Clinical analysis of prophylactic para-aortic intensity-modulated radiation in cervical cancer.

AIM
This study aimed to compare the survival and toxicity of patients with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IB1-IIIC cervical cancer without common iliac node metastasis treated with extended-field intensity-modulated radiotherapy (EF-IMRT) or pelvic IMRT (P-IMRT).


MATERIALS AND METHODS
Thirty-one patients treated with EF-IMRT and 37 patients who underwent P-IMRT were analysed retrospectively. Both groups were treated with high-dose-rate 192Ir two-dimensional brachytherapy and concurrent chemotherapy. The chi-square test and Kaplan-Meier method were used to compare toxicity and survival between the two groups.


RESULTS
The median follow-up time of EF-IMRT group and P-IMRT group was 22 and 30 months, respectively. The 3-year overall survival (OS), progression-free survival (PFS), and para-aortic lymph node metastasis-free survival (PAMFS) in the EF-IMRT group and P-IMRT group were 87% versus 74.6%, 83.6% versus 61.7%, and 96% versus 80.5%, respectively. Treatment regimens, tumour size, and radiation time were independent prognostic factors of OS and PFS. Treatment regimens, tumour size, and total equivalent dose in 2 Gy/f (EQD2) of point A were independent prognostic factors of PAMFS. Five patients in the EF-IMRT group and 14 patients in P-IMET group experienced treatment failure. The cumulative incidence of grade 3 and 4 acute leukopenia in the EF-IMRT group was 51.6%, in comparison with 27.03% in the pelvic group. No difference was found in thrombocytopenia between two groups.


CONCLUSIONS
Patients with FIGO 2009 stage IB1-IIIC cervical cancer without common iliac node metastases may be benefit from EF-IMRT. Notably, EF-IMRT exhibits increased toxicity incidence; however, this remains within an acceptable range.


Introduction
Cervical cancer is a common malignancy in the female reproductive tract, with the highest incidence in low-and middle-income countries [1] . Lymph node metastasis is a major route of cervical cancer spread and a vital predictor of prognosis [2] . The prognosis of patients with para-aortic lymph node (PALN) metastasis is worse than that of patients with pelvic lymph node (PLN) metastasis [3] . One prospective study [4] showed that the PALN metastasis rates of stage II and stage III cervical cancer con rmed by surgical and biopsy pathology were 20% and 37%, respectively. Once PALN metastasis of cervical cancer occurs, the treatment failure rate can reach 70% [5] . Therefore, it is crucial to prevent PALN metastasis after cervical cancer treatment, especially in advanced cases.
Few studies have focused on prophylactic, extended-eld, intensity-modulated radiation treatment (EF-IMRT) of cervical cancer, and no consistent conclusion has been reached regarding the e cacy and toxicity of this treatment. In the present study, we recruited 31 patients with cervical cancer and pelvic lymphadenopathy but without para-aortic lymphadenopathy as the EF-IMRT group, as well as 37 such patients as the pelvic intensity-modulated radiation group (P-IMRT group). The clinical e cacy, prognosis, and related complications in the two groups were examined to guide clinical work.

Baseline data
To construct the prophylactic EF-IMRT group, we recruited 31 patients with cervical cancer who were undergoing rst-time treatment using this method in the Department of Gynecological Oncology of the Fourth Hospital of Hebei Medical University between August 2012 and August 2016. During the same period, we recruited 37 patients undergoing P-IMRT. None of the enrolled patients had undergone surgery, radiation, or chemotherapy related to their cervical cancer, and all had been diagnosed histopathologically with cervical squamous cell carcinoma before treatment. The following parameters were examined in all patients before treatment: blood routine, coagulation function, liver and kidney function, urine routine, squamous cell carcinoma antigen (SCC), carcinoembryonic antigen hematology, chest X-ray(orthotopic lm), and whole abdominal computed tomography (CT) or magnetic resonance imaging (MRI) scan. In all patients, blood routine showed normal indexes, as did the liver and kidney function tests. Imaging revealed PLN metastasis in all patients, while those with PALN metastasis or metastasis at other sites were excluded. All patients had an Eastern Cooperative Oncology Group (ECOG) score of < 2 points. In the present study, lymph node metastasis was diagnosed when CT or MRI showed that the short diameter of the lymph nodes was > 1 cm, or that the short diameter of the lymph nodes was < 1 cm, but combined with central necrosis, ring enhancement, or capsular invasion. All patients were informed and consented to medical treatment by signing the relevant notices. This research has been performed in accordance with the principles stated in the Declaration of Helsinki. The study was approved by the Ethics Committee of The Fourth Hospital of Hebei Medical University.

