Lymph node metastasis is the main mode of cervical cancer metastasis, and the most common mode of lymph node metastasis in cervical cancer is progressive metastasis from the pelvic lymph nodes to the common iliac and para-aortic lymph nodes, and finally to distant metastasis. PALN metastasis is closely related to the status and number of PLN metastases . In patients with PLN metastasis, the risk of PALN metastasis is significantly increased [10, 11]. The scope of routine radical surgery and radiation to treat cervical cancer does not contain the drainage area of the PALN, but patients with positive PLN metastasis may have micrometastas is in the PALN, which can result in PALN and distant metastases that form after treatment. Positron emission tomography (PET)/CT is used to evaluate the lymph nodes. This method has high diagnostic sensitivity, but cannot completely exclude lymph node metastases with small diameter. Therefore, patients with cervical cancer and PLN metastasis may benefit from prophylactic radiation of the PALN to reduce recurrence and metastasis.
At the end of the 20th century, five large-scale clinical studies investigated cisplatin-based concurrent radiation and chemotherapy [14–18]. They confirmed that radiation combined with chemotherapy was important in the treatment of cervical cancer. Park et al. retrospectively reviewed the efficacy of extended-field concurrent radiation and chemotherapy to treat locally advanced cervical cancer. Out of 88 cases in the para-aortic group and 115 in the pelvic group, 62 cases and 71 cases received chemotherapy, respectively. In the patients treated with concurrent chemotherapy, the 5-year survival rates in the para-aortic and pelvic groups were 72.3% and 84.3%, respectively (P = 0.140). In patients who were not treated with chemotherapy, the 5-year survival rates in the para-aortic and pelvic groups were 72.1% and 60.5%, respectively (P = 0.056), and PALN metastasis occurred in four cases in the para-aortic group and three cases in the pelvic group. The researchers concluded that prophylactic radiation of the PALN, especially when combined with chemotherapy, could not improve the prognosis of patients with advanced cervical cancer. However, in that study, the rate of PALN metastasis was high, the diameter of the local tumor was large, and traditional four-field box radiation was applied. All these factors may have affected the efficacy of extended-field radiation. Since the start of the 21st century, high-precision radiation technology has developed rapidly. Intensity-modulated radiation has been widely applied in radiation centers, which can minimize the tolerable dose in normal tissues. Thus, some researchers have investigated the efficacy of extended-field intensity-modulated radiation combined with chemotherapy. Asiri et al. applied concurrent chemotherapy and radical radiation to treat locally advanced cervical cancer. Thirty-six cases and 38 cases were randomized into the pelvic and para-aortic groups, respectively. Both groups were treated with 40 mg/m2of cisplatin therapy weekly. External radiation was performed using 3-dimensional conformal radiation and IMRT techniques, whereas internal radiation was performed using high dose rate 192Ir brachytherapy. The 5-year survival rates in the para-aortic and pelvic groups were 72.4% and 60.4%, respectively (P = 0.04), and the PFS rates were 80.3% and 69.1%, respectively (P = 0.03), with one case (2.6%) and five cases (13.9%) of PALN metastasis, respectively. The above studies arrived at no unified conclusion regarding the efficacy of extended-field radiation combined with chemotherapy. As no detailed evaluation of the pelvic lymph node status was carried out, the baseline data of the experimental and control groups were unbalanced, leading to large differences in results across studies. In the present study, no significant differences occurred in the number of metastatic PLNs between the para-aortic and pelvic groups. We employed IMRT external radiation and high dose rate 192Ir brachytherapy, and all patients completed radiation, with only one patient in each group receiving no chemotherapy. The 3-year survival rates in the present study were higher than in the study by Asiri et al.—87.0% in the para-aortic group and 74.6% in the pelvic group. Univariate analysis indicated no difference in OS rate between the two groups, but Cox multivariate analysis revealed a significant difference after correction. This discrepancy may have occurred because of the small sample size, short follow-up time, and interactions among influencing factors. In the PFS and PAMFS survival analysis, the 5-year PFS (P = 0.000) and PAMFS (P = 0.027) in the EF-IMRT group were appreciably longer than those in the P-IMRT group, and the difference was significant in both cases. These results were similar to those of recent studies. Liang et al.recruited patients with cervical cancer and PLN metastasis but without PALN metastasis; this approach somewhat reduced the error caused by PLN, and the 3-year OS rates were the same as in the present study. Lee et al. suggested that OS and PFS were significantly higher in the para-aortic group than in the pelvic group in patients with PLN metastasis, but there was no significant difference between the two treatment groups in patients without PLN metastasis. There were three cases (3.1%) and 13 cases (11.8%) of PALN metastasis in the para-aortic and pelvic groups, respectively (P = 0.02), and the 5-year PAMFS was 97.9%. In the present study, one case (3.23%) in the para-aortic group and seven cases (18.92%) in the pelvic group had PALN metastasis (P = 0.105), and the 3-year PAMFS was 96.0%. Both studies showed satisfactory control over PALN. In addition, the distant metastasis rate in the EF-IMRT group was below 10% in the present study, and the extrapelvic metastasis rate was significantly lower than that in the P-IMRT group (P = 0.035). The above analysis suggests that extended-field radiation combined with chemotherapy to treat high-risk patients with cervical cancer and PLN metastasis may improve survival prognosis and reduce the treatment failure rate to varying degrees. However, this conclusion requires further study with a larger number of cases.
