Clinical Aspects and Prognostic Factors for Survival in Patients with Recurrent Cervical Cancer after Radical Hysterectomy and Adjuvant Radiochemotherapy

Purpose To investigate the recurrence patterns and prognostic factors of patients with recurrent cervical cancer after radical hysterectomy with node dissection (RHND) followed by adjuvant radiotherapy (RT)/concurrent radiochemotherapy (CCRT). Methods Between January 1, 2012 and May 31, 2018, the medical records of 153 patients with pre-operative FIGO stage IB-IIA disease treated with RHND followed by adjuvant RT/CCRT in Liaoning Cancer Hospital were retrospectively analyzed. Results The median disease progression-free survival (PFS) time was 16 months. 75.2% (115/153) patients had disease relapse within 2 years. The survival of patients with recurrences in multiple organs was signifificantly lower in comparison to those with recurrences in single organ ( P <0.001). The survival rate of patients with distant metastasis (DM) and distant metastasis with local recurrence (LR) was significantly lower than that of patients with simple LR ( P =0.006, P <0.001). Furthermore, the survival rate of patients with LR+DM was significantly lower than that of patients with simple DM ( P =0.046).The multivariate analysis showed that resection margin involvement, para-aortic and common iliac lymph node metastasis, DM, no treatment after disease relapse and early disease relapse were independent prognostic fators asscociated with poor survivals. Conclusion Most cervical cancer patients who received initial RHND followed by adjuvant RT/CCRT occurred disease relapse within 2 years. Resection margin involvement, para-aortic and common iliac lymph node metastasis, DM, no treatment after recurrence and early disease relapse were found to be prognostic factors in patients with recurrent cervical cancer after RHND followed by adjuvant RT/CCRT.


Introduction
Cytological screening has made the incidence rate and mortality rate of cervical cancer significantly reduced, but cervical cancer is still the fourth most common malignancy in women [1][2]. When cervical cancer patients detected at early stage (stages IB-IIA) based on the 2009 International Federation of Gynecology and Obstetrics (FIGO) staging system, radical hysterectomy with node dissection (RHND) is the preferred surgical treatment. Postoperative adjuvant radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) is recommended according to the risk factors on postoperative histopathological examination [3][4].
Intermediate-risk factors include large tumor size, lymphovascular space invasion (LVSI) and deep cervical interstitial infiltration [5][6]. High-risk factors include lymph node metastasis (LNM), parametrial invasion and resection margin involvement [7][8]. The existence of risk factors is associated with higher recurrence rate and poor survival outcome in patients with early cervical cancer. These patients can benefit from postoperative RT or CCRT, prolong disease progression-free survival (PFS) time and overall survival (OS) time [7].
Considering the short survival time of patients with recurrent cervical cancer, it is vital to identify the prognostic factors for recurrent cervical cancer after initial treatment. However, the clinical features and the effect of each risk factor on the recurrent cervical cancer patients is much less known. In addition, according to the latest FIGO staging system, LNM is defined as stage IIIC, and the prognosis of these patients after radical surgery and adjuvant RT/CCRT is not very clear.
Therefore, the purpose of this retrospective study was to identify the recurrence pattern and prognostic factors of patients with recurrent cervical cancer after initial treatment with RHND followed by adjuvant chemoradiotherapy (RT/CCRT) .

Study population
Medical records of recurrent cervical cancer patients who initially treated with RHND and adjuvant chemoradiotherapy (RT/CCRT) registered from January 2012 to May 2018 in Liaoning Cancer Hospital were retrospectively analyzed.
Inclusion criteria included histologically diagnosed cervical cancer, preoperative FIGO stage IB-IIA disease, no history of neoadjuvant chemoradiotherapy, received RHND, received postoperative pelvic radiotherapy (dose≥40Gy) with or without concurrent chemotherapy.
Pre-treatment examinations included gynecological examination, blood routine examination, blood biochemical examination, urine routine examination, squamous cell carcinoma antigen (SccAg), chest and abdomen CT, pelvic magnetic resonance imaging (MRI) or PET/CT. Cystoscopy and colonoscopy were performed when bladder and rectum were suspected to be involved. The pathological reports included histological subtype, pathological differentiation degree, tumor size, LVSI, interstitial infiltration depth, number of lymph nodes dissected, number of positive lymph nodes in each site, parametrial invasion and margin resection involvement were analyzed retrospectively.

