The results of the present study suggested that para-aortic involvement was the strongest predictor of recurrence and a poor prognostic factor for long-term OS and DFS in grades IIICr and IVA cervical cancer patients with regional lymph node metastasis. This finding is consistent with the results reported in previous studies . In a previous study it was reported that there seemed to be a pattern of lymphatic spread among cervical cancer patients from the pelvic to the PALNs and the supraclavicular lymph nodes . Thus, extended-field radiotherapy,which prophylactically addresses the para-aortic region to prevent PALN metastasis, is a feasible strategy to treat stage IIIC1r and IVA cervical cancer patients without PALN metastasis at the time of diagnosis to improve their OS and DFS.
In our study, we implemented EF-IMRT to not only prevent but also to treat PALN metastasis. Additionally, SIB-IMRT and SeB-IMRT were delivered to treat all positive regional lymph nodes. Currently, compared with the conventional techniques, IMRT could reduce the incidence of treatment-related toxicities when delivering extended-field radiotherapy and nodal boost to treat lymph node metastasis . SIB and SeB were two delivery methods of IMRT boost, but most studies concentrating on IMRT boost only implemented one of these modalities, and very few studies have utilized both SIB and SeB to treat nodal metastasis . In the present study, 22 patients with stage IIIC1r and IVA cervical cancer and without positive PALNs were administered prophylactic EF-IMRT, and 12 patients with stage IIIC2r and IVA cervical cancer and with positive PALNs were administered definitive EF-IMRT. Regional positive lymph nodes found in all 34 patients were treated with SIB-IMRT, and 8 received SeB-IMRT for the remaining positive lymph nodes according to CT/MRI conducted at the end of SIB-IMRT. Feng et al.  indicated that SeB-IMRT would extend the total treatment time and also increase the treatment-related toxicity due to the additional boost, which delivers an increased dose to the surrounding normal structures. In our study, the SeB-IMRT irradiation fields were very small, as it was only aimed at the remaining positive regional lymph nodes (short-axis diameter ≥ 5 mm) after SIB-IMRT. Due to the small irradiation fields of SeB-IMRT, the planning process for SeB-IMRT was simple, with limited treatment-related toxicity; thus, brachytherapy was carried out simultaneously with SeB-IMRT. Therefore, SeB-IMRT did not increase the treatment time in our study and the resultant adverse events were also of acceptable levels.
In the negative PALN cohort in our study, the 3-year OS, DFS, RCR, and rate of ≥ grade 3 delayed toxicity were 90.9%, 90.9%, 95.5%, and 4.5%, respectively. Liang et al. enrolled 47 patients with positive PLNs (negative PALNs) and delivered extended-field external beam radiation therapy and nodal boost via 2- or 3-dimensional technique, and reported a 54% DFS, 62% OS, 51% RCR, and 11% accumulative rate of ≥ grade 3 treatment-related late toxicity at 3 years. Obviously, compared with the conventional technique mentioned in the above study, our study had improved survival and lower treatment-related toxicity. Furthermore, our outcomes of the negative PALN cohort were comparable with the study of Vargo et al., which delivered EF-IMRT and SIB-IMRT to 41 patients without positive PALNs and achieved a 3-year OS, DFS, RCR, and rate of ≥ grade 3 delayed toxicity of 73%, 64%, 95%, and 4%, respectively . In this comparison, the OS and DFS were improved and the rate of treatment-related toxicity was low with addition of SeB-IMRT in the nodal dosage boost. The favorable results of the present study suggested that EF-IMRT and nodal dosage boost were safe and could control the involved PLNs and improve the OS and DFS for stage IIIC1r and IVA patients with positive PLNs (negative PALNs).
