abu-Rustum are supported in part by the NIH/NCI MSK Cancer Center Support Grant P30CA008748.
Footnotes
COMPETING INTERESTS
We have no conflicts of interest to disclose.
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