Treatment
All patients initially received adjuvant RT or CCRT after RHND. Conformal radiotherapy (CRT) or intensity-modulated radiotherapy (IMRT) started within 4-6 weeks after radical surgery. According to the CTV guidelines of radiotherapy tumor group for whole pelvis, the clinical target volume (CTV) included parauterine area, upper vagina and pelvic lymph drainage area (common iliac blood vessel area, internal and external iliac blood vessel area, obturator lymph node area and presacral lymph node area) . In addition, the para-aortic lymph node area was included when para-aortic lymph node metastasis occurred.
Treatment of recurrent cervical cancer depends on the initial treatment methods, site of recurrence and patient's physical condition. The treatment modes included operation, radiotherapy, chemotherapy, comprehensive treatment, immunotherapy and palliative care. Surgery was defined as therapeutic surgery, not including symptomatic surgery. Palliative care was defined as symptomatic supportive care.

Follow-up evaluations
Patients received first follow-up evaluation one month after the end of treatment. Then, every 3 months in the first 2 years, every 6 months in the 3-5 years, and once a year after 5 years. Main follow-up examinations included gynecological examination, SccAg, chest and abdomen CT and pelvic MRI. PET-CT was recommend only when disease relapse was suspected.
Local recurrence (LR) was defined as any disease relapse in the radiation field, including vaginal stump and pelvic lymph node area below aortic bifurcation. Distant metastasis (DM) was defined as disease relapse outside the radiation field. Disease PFS was defined as time from the day of surgery to disease relapse or the latest follow-up. OS after recurrence was defined as time from the day of disease relapse was diagnosed to cervical cancer-specific death or the latest follow-up. In our study, death after recurrence was defined as specific death of cervical cancer, excluding death due to other reasons.

Statistical analysis
The risk factors for specific death of recurrent cervical cancer were analyzed. The variables included age (continuous variable), disease early relapse (recurrence occurred within 6 months after the day of surgery), number of recurrent organs, recurrence site, histological diagnosis, tumor size, pathological differentiation degree, LVSI, interstitial infiltration depth, parametrial invasion, resection margin involvement, pelvic LNM, para-aortic LNM were categorical variables.
Chi-square test or Fisher exact test were used for univariate analysis of categorical variables.
Variables with statistical significance in univariate analysis were used in the subsequent multivariate analysis. Multivariate analysis was performed with Cox proportional hazard model. Kaplan-Meier method and Log-rank test were used to evaluate the influence of risk factors on the survival rate after disease relapse. Results showed as risk ratio (HR) of 95% confidence interval. P<0.05 was considered as statistically significant.

Patient characteristics
Between January 2012 and May 2018, a total of 415 patients with biopsy proven cervical cancer were treated with RHND followed by adjuvant radiochemotherapy (RT/CCRT). 153 patients occurred disease relapse and were enrolled in our study.
The clinicopathological characteristics of recurrent cervical cancer patients was presented in table 1.

Recurrence pattern
In

Survival analysis
Our study further analyzed the survival outcome of cervical cancer patients after recurrence. The The survival curves according to the number of organ involvement and the recurrence patterns are shown in Fig. 1   Univariate analysis showed that disease stage, tumor size, pathological differentiation degree, positive resection margin, positive lymph nodes in pelvic cavity, positive para-aortic lymph nodes, different metastatic sites, number of involved organs, treatment modes after disease relapse and early disease recurrence were associated with death after disease relapse. In multivariate analysis, the variables with statistical differences in the above univariate analysis were included in the Cox proportional hazard regression model. The results showed that the risk factors of death after disease relapse were positive resection margin, positive common iliac lymph node, positive para-aortic lymph node, different metastatic sites, no treatment after recurrence, and early disease recurrence.  Table 4 Cox proportional hazard analysis for prognositc factors associated with survival outcomes in recurrent cervical cancer

