Introduction

Cervical cancer (CC) remains a significant public health problem in developing countries, often presenting at advanced stages and accounting for a large proportion of gynecologic cancer deaths [1-3]. In 2022, the World Health Organization estimated 111,200 new cancer cases in women in Mexico, of which 21,609 (19.4%) occurred in the genital tract, with CC being the most common gynecologic cancer with 10,348 new cases and 4,909 deaths [4].

In Mexican institutions such as the National Cancer Institute and the General Hospital of Mexico [5,6], CC is only surpassed by breast cancer in terms of incidence. Advanced stages predominate in CC, for which the treatment is a combination of external beam pelvic radiotherapy followed by concurrent chemotherapy based on platinum regimens, and brachytherapy for the central lesion (CCRT) [1,7]. Since 1999, following recommendations from the National Cancer Institute of the United States (NCCN), this treatment regimen has replaced the traditional radiotherapy scheme based on external beam radiotherapy followed by brachytherapy (RT) [1,3,7].

Although the CCRT scheme [1, 3,7] and rescue radical surgery in selected irradiated patients with central tumor persistence or recurrence remains valid for the management of advanced CC, recent publications refer to pelvic exenterations (PE) only as surgeries of choice, because of the high morbidity after Radical Hysterectomy (RH) when used in these patients [1,3,8,9].

As a salvage surgery in patients with recurrent CC after RT or CCRT, RH is a procedure on which we have little information in the literature. In 1993 Magrina FJ [9] published an article reviewing a total of 203 such procedures performed [10-13] over 54 years (1930-1984). The author concluded that this surgery was associated with high morbidity and mortality as a result of complications, related to the development of fistulas, which require colostomies or pelvic exenterations (PE).

The present article describes the experience of the Oncology Unit (OU) within the General Hospital of Mexico – Dr. Eduardo Liceaga (GHM). It includes 85 cases of Radical Hysterectomy as salvage surgery, in patients with persistent or recurrent CC after RT or CCRT, over a period of 51 years. Fifty of these cases [13] were included in the report on the 203 RH procedures, published in 1987 by Rubin CS et al of Memorial Sloan-Kettering Cancer Center New York [10].

Materials and Methods

A retrospective review of patient records was conducted from January 1, 1966, to December 31, 1979(earlier period), and from January 1, 1980 to December 31, 2006 and from January 1, 2008, to December 31, 2018 (later period), involving 1,082 laparotomies performed in the Oncology Unit of the General Hospital of Mexico (GHM) on patients with persistent or recurrent(CC) following (RT) (50 Gy teletherapy followed by intracavitary radiotherapy, brachytherapy 30 Gy) and/or concomitant chemotherapy with platinum or carboplatin (CCRT). Patients were included if they had optimal functional reserve and tumor confined to the cervix and/or vagina, based on clinical examination and imaging studies.

Following bowel preparation, a midline supra- and infraumbilical laparotomy was performed, and the abdominal and pelvic cavities were explored. If suspicious abdominal disease was identified, an intraoperative biopsy was obtained, followed by pelvic lymph node dissection. If the biopsy confirmed metastatic disease, the procedure was terminated. Otherwise, a complete pelvic lymph node dissection was performed. During the period from 1966 to 1979 (earlier period), pelvic lymphadenectomy was performed according to the criteria of JV Meigs [14], dissecting the anterior branches of the hypogastric plexus to the middle hemorrhoidal vessels (Figure 1). In subsequent periods, the procedures were primarily based on the technique described by Piver and Rutledge [15], preserving these branches. The specimen was removed in bloc with adequate vaginal margins and a Penrose drain was placed in the surgical bed. The drain was removed within 3 days postoperatively. The Foley catheter was removed after the second postoperative week if residual urine in the bladder was less than 100 ml. Urinary dysfunction lasting 3 months or longer was considered a major complication.

Figure 1: Pelvic lymphadenectomy and surgical bed in 50 radical hysterectomies performed in the period 1966-1979.

For the purpose of analysis, the evaluation of postoperative morbidity and mortality was divided into two periods: the first from 1966 to 1979 (earlier period), and the second from 1980 to 2006 and 2008 to 2018 (later period). Records from 2007 were lost due to archival remodeling.

Postoperative mortality was defined as death within the first 30 days of surgery, and major complications included pulmonary embolism, pneumonia, urinary dysfunction lasting more than 3 months, and vesicovaginal and rectovaginal fistulas requiring urinary diversion or permanent colostomy [1, 3, 8, 9], as well as ureterovaginal fistulas, intestinal anastomotic dehiscence, and bowel obstruction. The FIGO 2018 staging system [1] was used, with stage I defined as IB2-B3 and stage III as IIIA and IIIB.

