Objective Recent evidence has suggested that laparoscopic radical hysterectomy is associated with an increased risk of recurrence in comparison with open abdominal radical hysterectomy. The aim of our study was to identify patterns of recurrence after laparoscopic and open abdominal radical hysterectomy for cervical cancer.
Methods This a retrospective multi-institutional study evaluating patients with recurrent cervical cancer after laparoscopic and open abdominal surgery performed between January 1990 and December 2018. Inclusion criteria were: age ≥18 years old, radical hysterectomy (type B or type C), no recurrent disease, and clinical follow-up >30 days. The primary endpoint was to evaluate patterns of first recurrence following laparoscopic and open abdominal radical hysterectomy. The secondary endpoint was to estimate the effect of the primary surgical approach (laparoscopy and open surgery) in post-recurrence survival outcomes (event-free survival and overall survival). In order to reduce possible confounding factors, we applied a propensity-matching algorithm. Survival outcomes were estimated using the Kaplan-Meier model.
Results A total of 1058 patients were included in the analysis (823 underwent open abdominal radical hysterectomy and 235 patients underwent laparoscopic radical hysterectomy). The study included 117 (14.2%) and 35 (14.9%) patients who developed recurrent cervical cancer after open or laparoscopic surgery, respectively. Applying a propensity matched comparison (1:2), we reduced the population to 105 patients (35 vs 70 patients with recurrence after laparoscopic and open radical hysterectomy). Median follow-up time was 39.1 (range 4–221) months and 32.3 (range 4–124) months for patients undergoing open and laparoscopic surgery, respectively. Patients undergoing laparoscopic radical hysterectomy had shorter progression-free survival than patients undergoing open abdominal surgery (HR 1.98, 95% CI 1.32 to 2.97; p=0.005). Patients undergoing laparoscopic radical hysterectomy were more likely to develop intrapelvic recurrences (74% vs 34%; p<0.001) and peritoneal carcinomatosis (17% vs 1%; p=0.005) than patients undergoing open surgery.
Conclusions Patients undergoing laparoscopic radical hysterectomy are at higher risk of developing intrapelvic recurrences and peritoneal carcinomatosis. Further evidence is needed in order to corroborate our findings.
- cervical cancer
- neoplasm recurrence, local
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Laparoscopic radical hysterectomy increases intrapelvic recurrence in comparison to open radical hysterectomy.
Peritoneal carcinomatosis was more commonly detected after laparoscopic than open abdominal surgery (17% vs 1%).
Site-specific recurrences (vaginal, lymphatic, and distant) are similar after laparoscopic and open surgery.
Cervical cancer represents a major concern as the third most common malignancy among women aged <39 years, and the second most common cause of death from cancer among women aged between 20 and 39 years in the USA.1 Surgery represents the mainstay treatment for cervical cancer patients with early-stage disease.2 In the last decades, minimally invasive surgery has replaced open surgery for the treatment of several malignancies including cervical cancer.3 4 Accumulating data from retrospective studies suggested that the minimally invasive approach had similar oncologic results to conventional open surgery, improving short-term postoperative outcomes.5 6
Recently, the unexpected results of the Laparoscopic Approach to Cervical Cancer (LACC) trial have led to a strong debate in the gynecologic oncology community.7 The LACC trial randomized patients to minimally invasive or open abdominal radical hysterectomy; the results showed that patients undergoing minimally invasive surgery had an increased risk of local recurrences and worse disease-free and overall survival compared with patients undergoing open radical hysterectomy. Similarly, data from more than 2000 cervical cancer patients included in the Surveillance, Epidemiology & End Result (SEER) database study by Melamed and colleagues suggested similar findings.8 After the publication of these results, other studies demonstrated similar findings (even for patients with tumor diameter smaller than 2 cm), highlighting that cervical cancer patients are more likely to develop recurrent disease when undergoing minimally invasive surgery.9–12 Odetto et al reported an overall recurrence rate following laparoscopic radical hysterectomy of 15% and 12% in the overall population and for patients with tumor size ≤2 cm, respectively.13
In this study, we aimed to evaluate recurrence after minimally invasive and open abdominal radical hysterectomy in order to determine whether patients treated by minimally invasive surgery experienced different patterns of recurrence in comparison to patients undergoing open abdominal radical hysterectomy. As the secondary endpoint, we sought to investigate whether primary treatment by laparoscopy or open surgery might impact results achieved by salvage therapy in patients with recurrent disease.