Discussion
Palliative chemotherapy is the main treatment for patients with recurrent cervical cancer.
Individualized treatment also includes surgery, radiotherapy, targeted therapy and immunotherapy, etc.
Although great efforts have been made to prolong the survival time of patients with recurrent cervical cancer in the past decades, the prognosis of these patients is still not optimistic. Some studies reported that the 1-year survival rate of recurrent cervical cancer was only 15% -20% [9].
This study analyzed the recurrence patterns and prognostic factors of patients with recurrent cervical cancer after radical surgery followed by adjuvant chemoradiotherapy (RT/CCRT  [10][11][12][13]. 24.8% patients were early disease recurrence in this study. In addition, our study showed that early disease recurrence was an independent risk factor for the prognosis of patients with recurrent cervical cancer (P=0.012). NCCN guidelines suggest that follow-up evaluation should be conducted every 3 months within 2 years after initial treatment completed. Early detection and early treatment may improve the prognosis of patients with early disease recurrence. Therefore, cervical cancer patients with high risk factors proved by postoperative pathology can consider increasing the frequency of reexamination within half a year after the end of initial treatment.
Our study indicated that the surgical variables of the independent risk factors leading to poor survival of recurrent cervical cancer included positive resection margin, positive common iliac lymph node and positive para-aortic lymph node, which were all high risk factors in pathological examination.
Cisplatin based concurrent chemotherapy during radiotherapy is the standard treatment of postoperative adjuvant therapy for middle and high-risk cervical cancer patients. Additional treatment could be considered to prolong the survival time of patients with pathological high-risk factors, such as targeted therapy, systemic chemotherapy before/after radiotherapy. In another study [14], In recent years, many studies have investigated the effect of positive pelvic lymph nodes on the survival outcome of cervical cancer. Shyu et al. [15] showed that 5-year survival rate of recurrent cervical cancer patients who underwent radical surgery with LNM was significantly lower than that of patients with no LNM. Meir et al. [16] suggested that LNM is an independent risk factor for OS and disease PFS of recurrent cervical cancer. The latest FIGO staging system classifies LNM as IIIC stage, which indicates that LNM can lead to worse prognosis. Pelvic lymph nodes metastasis were classified as stage IIIC1 in generalities according to the 2018 FIGO staging system, however, there was no more detailed staging. Our study found that positive common iliac lymph node was independent risk factor for poor prognosis in recurrent cervical cancer patients, while other sites of pelvic lymph nodes metastasis are not. Therefore, further study are necessary to clarify the difference between the prognosis of patients with positive common iliac lymph nodes and those with positive internal iliac, external iliac and obturator lymph nodes.
Our study indicated that the independent risk factors for poor survivals after disease relpase of cervical cancer patients also included distant metastasis (simple DM / LR+DM) and multiple organs involvement. This is consistent with previous studies. Qiu et al. [17] evaluated the prognosis of 121 patients with recurrent cervical cancer after radical surgery and indicated that DM was significantly associated with poor prognosis. Moreover, we found that the incidence of LVSI was higher in patients with recurrent cervical cancer. It may be related to the fact that LVSI is more likely to occur hematogenous metastasis to distant organs [18]. Systemic chemotherapy as consolidation therapy in patients with LVSI may reduce distant metastasis incidence.
This study is a single-institution retrospective study, which may lead to selection bias and time-trend bias. In addition, sample size is also a limitation.

Conclusion
Our study indicated that positive resection margin, positive common iliac lymph node and para-aortic lymph node, no treatment after disease recurrence, early disease relapse and DM were significantly associated with poor prognosis of patients with recurrent cervical cancer.
Patients with high-risk factors and LVSI could be considered to receive targeted therapy, consolidation chemotherapy or oral drug maintenance therapy after adjuvant chemoradiotherapy to reduce disease relapse and prolong survival time. Patients can increase the frequency of reexamination within half a year after the end of initial treatment, which can help the patients with early disease recurrence receive treatment earlier and improve the prognosis.
Ethics approval Ethical approval was waived by the local Ethics Committee of the Hospital in view of the retrospective nature of the study and all the procedures being performed were part of the routine care.

Funding details
No funding was obtained for this study.

Conflict of interest All the authors declare no conflict of interest.
Informed Consent Informed consent was obtained from all individual participants included in the study.