Descriptive statistics were used to analyze the data, including means and proportions for numerical and categorical variables, respectively. Survival analysis was performed using the KaplanMeier method. Differences between groups were evaluated using the log-rank test. Univariate and multivariate Cox proportional hazards models were used to identify variables associated with disease-free survival (DFS) and overall survival (OS). Ninety-five percent confidence intervals were calculated for the hazard ratio, and a p-value less than 0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 22.0

Results

The 1,082 patients who underwent laparotomy during the 51-year study period, 85 cases (7.8%) underwent radical hysterectomy (RH) (Table 1). The youngest patient was 21 years old and the oldest was 65. The median age was 46.4 years. The most common histopathological type was squamous cell carcinoma (SCC) (72.9% of cases), and most of patients (82.3%) were diagnosed at an advanced stage. Additionally, 50.6% received a complete pelvic cycle of radiotherapy (RT) as initial treatment (Table 2).

Table 1: Surgeries performed during the different periods.

Rescue surgeries, 565: Pelvic Exenterations, 480 (84.9 %) Radical Hysterectomies:85 (15.0%).

 Table 2: Descriptive analysis of 85 cases of radical hysterectomy.

Morbidity and Mortality: Major postoperative complications occurred in 24 of the 85 patients (28.2%). This included 18 of the 50 patients in the earlier period from 1966 to 1979 (36.0%) and 6 of the 35 patients in the later period from 1980 to 2018 (17.1%). Complications included 8 vesicovaginal fistulas, 6 ureterovaginal fistulas, 6 rectovaginal fistulas, 2 cases of pneumonia, 1 case of bowel obstruction, and one case of severe urinary dysfunction (Table 3). Five of the 8 patients who developed vesicovaginal fistulas underwent urinary diversion, while 3 refused treatment. Two of the 6 patients with ureterovaginal fistulas underwent ureteroneocystostomy, one had a nephrostomy, and one was managed conservatively with a double-J stent. Two of these 6 patients died from sepsis. Five of the 6 patients who developed rectovaginal fistulas underwent permanent colostomy, and the last patient declined intestinal diversion. The two patients who developed pneumonia died postoperatively, and the patient with bowel obstruction, as well as the patient with urinary dysfunction, were managed conservatively. All four deaths (4.7%) occurred in the group of patients operated on between 1966 and 1979.

Table 3: Major complications in 85 patients*

Surgical Outcomes: Disease-free survival (DFS) of 25-72 months was achieved in 33/62 patients (53.2%) with a median follow-up of 32.3 months for these 62 cases. Overall survival (OS) for all 85 cases was 54.1% with a median follow-up of 34.1 months (Figure 2). Twenty-one of the 85 cases (24.7%) died from tumor recurrence, and follow-up data was lost for 2 patients (2.3%). Univariate analysis for DFS in the 85 radical hysterectomies showed statistically significant differences for the following variables: adenocarcinoma versus squamous cell carcinoma (p=0.031), prior treatment with CCRT versus RT (p=0.001), tumor size less than 3 cm versus greater than 3 cm (p=0.002), and absence versus presence of nodal metastases (p=0.034). (Table 4, Figures 3 and 4).

Figure 2. DFS from 25-72 months in 62 patients: 53.2% and, OS25-72 months in 85 patients: 54.1%.

Figure 3. Log-rank test for DFS in 85 patients with radical hysterectomies.

Figure 4. Log-rank test for DFS in 85 patients with radical hysterectomies.

Table 4: Univariate analysis of disease-free survival (DFS) for different variables in 85 cases of radical hysterectomy for cervical cancer.

Multivariate Cox regression analysis for variables with significant DFS did not show significant differences. The closest was the type of radiotherapy, favoring CCRT (p=0.065) (Table 5). Univariate analysis for OS showed significant differences favoring the following variables: age 51-60 years (p=0.005), prior treatment with CCRT versus RT (p=0.013), and tumor size less than 3 cm (p=0.038) (Table 6, Figures 5 and 6). Multivariate Cox regression analysis for OS showed that only tumors 3 cm or smaller were a significant variable (p=0.014) (Table 7).

Figure 5. Log-rank test for OSin 85 patients with radical hysterectomies.

Figure 6. Log-rank test for OS in 85 patients with radical hysterectomies.

Table 5: Multivariate analysis of disease-free survival (DFS) for different variables in 85 cases of radical hysterectomy for cervical cancer (Cox Regression).

Only variables that were statistically significant in the univariate were analyzed in multivariate Cox regression models.

Table 6: Univariate analysis of overall survival (OS) for different variables in 85 cases of radical hysterectomy for cervical cancer.

Table 7: Multivariate analysis of overall survival (OS) for different variables in 85 cases of radical hysterectomy for cervical cancer (Cox Regression).

Only variables that were statistically significant in the univariate were analyzed in multivariate Cox regression models.

Tumor Recurrences: Twenty-three patients (27.0%) developed tumor recurrences within 5-56 months with a median of 11.5 months. In 6 cases (26%), recurrences were local, in 10 (43.4%) locoregional, in 5 (21.7%) locoregional and distant, and in 2 (8.6%) distant only (Table 8). Distant metastases were found in two cases in the supraclavicular lymph nodes and in one case with peritoneal carcinomatosis, para-aortic lymph node metastases, splenic metastases, pulmonary metastases, and bone metastases. Only 2 of these 23 patients (8.7%) achieved disease control with a disease-free follow-up of 36 and 24 months, respectively.

Table 8: Tumor recurrences in 23 patients.