International Radical Trachelectomy Assessment: IRTA Study

Abstract

Background:

Radical trachelectomy is considered a viable option for fertility preservation in patients with low-risk early-stage cervical cancer. Current standard approaches include laparotomy or minimally invasive surgery when performing radical trachelectomy.

Primary objective:

The aim of this study is to compare disease-free survival between patients with FIGO (2009) stage IA2 or IB1 (≤2cm) cervical cancer who underwent open versus minimally invasive (laparoscopic or robotic) radical trachelectomy.

Study hypothesis:

We hypothesize that minimally invasive radical trachelectomy has similar oncologic outcomes compared to the open approach.

Study design:

This is a collaborative, multi-institutional, international, retrospective study. Patients who underwent a radical trachelectomy and lymphadenectomy between January 1, 2005 and December 31, 2017 will be included. Institutional Review Board approval will be required. Each institution will be provided access to a study-specific REDCap (Research Electronic Data Capture) database maintained by MD Anderson Cancer Center and will be responsible for entering patient data.

Inclusion criteria:

Cervical cancer FIGO (2009) stages IA2 and IB1 (≤2 cm) squamous, adenocarcinoma, or adenosquamous will be included. Surgery performed by the open approach or minimally invasive approach (laparoscopy or robotics). Tumor size >2cm, by physical examination, ultrasound, magnetic resonance imaging, computed tomography, or positron emission tomography (at least one should confirm a tumor size ≤2cm). Centers must contribute at least with 15 cases of radical trachelectomy (open, minimally invasive or both).

Exclusion Criteria:

Prior neoadjuvant chemotherapy or radiotherapy to the pelvis for cervical cancer at any time, prior lymphadenectomy, or pelvic retroperitoneal surgery, pregnant patients, aborted trachelectomy (intra operative conversion to radical hysterectomy), or vaginal approach.

Primary endpoint:

The primary endpoint is disease free survival (DFS) measured as the time from surgery until recurrence or death due to disease. To evaluate the primary objective, we will compare DFS among patients with FIGO (2009) stage IA2 or IB1 (≤2cm) cervical cancer who underwent open versus minimally invasive radical trachelectomy.

Sample Size:

An estimated 535 patients will be included: 256 open and 279 minimally invasive radical trachelectomy. Previous studies have shown that recurrence rates in the open group range from 3.8 to 7.6%. Assuming that the 4.5-year disease free survival rate for patients who underwent open surgery is 95.0%, we have 80% power to detect a 0.44 hazard ratio using alpha level 0.10. This corresponds to an 89.0% disease free survival rate at 4.5 years in the minimally invasive group.

1. Introduction

Cervical cancer is the fourth most common cancer in women worldwide [1,2] with 85% of cases occurring in developing countries. [3,4] Radical hysterectomy with pelvic lymphadenectomy represents the standard of care of patients with early-stage disease (FIGO 2009 IA with LVSI-IB1) who are not interested in future fertility. According to the 2018 National Comprehensive Cancer Network (NCCN) guidelines; radical hysterectomy can be performed either by laparotomy (open) or minimally invasive approach (laparoscopy or robotic). [5] Thirty-eight percent of cervical cancers are diagnosed in women under the age of 45 [6] and therefore, fertility sparing surgery has emerged as an alternative for patients who wish to preserve fertility. The 2018 NCCN guidelines recommendation is to perform a radical trachelectomy and pelvic lymphadenectomy with or without sentinel lymph node mapping in patients interested in future fertility. [5] Several publications have documented the safety and feasibility of the vaginal [7–11] and laparotomic approach when performing radical trachelectomy. [12–16] As minimally invasive surgery gained popularity, a number of investigators [17–21] have published the safety and feasibility of the minimally invasive radical trachelectomy. Data on oncologic outcomes seemed to suggest that the minimally invasive approach was equivalent to the open approach when performing radical trachelectomy. In a recently published systematic review by Bentivegna et al., [22] the authors analyzed six different fertility-sparing surgeries to treat stages IA to IIA1 cervical cancer. A total of 660 patients who underwent open radical trachelectomies were evaluated with a 5% recurrence rate. Overall, 238 patients who underwent laparoscopic radical trachelectomy were analyzed with a 6% recurrence rate.

A recent multicenter, prospective, randomized trial (LACC Trial), compared oncologic outcomes in patients with early-stage cervical cancer who underwent radical hysterectomy by an open versus minimally invasive approach.[23] In that study, the investigators found that minimally invasive radical hysterectomy was associated with lower rates of disease-free survival, higher rates of recurrences, and lower overall survival. Patients who underwent minimally invasive surgery were almost four times more likely to have a recurrence or death from disease than those who had open surgery [HR: 3.74 (95% CI 1.63 – 8.58), p=0.002]. Minimally invasive radical hysterectomy was associated with higher rates of loco-regional recurrences [HR: 4.26 (95% CI 1.44–12.6), p=0.009]. Also, patients who underwent minimally invasive surgery had a higher risk of death [HR: 6.00 (95% CI 1.77 – 20.3), p=0.004]. The unexpected result of the LACC trial raised a very important concern regarding the oncologic outcomes of patients undergoing radical trachelectomy by minimally invasive approach.