In recent years, many researchers have attempted to identify risk factors for the recurrence and metastasis of cervical cancer, and several have given prophylactic treatments to high-risk patients to prolong survival time. After examining the pathological factors related to PALN metastasis, Chen et al. suggested that clinical stage, histological grade, depth of cervical interstitial invasion, tumor size, para-uterine invasion, vascular tumor thrombus, and PLN metastasis were all associated with PALN metastasis, whereas pre-treatment SCC level, age, and pathological type were not. Some other researchers believe that treatment, FIGO stage, and pathological type are independent factors that affect prognosis . This suggests that study endpoints and outcomes vary among centers. Thus, researchers must examine and identify relevant prognostic factors that are clinically available before treatment. Cervical cancer is classified as local, early-stage or locally advanced, with a 4-cm cut-off. However, the present study focused on locally advanced cervical cancer and investigated independent risk factors for OS, PFS, and PAMFS with tumor size > 5 cm (cut-off). The findings accorded with those of a study by Han et al.. A Korean study attempted to predict the risk of PALN metastasis and showed that tumor size on magnetic resonance imaging and PALN status on PET/CT were independent predictors of PALN metastasis. Based on these two factors, the investigators established a PALN recurrence prediction model, which assigned 0, 1, and 3 points to patients with tumor size ≤ 4 cm, 4–5 cm, and > 5 cm, respectively. The model produced good predictions, and the investigators recommended concurrent chemotherapy with extended-field PALN + pelvic radiation in patients with high scores. The present study corroborated that model, showing that a tumor size > 5 cm can reduce PAMFS significantly. A previous study indicated that radiation time could dramatically affect the prognosis of cervical cancer: for every 1 day extension of radiation time over 55 days, the survival rate and local control rate were reduced by 0.6% and 0.7%, respectively. Lin et al.  also found that, in patients with stage I–II B cervical cancer, the 5-year survival rate with a total radiation time of ≤ 56 days was significantly higher than that with a total radiation time of > 56 days (70% vs. 65%, respectively, P = 0.002). The present study revealed that the risk of mortality and disease progression with a total radiation time of > 56 days was 6.131 and 3.021 times higher than that with a total radiation time of ≤ 56 days. The American National Comprehensive Cancer Network guidelines recommend a radiation dose of EQD2 ≥ 85 Gy to treat locally advanced tumors, and emphasize that an adequate dose (45 Gy) should be given during extended-field radiation to patients with occult metastasis or micrometastas is in the PALN. The present study confirmed this view, with the risk of PALN metastasis at point A in the EQD2 ≥ 85 Gy group being significantly lower than that in the EQD2 < 85 Gy group (P = 0.027). The probability of PALN metastasis is significantly higher in patients with PLN metastasis than in those without. Nevertheless, few studies have measured the effect of the number of metastatic PLNs on PALN metastasis. Wei et al. found that the probability of PALN metastasis increased with the number of metastatic PLNs. Zeng et al. suggested that a positive PLN count of ≥ 2was more likely to cause PALN metastasis. In the present study, pelvic lymph nodes were grouped, with ≥ 2 as the cut-off count, but there were no differences in OS, PFS, and PAMFS between the group with ≥ 2 positive PLNs and that with < 2. In imaging, there were marked differences in shape and size of the metastatic PLNs, as well as number. There was one case of lymphadenopathy with a tumor size of > 2 cm, which may have affected the findings. It follows that the lymph node screening scheme should be further improved. In summary, with regards to tumor characteristics, a tumor size of > 5 cm results in poor survival prognosis. These findings will inform the screening of high risk patients at for recurrence, as well as the timely prevention and intervention of PALN in clinical work. In terms of treatment, prophylactic radiation of the PALN should be given to high-risk patients, with a total dose of EQD2 ≥ 85 Gy at point A, and the total radiation time should be kept within 8 weeks as much as possible to improve the efficacy and reduce the risk of recurrence and metastasis.
Regarding treatment-related toxicities, the present study demonstrated that only acute hematological toxicity reached grade 4. There was significantly more leukopenia in the EF-IMRT group than in the P-IMRT group, with 16 cases (51.61%) and 10 cases (27.03%) of leukopenia of grade 2 or above, respectively (P = 0.038). There was no significant difference in late reaction between the two groups, and no toxicity of grade 3 took place. All patients with leukopenia were corrected to the normal range after timely treatment with elevated leukocytes, and no patients developed agranulocytosis with fever and related death. Oh et al. found that the acute gastrointestinal reaction in the para-aortic group was significantly higher than that in the pelvic group (40.4% vs. 35.1%, P = 0.046), with no significant difference in late reaction between the two groups. The authors stressed that stronger gastrointestinal reactions did not affect the completion rate of radiation in vitro, and that overall toxicity was tolerable. Several studies have demonstrated that the acute toxicity of concurrent radiation and chemotherapy were mild, all late reactions were tolerable, and that toxicity was not significantly higher in the para-aortic group than in the pelvic group [19, 21]. Furthermore, Park et al. emphasized that late reactions of grade 4 in the para-aortic group, such as rectal perforation in the pelvis, might be unrelated to extended-fieldradiation. As such, extended-fieldradiation with concurrent chemotherapy may increase acute reactions, but the reactions was controllable and do not increase late toxicity.
The present study revealed that prophylactic intensity-modulated radiation combined with chemotherapy to treat PALN metastasis can improve survival prognosis in high-risk patients with cervical cancer, with more tolerable toxicities than conventional radical pelvic radiation and chemotherapy. However, because we only used a small sample size and a short follow-up time, the evaluation of lymph node status using contrast-enhanced CT or MRI scan may have contained errors. In future work, we need to expand the sample size, pay attention to the shape and size of lymph nodes, and improve the PLN evaluation.