Formulation and implementation of radiation plan
We devised guidelines with reference to the Radiation Therapy Oncology Group (RTOG) in the United States [6] . The following measurements were performed: gross tumor volume (GTV), de ned as the volume of both the cervical mass and the pelvic lymph node metastasis and diagnosed by physical examination and clinical imaging; clinical target volume (CTV), which included the GTV combined with the volumes of the cervix, part of the vagina, uterus, parauterine, and drainage area of the pelvic lymph nodes (parauterine, obturator, internal and external iliac, presacral, and common iliac lymph nodes). The inguinal lymph node drainage area was included for patients with stage III A cancer, while the para-aortic lymph node drainage area was delineated in the EF-IMRT group. The planning target volume (PTV) was de ned as the expansion of CTV in the L/R, A/P, and S/I directions by 0.7, 0.5, and 1 cm, respectively. The upper boundary of the CTV was the level of the left renal vein in the EF-IMRT group and between the upper and lower margins of waist 4 in the P-IMRT group, whereas the lower boundary in the two groups was set according to the scope of vaginal invasion. Enlarged pelvic lymph nodes were evenly dilated by 0.3cm to their planning GTV. With the PTV as the reference volume, the two groups were given a prescribed dose of 45-50.4 Gy, 1.8-2 Gy/time, once per day, 5 times/week, with more than 95% of the PTV required to reach the prescribed dose. In the EF-IMRT group, the same prescribed dose was given in the abdominal para-aortic lymph node drainage area as in the pelvic area. With the planning GTV of the lymph nodes as the reference volume, the enlarged lymph nodes in the two groups were simultaneously pushed to 52-64.4 Gy. Intraluminalbrachy therapy was performed, with a dosage at point A of 6-7 Gy/time, 4-5 times, once per week, with a total dose of 24-33 Gy. With regards to chemotherapy, the patients were treated using 800-1000 mg/day tegafur for 5 consecutive days, as well as130 mg/m 2 oxaliplatin. Beginning on the rst day, the patients were treated with chemotherapy at an interval of 3-4 weeks for 2-3 courses.

Evaluation criteria for e cacy and toxicity
The short-term e cacy was evaluated within 6 months of radiation therapy based on imaging examination, gynecological examination, and tumor markers. The e cacy evaluation criteria for solid tumors [7] were divided into complete response, partial response, stable disease, and progressive disease. Six months after radiation, the long-term e cacy was evaluated according to the patient's symptoms, imaging, gynecological examination, and tumor markers. Any local pelvic tumor was de ned as recurrence, and any tumor beyond the pelvic cavity was de ned as metastasis. Para-aortic lymph node metastasis was not de ned as distant metastasis.
Acute toxicities were de ned as treatment-related toxic reactions that occurred 3 months from the start to the end of radiation, evaluated according to the Common Terminology Criteria for Adverse Events Version 4.0 (CTCAEv4.0) [8] . Long-term toxicity was de ned as treatment-related toxic reactions within 3 months of the end of radiation, evaluated according to the RTOG classi cation criteria.