This is a multi-institutional retrospective study of patients treated for cervical cancer in two referral centers in Northern Italy. Data of all consecutive women undergoing radical hysterectomy at two Italian gynecologic oncology units were retrospectively evaluated between January 1990 and December 2018. The institutions included were: (1) Fondazione IRCCS Istituto dei Tumori, Milano; (2) University of Insubria – Ospedale di Circolo, Fondazione Macchi (Varese). Institutional review board approval was obtained by the centers. All women included in the study gave written informed consent for data collection for research purposes. Inclusion criteria were: age ≥18 years old, underwent radical hysterectomy (type B or type C), no recurrent disease, and follow-up >30 days. The primary outcome measure was to evaluate patterns of first recurrence following laparoscopic or open abdominal radical hysterectomy. The secondary endpoint was to estimate the effect of the primary surgical approach (laparoscopy or open surgery) in influencing post-recurrence survival (event-free survival and overall survival).
Generally, patients with cervical cancer with low volume disease (<2 cm) had type B radical hysterectomy, while patients with a tumor >2 cm had type C1 radical hysterectomy. Patients with locally advanced stage cervical cancer responding to neoadjuvant chemotherapy had type C1 radical hysterectomy, regardless of the response (partial or complete) to chemotherapy. Patients with locally advanced disease (stage IB2-II disease) were informed regarding concomitant chemoradiation as standard treatment, and that neoadjuvant chemotherapy plus radical surgery represented a non-standard option. A detailed description of the neoadjuvant chemotherapy schedules and patient selection is reported elsewhere.14 Response to neoadjuvant chemotherapy was defined according to the Response Evaluation Criteria in Solid Tumors.14 Patients achieving complete or partial (at least 30% in tumor diameter reduction) responses were selected to have surgery. The level of radicality was assessed through the Querleu and Morrow classification.15 Radical hysterectomies performed before 2009 were re-classified according to the more recent Querleu and Morrow classification.15
Teams of laparoscopic surgeons (with a surgeon volume of more than 100 laparoscopic procedures per year) performed all operations in every institution following the same standardized surgical steps. Detailed description of the surgical technique for radical hysterectomy and pelvic lymphadenectomy is presented elsewhere.16 During the laparoscopic procedures, a uterine manipulator was used in all cases. Over the study period, surgery consisted of performing a type B or C radical hysterectomy, with or without bilateral salpingo-oophorectomy plus systematic pelvic lymphadenectomy; para-aortic lymphadenectomy was limited to patients with bulky nodes or it was performed in case of suspicious lesions in the para-aortic area detected at preoperative radiological examination.16 In these latter cases, radical hysterectomy was performed when lymph nodes were negative at frozen section. Data on surgical procedures, perioperative details, adjuvant therapy as well as follow-up evaluations were recorded prospectively in computerized databases, which are maintained and updated by trained residents and trained nurses. The taxonomy proposed by the World Health Organization was used to designate histological subtypes.16 The degree of glandular differentiation and cytologic atypia to determine architectural grade and stage were in accord with the International Federation of Obstetrics and Gynecologists (FIGO) criteria.17 Criteria regarding adjuvant therapy (radiotherapy and/or chemotherapy used after primary treatments) administration and description of follow-up protocols are reported elsewhere.16 Dates and sites of first recurrence were also registered. Recurrences were assessed using imaging techniques including computed tomography (CT) scan, ultrasound, positron emission tomography-CT (PET-CT), and magnetic resonance imaging (MRI). The presence of multiple sites of recurrence was defined as the presence of two or more metastatic sites. When possible, histological assessment of the lesions was performed through radiological-guided biopsy or diagnostic laparoscopy, in order to confirm the presence of the disease.
