Analysis of the surgical management of patients with recurrent cervical cancer after radiotherapy and chemotherapy

1 Hospital de Caridade de Ijuí, Cirurgia Oncológica Ijuí RS Brasil. 2 Santa Casa de Misericórdia of Porto Alegre, Cirurgia Oncológica Porto Alegre RS Brasil. 3 Universidade Federal do Piuaí, Oncologia Teresina Piauí Brasil. 4 Universidade de Cruz Alta, Programa de Pós Graduação em Atenção Integral à Saúde Cruz Alta RS Brasil. 5 Universidade de Cruz Alta, Cruz Alta, Biomedicina Cruz Alta RS Brasil. Zanini Analysis of the surgical management of patients with recurrent cervical cancer after radiotherapy and chemotherapy. 2 Rev Col Bras Cir 47:e20202443 that underwent surgery due to recurrent cervical cancer after chemoradiation are rare, and involve a small number of patients5. This study aimed to analyze the results of morbidity and survival after curative and palliative surgery in patients with cervical cancer who recurred after primary treatment with chemotherapy and radiotherapy. Another goal was to assess the factors associated with curative and non-curative procedures.


INTRODUCTION
C ervical cancer is the fourth most frequent neoplasm in the female population in the world 1 . Approximately 70% of this type of neoplasm occurs in less developed countries, where the risk of death is three times higher 2 . In Brazil, 60% of cervical neoplasms are diagnosed in advanced stages 3 .
The standard treatment for locally advanced lesions is chemotherapy associated with radiotherapy 4 . In this scenario, the recurrence rate varies from 15% to 30%, with a minority of these cases eligible for surgery 5,6 . Prognostic factors that decrease recurrence or increase survival rates are: (i) a disease-free interval greater than two years after the completion of primary treatment 7,8 , (ii) tumor size less than four centimeters 9 , (iii) negative margins after an exenteration 7,10 , (iv) negative lymph nodes 11 , and (v) surgery with curative intention 7 .
Surgeries in recurrent cases that had an initial treatment with radiotherapy and chemotherapy vary in complexity. A hysterectmony can be performed when the lesions are small and restricted to the uterus and/or vagina, and pelvic exenteration is chosen when the lesions involve adjacent structures 12,13 .
Relevant studies on the management of patients with advanced pelvic disease of cervical origin were diverse. They included primary exenterative procedures 7,11 , pelvic exenteration as the only surgical modality 10,11,14,15 , other pelvic neoplasms 8,10,16,17 , or isolated radiotherapy as primary treatment 18,19 . Studies specifically focusing on patients Original Article

Analysis of the surgical management of patients with recurrent cervical cancer after radiotherapy and chemotherapy.
Análise do manejo cirúrgico de pacientes com câncer cervical recidivado após radioterapia e quimioterapia. 2 Rev Col Bras Cir 47:e20202443 that underwent surgery due to recurrent cervical cancer after chemoradiation are rare, and involve a small number of patients 5 .
This study aimed to analyze the results of morbidity and survival after curative and palliative surgery in patients with cervical cancer who recurred after primary treatment with chemotherapy and radiotherapy. Another goal was to assess the factors associated with curative and non-curative procedures.

RESULTS
Recurrence or progression of the disease was seen in 76 cases (50.3%) after completion of treatment with radiotherapy and chemotherapy. Of these, 54 cases (71%) were above stage II at admission. Surgery was indicated for 12 cases (15.78%), but two patients (2.63%) refused to receive intervention.
The procedures performed are shown in Figure 1.
Regarding patients submitted to surgery, the age ranged from 27 to 62 years, and 40% of them were in stage IIB. The time interval between completion of initial treatment and recurrence ranged from three to 21 months. Symptoms at diagnosis were observed in 90% of the patients (Table 1).  All tumors were squamous cell carcinoma.
Perineural, vascular, and lymphatic invasion were present in all surgical specimens. The tumor diameter ranged from two to nine centimeters. The number of organs involved ranged from one to five (Table 2).
In the curative intent group, the uterus was the only structure involved in one case; uterus and vagina were involved in two cases; and uterus, vagina and bladder in two other cases.
During exploratory laparotomy, two patients were found to have peritoneum implants in the pelvis, one had paraaortic lymph node metastasis, and another patient developed ovarian metastasis. All of these patients underwent palliative pelvic exenteration.   (Table 3).
The rate of tumor recurrence in the group undergoing surgical salvage was 66%.
One case had progression of the disease in the bladder after radical hysterectomy, one case had progression of the disease in the peritoneum after anterior pelvic exenteration, and one case had inguinal lymph nodes after total pelvic exenteration.
The time between the end of primary treatment and recurrence correlates with overall survival and the disease-free interval. According to Marnitz et al. 7 , the overall survival at five years was 16% for those who relapsed within two years, and 28% when the interval was between two and five years (p-value=0.01). A retrospective study 8 was carried out with gynecological tumor patients who were submitted to pelvic exenteration after treatment with radiotherapy. Of those patients, 66% had cervical cancer. Results showed a recurrence rate of 50%, and a shorter overall survival time for those who required surgery within two years after the end of the initial treatment. Comparatively, in our study, no patient had a disease-free interval greater than two years after completion of radiotherapy and chemotherapy.
The tumor size has been one of the criteria for identifying who would benefit from surgical management; however the cutoff point is not clearly defined. A Korean study 9 showed, through a multivariate analysis, that a tumor larger than four centimeters is a predictive factor for recurrence after exenterative procedures. However, a Brazilian cohort on pelvic exenteration for gynecological tumors found that the number of organs involved was more relevant than tumor diameter regarding survival. Perineural invasion was also relevant in cancer-specific and progression-free survival 31 . In our cohort, perineural invasion was present in all surgical specimens.
Palliative pelvic exenteration is a controversial and largely debated topic 22 . This procedure was carried out in patients with significant symptoms such as rectovaginal fistula and vaginal bleeding / discharge associated with pelvic pain. It was only considered if there were no other effective therapies available. Our study indicated that besides the significant symptoms, advanced stage, tumor size greater than five centimeters, and more than three organs involved were factors significantly associated with non-curative surgery. Median survival time in the palliative group was low (five months).
Marnitz et al. 7 reported that the twoyear survival rate was 60% for patients treated with curative intent and 10.5% for those treated with palliative intent (p-value=0.0001). A study 16 with 13 patients with gynecological malignancies undergoing palliative total pelvic exenteration reported two procedure-related deaths, a morbidity rate of 38.4%, an overall two-year survival rate of 15%, and a cancer-specific survival rate of 20%.
Only three patients survived more than 12 months.
The main limitation of our study is the retrospective analysis of a small number of cases, which decreased the statistical power of the study.

Zanini
Analysis of the surgical management of patients with recurrent cervical cancer after radiotherapy and chemotherapy. There are a few pelvic recurrence cases that occur after radiotherapy and chemotherapy that are eligible for surgery. Therefore, the publication of studies with a considerable sample size from a single health center will be scarce.
Positive aspects of our study include: (i) the homogenization of the sample, (ii) the clear methods in relation to the origin of the patients submitted to surgical procedures, and (iii) the Brazilian pioneering spirit of the study, which may serve as a basis for the elaboration of a multicenter study.

CONCLUSION
The morbidity rates of this study were higher in the palliative group. The median survival time was lower in the palliative group than in the curative group, but this difference in survival was not statistically significant. Advanced