Statistical analysis
Statistical analysis was performed using SPSS 21.0 (IBM, Armonk, NY, USA) statistical software. The ttest or rank-sum test was used to compare baseline data and measurement data between the two groups. The chi-square test was used to compare count data, failure modes, and acute and late toxicity between the two groups. The Kaplan-Meier method was adopted to calculate overall survival (OS), progressionfree survival (PFS), and progression-and metastasis-free survival (PAMFS). Survival curves were plotted on this basis. The log-rank test was used for univariate survival analysis. The time-dependent covariate method was used to test the Cox proportional hazards hypothesis. The Cox proportional hazards regression model was used for multivariate survival analysis. The signi cance level was α = 0.05, and Pvalues < 0.05 were determined as statistically signi cant.

Results
Therapeutic e cacy With regards to short-term e cacy, 6 months after radiation, the EF-IMRT group reached a complete response rate of 100%. In the P-IMRT group, one case of cervical cancer and two cases of para-iliac lymph node metastasis were uncontrolled, but showed partial response; the remaining patients reached complete response, resulting in a complete response rate of 91.89%. There was no statistical difference between the two groups in this regard (P = 0.304). In terms of long-term e cacy, at the nal follow-up, there were ve cases of recurrence or metastasis in the EF-IMRT group and 14 cases in the P-IMRT group. PALN metastasis occurred in one case in the EF-IMRT group and seven cases in the P-IMRT group. Among these seven cases, three had solitary metastasis, three had distant metastasis, and one had local PLN recurrence. In the EF-IMRT and P-IMRT groups, there were one and ve cases of local recurrence, respectively, as well as ve and 13 cases of metastasis (including PALN). As a result, the local recurrence and metastasis rates (including PALN metastasis) in the EF-IMRT group were 3.23% and 13.51% (P = 0.289), respectively, while those in the P-IMRT group were 12.90% and 35.14% (P = 0.035).

Prognostic factor analyses
The univariate survival analysis included treatment regimen, age, FIGO stage, tumor size, pre-treatment SCC level, pre-treatment hemoglobin level, total radiation time, total equivalent dose in 2 Gy/f(EQD2) at point A, and number of metastatic PLNs. A log-rank test was performed on these variables. The results showed that tumor size (P = 0.000) and total radiation time (P = 0.001) were related to the prognosis of OS. The following factors were signi cantly related to the prognosis of PFS: treatment regimen (P = 0.037), tumor size (P = 0.000), total radiation time (P = 0.037), and FIGO stage (P = 0.047). The following factors were related to the prognosis of PAMFS at point A: treatment regimen (P = 0.048), tumor size (P = 0.028), and total EQD2 (P = 0.025). The univariate analysis is shown in Table 1. The number of cases not treated with chemotherapy in the two groups was too small and not included in the univariate analysis.  After FIGO stage was excluded, the following factors were included in the multivariate survival analysis of OS and PAMFS: treatment regimen, age, tumor size, pre-treatment SCC level, pre-treatment hemoglobin level, total radiation time, total EQD2 at point A, and number of metastatic PLNs. The above factors, including FIGO stage, were included in the multivariate survival analysis PFS. The results showed that treatment regimen, tumor size, and total radiation time were independent prognostic factors of OS and PFS, and that treatment regimen, tumor size, and total EQD2 at point A were independent prognostic factors of PAMFS. The results of the multivariate analysis are shown in Table 3 and indicated signi cant interactions among various factors. After correction by Cox multivariate prognostic analysis, the treatment regimen, i.e.prophylactic extended-eld radiation, was an independent prognostic factor of OS, PFS, and PAMFS. The risk of mortality, disease progression, and PALN metastasis in the P-IMRT group were 4.764, 6.097, and 11.318 times higher than those in the EF-IMRT group. No fatal toxicities (grade 5) occurred in any of the patients enrolled. Three cases in each group had acute,grade 3 gastrointestinal reactions (P = 1.000), butno acute, grade 3 or above genitourinary reactions occurred. With regards to acute hematological toxicity, there was signi cantly more leukopenia of grade 3 or above in the EF-IMRT group than in the P-IMRT group (P = 0.038), with 16 cases (51.61%) and 10 cases (27.03%), respectively, and there was a signi cant difference between the two groups (P = 0.047). There were 17 cases (54.84%) of thrombocytopenia in the EF-IMRT group and 11 cases (29.93%) in the P-IMRT group, constituting a signi cant difference between the two groups (P < 0.036). Among these cases, only onein each group showed reactions of grade 3 or above (P = 1.000). Elevenpatients (35.48%) in the EF-IMRT group and nine (24.32%) in the P-IMRT group sustained liver injury during radiation and chemotherapy, but there was no signi cant difference between the two groups. None of the patients had renal injury in either group. Treatment interruptions due to severe acute reactions of grade 3 or above occurred within 5 weeks of the start of the treatment. None of the patients enrolledshowed late toxicities of grade 3 or above, and the most severe late gastrointestinal reaction was hematochezia. Intermittent hematochezia occurred in ve cases (16.1%) in the EF-IMRT group and three cases (8.1%) in the P-IMRT group. These incidents were relieved after conservative treatments such as enema and drugs. The toxicity measurements are shown in Table 4.