Since this was a retrospective comparison between two groups, possible allocation biases might impair the quality of the results. Therefore, we performed a propensity-score matching analysis. Propensity-score matching analysis aims to reduce biases arising from different covariates. In order to perform this analysis, we developed a multivariable logistic regression model. Age, body mass index, histology, stage, neoadjuvant and adjuvant therapy were included in the model. Patients who had recurrence after laparoscopic radical hysterectomy were matched 1:2 to patients who had a recurrence after open abdominal radical hysterectomy. This latter group of patients was selected from a cohort of women undergoing open abdominal radical hysterectomy (in the years 1990–2007), using a caliper width ≤0.1 standard deviations (SDs) of the logit odds of the estimated propensity score. For the purpose of this study no patients undergoing open abdominal hysterectomy after 2007 were included in the control group, since after 2007 open surgery was used only in very selected cases. Detailed description of propensity matching is described elsewhere.18 19 Basic descriptive statistics were used to describe the two populations (patients recurring after laparoscopic and open abdominal surgery). Differences in categorical variables were analyzed using the Fisher exact test. Odds ratio (OR) and 95% confidence intervals (95% CI) were calculated for each comparison. T-test and Mann-Whitney test were used to compare continuous variables as appropriate. Survival outcomes (disease-free survival and overall survival) were estimated using the Kaplan-Meier model. Disease-free survival and overall survival were calculated starting from the date of primary surgery. The log-rank test was used to compare the risk of developing recurrence and the risk of death between the two groups over time. P values <0.05 were considered statistically significant. Statistical analysis was performed with GraphPad Prism version 6.0 (GraphPad Software, San Diego CA) and International Business Machines Corporation-Microsoft Statistical Package for the Social Sciences (SPSS) version 20.0 (SPSS Statistics, IBM 2013, Armonk, USA) for Mac.
A total of 1058 cervical cancer patients were evaluated: 823 and 235 underwent open abdominal or laparoscopic surgery, respectively. Overall, the study included 152 (14.3%) patients who had a recurrence after radical hysterectomy. Among those, 117 (14.2%) and 35 (14.9%) patients had open abdominal or laparoscopic surgery, respectively. Online supplementary table 1 reports baseline characteristics of the two groups before propensity matched comparison.
We performed a propensity matched comparison (1:2) comparing 35 patients with recurrence after laparoscopic radical hysterectomy with 70 patients with recurrence after open abdominal radical hysterectomy. Figure 1 details the study design. Table 1 shows the patients’ characteristics. The median follow-up time was 39.1 months (range 4–221) and 32.3 months (range 4–124) for patients having open or laparoscopic radical hysterectomy, respectively. Baseline characteristics (at the time of primary treatment) were similar between groups as a result of a propensity-matched comparison. Adjuvant therapy and type of adjuvant therapy administered was similar between groups. We tested if year of primary treatment impacted outcomes, and noted that year of surgery (each for open surgery and laparoscopy) did not impact progression-free survival (HR 0.98, 95% CI 0.93 to 1.04; p=0.70 for open surgery; and HR 1.09, 95% CI 0.97 to 1.15; p=0.69 for laparoscopy).
Starting from similar baseline characteristics, patients undergoing laparoscopic radical hysterectomy had shorter progression-free survival than patients undergoing open abdominal procedures (median progression-free survival: 8.0 vs 15.8 months, respectively; HR 1.98, 95% CI 1.32 to 2.97; p=0.005). No difference in overall survival was observed (HR 1.20, 95% CI 0.74 to 1.96; p=0.08). Online supplementary figure 1 shows survival curves. Online supplementary table 2 reports a comparison between patients with early stage undergoing upfront surgery versus patients with locally advanced cervical cancer undergoing neoadjuvant chemotherapy followed by surgery.
Various pattern of recurrences are reported in Table 2. Analyzing crude numbers of recurrences, we observed that the type of surgical approach did not impact the risk of developing vaginal vault, pelvic nodes, extrapelvic nodes and extra-abdominal recurrences (p>0.1). Patients undergoing laparoscopic radical hysterectomy were more likely to develop intrapelvic recurrences than patients undergoing open surgery (74% vs 34%; p<0.001). Furthermore, peritoneal carcinomatosis was more commonly detected after laparoscopic than open abdominal surgery (17% vs 1%; p=0.005). Multiple sites of metastases were noted in 15 (22%) and 11 (32%) patients undergoing laparoscopic and open abdominal radical hysterectomy, respectively (p=0.33). Online supplementary figure 2 displays the site-specific risk of recurrence over time. Patients with recurrence who underwent laparoscopy had a 17-fold increase in peritoneal carcinomatosis in comparison to patients who had open surgery (HR 17.9, 95% CI 3.42 to 93.7; p=0.0006 log-rank test). Online supplementary table 3 shows various treatment modalities for recurrent disease. No difference in treatment for recurrent disease was observed in the two groups of patients. Looking at outcomes starting from the time of recurrent disease, we observed that the surgical approach did not impact on overall survival (Online supplementary figure 4). After first recurrence, median (range) survival was 15.7 (1–141) months and 17.7 (1–78) months for patients undergoing open surgery versus laparoscopic surgery, respectively (p=0.71, log-rank test).