In the positive PALNs cohort in our study, the 3-year OS, DFS, RCR, and rate of ≥ grade 3 delayed toxicity were 41.7%, 33.3%, 72.2%, and 8.3%, respectively. In arm 1 of the RTOG 0116 trial , 26 patients with positive PALNs were treated with extended-field radiation and nodal dosage boost via conventional technology, and the DFS, OS, RCR, and rate of ≥ grade 3 treatment-related toxicity at 1.5 years were reported to be 46%, 60%, 54%, and 40%, respectively. Obviously, the RCR and rate of delayed toxicity for the positive PALN cohort treated with definitive EF-IMRT showed favorable results in comparison with the historic control from the classic cooperative group data of cases treated with non-IMRT techniques. Additionally, Vargo et al.  analyzed 20 patients with positive PALNs treated with definitive EF-IMRT along with SIB-IMRT and reported a better 3-year RCR, DFS, OS, and rate of late ≥ grade 3 toxicity (89%, 40%, 61%, and 0 respectively) compared to the results obtained in our present study (72.7%, 33.3%, 41.7%, and 8.3% respectively). However, our study had more IVA patients (5/12, 42%) than the abovementioned study (5/61,8%). As previous studies reported that stage IVA is a poor prognostic factor with a high risk of PALN involvement [17, 18], stage IVA patients are more likely to experience treatment failure. The rate of ≥ grade 3 treatment-related delayed toxicity was found to be higher in our positive PALN cohort (8.3%) than in the report of Vargo et al. (0%), but only one patient (1/12) in the positive PALN cohort developed grade 3 treatment-related delayed toxicity. Our results from the positive PALNs cohort suggested that EF-IMRT and nodal dosage boost were well tolerated by the patients and could eradicate lesions in involved PLNs and PALNs for IIIC2r and IVA patients with positive PALNs.
Although stage IIIC2r and IVA patients with positive PALNs had better RCR in our study than in similar reports in previous studies utilizing traditional techniques, the OS and DFS were unsatisfactory compared to arm 1 of the RTOG 0116 trial . PALN involvement was considered to be regional metastasis in the 2018 version of the FIGO staging system, indicating that regional treatment could still be implemented for PALN-positive patients without distant metastasis. Among the 12 grades IIIC2r and IVA patients with positive PALNs, the 1-year and 3-year OS, LCR, and DFS were 66.7% and 41.7%, 65.6% and 65.6%, and 33.3% and 33.3%, respectively. These poor survival rates may probably be due to distant failure (4/12) and local failure (4/12). Four local failures were recorded in four of the twelve patients with PALN metastasis, and all four patients did not receive adequate concurrent chemotherapy. Concurrent chemotherapy is considered an important treatment strategy for LACC, reducing the local and distant recurrences and improving the survival for LACC . Although prognostic factor analysis for OS, DMFS, and LCR did not show statistical significance in concurrent chemotherapy in our study (Table 3), insufficiency of concurrent chemotherapy might partly explain why patients with PALN metastasis in our study had low OS and LCR.
Apart from local failure, there were three PALN failures and four distant failures, leading to 3-year RCR and DMFS values of 72.2% and 60.2%. These figures were significantly lower than those in PALN-negative patients in the present study, suggesting that PALN metastasis was more than a regional disease. Moreover, PALN disease was considered as stage IVB in several studies [8, 19].As we know, systemic chemotherapy is the crucial treatment to control dissemination in stage IVB cervical cancer, so adjuvant chemotherapy (ACT) may be a rational therapy to improve the OS of stage IIIC2 and IVA patients with positive PALNs. But four recent randomized controlled trials (RCTs) designed to compare concurrent chemoradiation therapy(CCRT) alone and CCRT followed by ACT showed two inconsistent conclusions about adjuvant chemotherapy [20–23]. Two of the four RCTs showed that patients with LACC got significant survival benefits from ACT [20, 21] whereas the other two trials concluded the opposite [22, 23]. The effect of ACT on LACC was unclear but it is worth noting that 2 or 3 cycles of cisplatin plus paclitaxel or gemcitabine were administered as adjuvant chemotherapyto most patients in the four RCTs mentioned above. Based on the view that PALN disease was more advanced than a regional metastasis but a type of distant disease, the addition of adjuvant chemotherapy cycles or adjusting the adjuvant chemotherapy regimen may be one way to improve the OS of stage IIIC2 and IVA patients with positive PALNs. Future studies are needed to address effective systemic therapy for stage IIIC2r and IVA cervical cancer patients with and without PALN metastasis.