Given the limited number of patients who are candidates for radical trachelectomy and the select indication, a randomized control trial comparing the open vs. minimally invasive surgical approaches, is not likely feasible. The aim of this study is to perform a large, multicenter, retrospective analysis comparing open versus minimally invasive (laparoscopic or robotic) radical trachelectomy in patients diagnosed with stage IA2 and IB1 ≤2cm, to evaluate oncologic outcomes.

2. Methods

a. Study Design

This is a collaborative multi-institutional retrospective study. Patients will be included if they were diagnosed between January 1, 2005 and December 31, 2017 inclusive, with early-stage cervical cancer (FIGO 2009 stage IA2 and IB1 ≤2cm), and underwent open, laparoscopic or robotic radical trachelectomy. A comparison regarding oncologic outcomes between laparotomy and laparoscopy or robotic radical trachelectomy will be performed. Each participating site will submit for institutional review board approval from their institution. An estimated 535 patients will be included in this study; 256 open and 279 minimally invasive surgery.

Each institution will be provided access to a study-specific REDCap database [24] maintained by MD Anderson Cancer Center, and will be responsible for entering patient data from their institutions. Twenty-one (21) sites are expected to participate in this study: MD Anderson Cancer Center (USA); Memorial Sloan Kettering Cancer Center (USA); General University Hospital in Prague, First Faculty of Medicine, Charles University (Czech Republic); Imperial College London (UK); Queen Elizabeth Hospital, Gateshead (UK); Instituto de Cancerologia de las Americas, Medellin (Colombia); Hospital Italiano de Buenos Aires (Argentina); Instituto de Oncologia do Parana, Curitiba (Brazil); Barretos Cancer Hospital, Barretos (Brazil); C. Camargo Cancer Center (Brazil); Karolinska Institute, Stockholm (Sweden); Skane University Hospital, LUND (Sweden); Fudan University Shanghai Cancer Center (China), First Clinic of Obstetrics and Gynecology, University of Medicine and Pharmacy of Târgu Mureş, (Romania), The Regional Institute of Oncology of Iasi (Romania), Copenhagen University Hospital Rigshospitalet (Denmark), North-Western State Medical University. N.N. Petrov Research Institute of Oncology, Saint-Petersburg (Russia), Kazakh Institute of Oncology and Radiology (Kazajstan), UPMC (USA), and RenJi Hospital Affiliatied to Shanghai Jiao Tong University School of Medicine (China). All variables collected on the trial are documented in the Supplementary Appendix.

b. Study monitoring

Data monitoring will be assessed by auditing all participating sites by random selection of ten percent of patients entered in the database. Sites will be asked for all source documents pertaining to selected patients. Data monitoring will be performed by the Study Management Committee (Supplementary Appendix), responsible for checking the accuracy, completeness, and credibility of all data and its compliance with the protocol.

c. Participants

Inclusion Criteria:

Trachelectomy must have been performed between January 1, 2005 and December 31, 2017. Patients who underwent radical trachelectomy and pelvic lymphadenectomy with or without sentinel lymph node mapping for FIGO (2009) stage IA2 and IB1 cervical cancer. Patients must have had squamous, adenocarcinoma, or adenosquamous carcinoma, tumors ≤2cm either by physical examination and/or imaging studies. Surgery performed at centers included in the study with each center enrolling at least 15 patients who underwent radical trachelectomy by the open, laparoscopic or robotics approach and all of these patients will be included in the final analysis. Negative nodes in preoperative images. Patients follow up will be performed every 3–4 months for 2 years and every 6–12 months in years 3 to 5. Follow up procedures will be according to institutional guidelines.

Exclusion Criteria:

Patients will be excluded if they have advanced stage disease (FIGO (2009) IB2, II, III and IV), tumor size >2 cm, prior neoadjuvant chemotherapy or radiotherapy to the pelvis for cervical cancer treatment at any time, prior lymphadenectomy or pelvic retroperitoneal surgery, pregnant, stage IA1 with lymph vascular space invasion, histology other than squamous, adenocarcinoma or adenosquamous carcinoma, aborted trachelectomy (conversion to radical hysterectomy), vaginal approach (if the colpotomy is the only surgical step performed vaginally it will not be considered an exclusion criteria).

d. Outcomes

i. Primary objective:

To compare disease free survival between patients with FIGO (2009) stage IA2 or IB1 ≤2cm cervical cancer who underwent open versus minimally invasive radical trachelectomy.

ii. Secondary Objectives:

To compare recurrence rates and overall survival between patients with early stage cervical cancer FIGO (2009) stage IA2 or IB1 (≤2cm) who underwent open versus minimally invasive (laparoscopic or robotic) radical trachelectomy. To explore covariates associated with disease free survival, overall survival and recurrence including, tumor size (≤1 cm vs. 1–2 cm), stage (FIGO 2009 IA2 vs. IB1 tumors), histology (squamous, adenocarcinoma or adenosquamus carcinoma), grade (I-II vs. III), surgical radicality (Type II vs. III), perineural invasion (yes vs. none), sentinel lymph node mapping (yes vs. no)

e. Sample Size

An estimated 535 patients will be included in this study: 256 open and 279 minimally invasive. Previous studies have shown that recurrence rates in the open group range from 3.8 to 7.6%.[25] Assuming that the 4.5-year disease free survival rate for patients who underwent open is 95.0%, we have 80% power to detect a 0.44 hazard ratio using alpha level 0.10. This corresponds to an 89.0% disease free survival rate at 4.5-years in the minimally invasive group. This power calculation was performed with nQuery Advisor ® 7.0 (Copyright © 1995–2007, Statistical Solutions, Saugus, MA).

f. Statistical Methods

The primary objective of this study is to compare disease-free survival between patients who underwent open radical trachelectomy versus minimally invasive surgery (laparoscopic or robotic radical trachelectomy). Disease-free survival will be measured from the time of surgery until the date of first recurrence or death from disease. Patients will be censored at their last clinic visit date known to be alive and disease free or at the date of death from other causes. We will use the product limit estimator of Kaplan and Meier to estimate disease-free survival at 4.5 years and compare open versus minimally invasive using the log-rank test. [26] Since this is a retrospective study, the power analysis describes the likelihood that we would achieve statistical significance with the available sample size.

The proportion of recurrences will be summarized for each group (open versus minimally invasive). We will use the methods of Gooley et al., [27] to estimate the cumulative incidence of disease recurrence as a function of surgical method (open versus minimally invasive) with death as a competing risk. We will estimate the cumulative incidence overall and for each surgery method with a 95% confidence interval. We will use the methods of Fine and Gray [28] to compare the two groups with respect to cumulative incidence of recurrence. Overall survival will be measured from the time of diagnosis until death. Patients will be censored at their last contact date known to be alive. We will use the product limit estimator of Kaplan and Meier to estimate overall survival and compare open versus minimally invasive using the log-rank test. We will use descriptive statistics to summarize the demographic and clinical characteristics of patients. We will also model disease-free survival and overall survival using Cox proportional hazards regression to estimate the hazard ratio and explore potential prognostic factors.

3. Discussion

Evidence from recently published prospective randomized trial [23] suggests that the oncologic outcomes are inferior when performing the minimally invasive radical hysterectomy compared to the open approach in patients with early cervical cancer. In another, study evaluating open vs. minimally invasive radical hysterectomy through an analysis of a national registry database,[29] the investigators found that for women who underwent minimally invasive surgery the 4-year mortality was 9.1% and 5.3% among those who underwent open surgery (hazard ratio, 1.65; 95% confidence interval [CI], 1.22 to 2.22; p=0.002) with median follow-up of 45 months. The adoption of minimally invasive surgery in 2006 coincided with a decline in the 4-year relative survival rate of 0.8% (95% CI, 0.3 to 1.4) per year (p= 0.01 for change of trend). The study concludes that minimally invasive radical hysterectomy was associated with shorter overall survival than open surgery among women with stage IA2 or IB1 cervical cancer. Neither of these studies were designed to answer the question as to why the inferior results of the minimally invasive surgery. Among the proposed hypotheses is the fact that perhaps in patients with grossly visible tumor, there may be contamination of the peritoneal cavity at the time of the colpotomy approach.[30] Another potential hypothesis is that CO2 may impart a higher propensity for cervical cancer cells to migrate and implant throughout the peritoneal cavity [31]

In the systematic review by Bentivegna et al.,[22] six different conservative strategies for cervical cancer were evaluated including series from January 1, 1987 to February 1, 2016. For open radical trachelectomy, 660 patients were included (stages IA-IIA). Thirty-one patients had recurrent disease (5%). A total of 238 patients had laparoscopic radical hysterectomy (stage IA-IIA). Fifteen patients had recurrences (6%) of whom 7 were diagnosed with tumors >2cm (93 patients had no tumor size reported). Median follow up was <24months (range, 4–66) and this was only reported in some series. A total of 89 patients underwent robotic surgery with only 1 series reporting follow up time (>34 months). With this approach, 2 patients had recurrent disease (1.8%) with 20% of patients had close or positive margins. There are some flaws that need to be taken into account when analyzing that review. First, it is based on a composite analysis of small retrospective series with the number of patients ranging from 1 to 73. Second, patients were included in the analysis that perhaps would not meet current criteria for radical trachelectomy, such as those with stages IB1 >2cm, IB2, and IIA. Third, histology other than squamous, adenocarcinoma and adenosquamous carcinomas were included. Fourth, the oncologic outcome, tumor size, and follow up time were reported in only a few series. Lastly, the time frame of the reported series was 29 years thus making it difficult to compare results.

One important question that remains unanswered is whether there is a difference in oncologic outcomes when comparing the open vs. the minimally invasive radical trachelectomy in patients with tumor size ≤2cms and negative lymph nodes. Many continue to wonder as to whether it is safe to perform the minimally invasive approach in these patients. We hypothesized that minimally invasive radical trachelectomy has similar oncologic outcomes compared to the open approach.