Discussion
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 nally to distant metastasis. PALN metastasis is closely related to the status and number of PLN metastases [9] . In patients with PLN metastasis, the risk of PALN metastasis is signi cantly 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 [12] , 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 [13] . Therefore, patients with cervical cancer and PLN metastasis may bene t from prophylactic radiation of the PALN to reduce recurrence and metastasis.
At the end of the 20th century, ve large-scale clinical studies investigated cisplatin-based concurrent radiation and chemotherapy [14][15][16][17][18] . They con rmed that radiation combined with chemotherapy was important in the treatment of cervical cancer. Park et al. [19] retrospectively reviewed the e cacy of extended-eld 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 paraaortic 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-eld box radiation was applied. All these factors may have affected the e cacy of extended-eld 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 [20] . Thus, some researchers have investigated the e cacy of extended-eld intensity-modulated radiation combined with chemotherapy. Asiri et al. [21] 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/m 2 of cisplatin therapy weekly. External radiation was performed using 3-dimensional conformal radiation and IMRT techniques, whereas internal radiation was performed using high dose rate 192 Ir 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 ve cases (13.9%) of PALN metastasis, respectively. The above studies arrived at no uni ed conclusion regarding the e cacy of extended-eld 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 signi cant differences occurred in the number of metastatic PLNs between the para-aortic and pelvic groups. We employed IMRT external radiation and high dose rate 192 Ir 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 .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 signi cant difference after correction. This discrepancy may have occurred because of the small sample size, short follow-up time, and interactions among in uencing 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 signi cant in both cases. These results were similar to those of recent studies. Liang et al. [22] 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. [23] suggested that OS and PFS were signi cantly higher in the para-aortic group than in the pelvic group in patients with PLN metastasis, but there was no signi cant 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 5year 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 signi cantly lower than that in the P-IMRT group (P = 0.035). The above analysis suggests that extended-eld 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. [30] suggested that clinical stage, histological grade, depth of cervical interstitial invasion, tumor size, parauterine 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 [24] . 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 classi ed 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 ndings accorded with those of a study by Han et al. [25] . A Korean study [26] 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-eld PALN + pelvic radiation in patients with high scores. The present study corroborated that model, showing that a tumor size > 5 cm can reduce PAMFS signi cantly. A previous study [26] 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. [27] 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 signi cantly 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-eld radiation to patients with occult metastasis or micrometastas is in the PALN. The present study con rmed this view, with the risk of PALN metastasis at point A in the EQD2 ≥ 85 Gy group being signi cantly lower than that in the EQD2 < 85 Gy group (P = 0.027). The probability of PALN metastasis is signi cantly 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. [16] found that the probability of PALN metastasis increased with the number of metastatic PLNs. Zeng et al. [9] 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 ndings. 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 ndings 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 e cacy 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 signi cantly 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 signi cant 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. [29] found that the acute gastrointestinal reaction in the para-aortic group was signi cantly higher than that in the pelvic group (40.4% vs. 35.1%, P = 0.046), with no signi cant 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 signi cantly 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 extendedeldradiation. As such, extended-eldradiation 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.