Our study found that patients undergoing laparoscopic radical hysterectomy had a shorter progression-free survival than patients undergoing open abdominal surgery. We also found that patients undergoing laparoscopic radical hysterectomy were more likely to develop intrapelvic recurrences and peritoneal carcinomatosis. Although patients undergoing laparoscopic and open radical hysterectomy had different patterns of recurrence, overall survival was not influenced by surgical approach
The results of the LACC trial changed the landscape of surgical treatment of cervical cancer, dramatically. Prior to this study, laparoscopy was widely accepted in many referral centers. Retrospective data highlighted that laparoscopic surgery had better short-term operative outcomes in comparison to open surgery. Before the results of the LACC trial, the laparoscopic approach was considered safe for cervical cancer patients.7 In the LACC trial, the authors proposed that the reason for the worse oncologic outcomes in patients undergoing laparoscopic radical hysterectomy was that cancer cells might contaminate the pelvis at the time of colpotomy. Additionally, the flow of CO2 might promote seeding of cancer cells into the abdominal cavity.20–22 The presence of a cervical tumor and the use of a uterine manipulator would be the main causes of dissemination of cancer cells. The ongoing analysis of the retrospective SUCCOR study will shed light on whether the use of a uterine manipulator has an impact on recurrence rates.23
Although recent evidence supports that patients undergoing laparoscopy are at higher risk of recurrence (especially those with tumor diameter >2 cm), no study thus far has investigated different patterns of recurrence after laparoscopic and open abdominal surgery.24 We believe that our study is the first to compare various patterns of recurrence in balanced undergoing neoadjuvant chemotherapy. Interestingly, we noted that patients undergoing laparoscopic radical hysterectomy are at high risk of developing peritoneal carcinomatosis.
We consider that our study has several strengths, including the use of a propensity-matching algorithm. Propensity score matching is not able to reduce biases as occur in a randomized trial, but a propensity-matching algorithm aims to reduce selection/allocation biases. We recognize that most retrospective studies comparing laparoscopic and open radical hysterectomy included patients in the open group that were high-risk and deemed not suitable for minimally invasive surgery. By applying a propensity-matching algorithm, we aimed to provide a fair comparison of two homogeneous groups of patients, thus potentially reducing a selection bias.
The main limitation of our study included the inherent biases related to the retrospective design. Other limitations are the non-standardized assessment of recurrence, the inclusion of high-risk patients (those with locally advanced disease undergoing neoadjuvant chemotherapy and surgery), the long-term study period (changes in surgical technique, radiotherapy, and diagnostic tools over the long study period), and the lack of a standardized modality for the treatment of recurrent disease, which might have an impact on the interpretation of our results, particularly the overall survival.25 We also recognize that in our study patients undergoing laparoscopic surgery were from a more recent time-frame where imaging indications and imaging technology might be better and thus our patient selection and the ability to detect recurrences might have been influenced.
In conclusion, the main finding of the study is that patients undergoing laparoscopy are at higher risk of developing intrapelvic recurrences and peritoneal carcinomatosis. Further evidence is needed in order to corroborate our findings. In our practice, after careful evaluation of the results of the LACC trial and our data, we are offering open radical hysterectomy. Minimally invasive radical hysterectomy is performed in very selected cases and after adequate counseling with the patients about possible risk. Molecular and genetic profiling of these tumors are needed in order to achieve a precise and personalized treatment for every patient.
Contributors All the authors meet the criteria given by your journal for authorship and gave their approval to the final version of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request.