UCCC, a relatively rare cancer of the endometrium, exhibits poor patients’ prognosis even at early stage of the disease such as stage I-II. CT or RT has been applied as the adjuvant treatment after surgery to improve prognosis. However, it remains controversial of the effectiveness of CT or RT as the adjuvant therapy for early stage UCCC due to small number of cases reported in a limited few studies. Our study is the first meta-analysis, which aims to evaluate the effectiveness of adjuvant CT or RT on survival outcomes in stage I-II UCCC.
Our meta-analysis results have supported the notion that CT is beneficial for early stage, i.e. stage I-II UCCC. In particular, we found that patients receiving CT showed a significant higher 5 year-OS rate compared to those receiving non-CT (p = 0.007). This result was evidenced based on the pooled extracted data from 494 CT and 1860 non-CT patients without internal difference from a total of 7 trials (p = 0.48, I2 = 0%). Interestingly, in the study of Hsu et al., 2 cases of death were reported from a total of 30 cases receiving adjuvant CT, while 9 death cases found from the 62 cases without receiving CT. According to the authors of this study, patients that did not receive adjuvant treatment tended to have lower risk of recurrence as evidenced by smaller tumor sizes and less myometrial invasion (6). In a study that consisted the largest study cohort, Hong et al. analyzed the data from the National Cancer Data Base (NCDB) and found that women undergoing hysterectomy, lymph node dissection (LND) and CT had the highest 5-year OS, followed by those with hysterectomy and LND without CT (13). Taken together, these results supported the use of CT in the treatment of early stage UCCC.
In the latest Randomized Trial of Radiation Therapy With or Without Chemotherapy for Endometrial Cancer (PORTEC-3), patients with serous or clear-cell cancers had an improvement in failure-free survival with the addition of CT, similar to those with endometriod endometrial cancer (18). In addition, the Society of Gynecologic Oncology (SGO) has recommended the use of adjuvant treatment with CT for stage I-II UCCC patients (19). Together, all data has again confirmed the effectiveness of adjuvant CT in improving OS of the UCCC patients.
On the other hand, adjuvant RT has been applied for the treatment of early stage UCCC, a rationale inferred from the outcome data for women with uterine serous carcinoma and grade III endometrioid carcinoma (20). Application of adjuvant RT in stage I-II patients remains as a controversial topic due to mixed patients’ outcome obtained from different studies. Unlike papillary serous tumors, clear-cell carcinoma does not seem to have high propensity for abdomen. So, outcome data from certain trial opposed the routine use of whole-abdominal RT in patients (21). Consistent to these observation, our analyses revealed that OR of RT vs non-RT groups was 0.71 (p = 0.19), implying that the OS was not significantly different between the RT and non-RT groups. Furthermore, Hsu et al. claimed that postoperative adjuvant RT was associated with poorer 5-year recurrence-free interval when compared to CT. Moreover, Chang-Halpenny et al. discovered poorer OS in patients treated with RT, by which the authors believed were due to the inclusion of a great proportion of patients with high-stage disease. Lastly, Hong et al. reported that women undergoing both hysterectomy and LND did not show improved survival rate with either brachytherapy or external beam RT. Taken together, these results have led to the non-favorable recommendation of RT in early-stage UCCC patients by some of the gynecologic oncologists.
Interestingly, our meta-regression analyses have identified nationality as the source of heterogeneity in the disparity of patients’ treatment outcome. After excluding the study of Hsu et al. from analysis, we observed that I2 had reduced to 19% from 55% while the p value had changed to 0.002 (OR: 0.60, 95%CI: 0.44–0.83), indicating the superiority of RT in the corresponding US and Europe patients. Consistently, in the PORTEC-3 clinical trial, which involved collaborative efforts of multicenter worldwide, no difference in OS was observed between 29 UCCC patients receiving CT and 33 receiving RT, indicating that both CT and RT could yield favorable prognosis in patients (18). In addition, Desteli et al. also recommended vaginal brachytherapy for the treatment of UCCC (22). Lastly, Kim et al. conducted a large retrospective analysis of 451 UCCC and 882 UPSC (uterine papillary serous carcinoma) patients from the SEER database and found that the 5-year OS for RT and non-RT patients at stage IB were 76% and 66% respectively (p = 0.006) whereas the 5-year OS for RT and non-RT patients at stage IC were 60.7% and 33.9% respectively (p = 0.001) (23). In short, all the evidences thus far have suggested adjuvant RT as a favorable treatment option for improving the survival of patients.
It is interesting to note that no survival improvement between patients receiving CT plus RT and CT or RT alone was observed in our meta-analysis (p = 0.70, I2 = 0%). However, we could not exclude the possibility that the negative results might be due to limited available data, i.e. 353 patients from 5 individual studies. Notably, some studies have casted doubts on the efficacy of combinatorial treatment involving both CT and RT. In particular, Mahdi et al. found no statistical difference in OS between CT plus RT and CT only groups in stage I-II UCCC patients (5-year OS is 65% versus 67%, p = 0.69). In one GOG study, which involved retrospective analysis of 13 patients with stage I-II UCCC treated with whole abdominal radiotherapy, the 5-year PFS was 54%. Interestingly, treatment failures were often observed in patients receiving RT. Therefore, the authors concluded that adjuvant CT was necessary for the patients with radio-resistant cancers (24).
The prevalence of usage of CT and RT in UCCC is increasing in the recent years though controversies remain. With limited number of cases, Vogel et al. found a survival benefit in patients with stage IB to II disease with any form of adjuvant treatments including RT, CT or both (25). From the periods of 1998 to 2001 and 2005 to 2006, Xu et al. also found a declining use of observation (43.4 versus 41.7%) and RT alone (42.2 versus 27.1%) for stage I-II UCCC (p < 0.001) (26). In comparison, the increased use of CT and RT throughout the years was noted. Consequently, we have focused on the studies published from 2004 to 2019, with most of the studies published between 2016 and 2019, to ensure that our analyses capture the timely and representative CT and RT emerging era.
Nevertheless, our study consists of several limitations. Firstly, we have only included 13 papers for analyses due to our strict inclusion criteria. In particular, certain studies that only had limited number of UCCC cases were omitted from our analyses. Secondly, we only selected OS and PFS as the indexes for prognostic analysis as most of the studies did not have survival data such as DFS (Disease-Free Survival), TTP (Time to Progression) or ORR (Objective Response Rate). Lastly, the design of each individual study, such as the CT regimens and types of RT, was different, which might influence the final reporting of our meta-analysis.
In conclusion, as the first meta-analysis with nearly 4000 patients, our results support the administration of RT and CT for stage I-II UCCC patients. However, it remains to be elucidated how the treatments should be integrated into the adjuvant setting. Therefore, more prospective and randomized clinical trials with larger sampling size should be performed in the future.