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Abstract
Background The management of patients with intraoperative detection of lymph node involvement remains controversial. The most significant aspect is the decision regarding the completion of the cervical procedure, such as hysterectomy, radical hysterectomy, or a fertility sparing procedure.
Primary objective The primary objective of the ABandoning RAd hyst in cerviX cancer (ABRAX) trial is to determine whether the completion of the cervical procedure (ie, radical hysterectomy) improves oncological outcome in patients with intraoperatively detected lymph node involvement before they are referred for definitive chemoradiation.
Study hypothesis We hypothesize that, in patients with intraoperative lymph node involvement, completion of radical hysterectomy or other cervical procedure does not improve the oncological outcome of definitive chemoradiation.
Trial design The ABRAX trial is a multicenter, retrospective, cohort study. Patients with negative lymph nodes in clinical staging, in whom lymph node involvement is detected intraoperatively, are included. Completion or abandonment of the planned cervical procedure stratifies the cohort into two subgroups in which oncological outcome and morbidity will be compared.
Major Inclusion/Exclusion criteria Patients with early stage (pT1a–pT2b) cervical cancer, who did not have positive lymph nodes on preoperative imaging, who were scheduled for primary surgical treatment, and in whom metastatic involvement of pelvic lymph node was found during surgery either as a grossly (macroscopically) involved or on intraoperative pathology assessment will be enrolled. Patients can be included irrespective of surgical approach (minimal invasive surgery or laparotomy) and type of cervical procedure performed (hysterectomy, radical hysterectomy, or a fertility sparing procedure).
Primary endpoint The primary endpoint of this retrospective study is a progression free survival in two subgroups with abandoned or completed cervical procedure followed by definitive chemoradiation in both groups.
Sample size The assumed sample size is 718 patients (in total for both groups).
Estimated dates for completing accrual and presenting results Estimated end of data collection: December 2019; estimated date of presenting results: Q2/3 2020.
Trial registration Clinicaltrials.gov: NCT04037124.
- cervical cancer
- sentinel lymph node and lympadenectomy
- surgery
- radiation
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Introduction
The management of patients with intraoperative detection of lymph node involvement currently varies widely. Options include completing or abandoning radical hysterectomy, performing or abandoning pelvic lymph node dissection, and even continuing with inframesenteric or infrarenal para-aortic lymph node dissection. The most significant aspect is the decision regarding the performance of radical hysterectomy, due to the high morbidity caused by combined treatment composed of radical parametrectomy and adjuvant radiotherapy in these patients—patients are referred for pelvic radiotherapy after distal ureters, bladder, and rectum have been surgically dissected.1
Data on the oncologic outcome of patients with lymph node involvement after radical hysterectomy and adjuvant radiotherapy are broadly available. Recent figures show 5 year survival in stage IB at around 70–85%.2 3 In contrast, the data on patients in whom radical hysterectomy was abandoned due to intraoperative detection of lymph node involvement are scarce. The available literature mostly refers to small groups of cases with grossly involved lymph node detected during surgery.4–7
The goal of this study is to obtain the best data available from an adequate number of patients treated by both types of management in the same period of time and to analyze the risks and benefits of the performance of radical hysterectomy if lymph node involvement is detected intraoperatively in spite of non-suspicious preoperative radiological assessment.
Methods
Trial Design
ABandoning RAd hyst in cerviX cancer (ABRAX) is an international, multicenter, retrospective trial. Data on cervical cancer patients with no signs of nodal involvement in clinical staging who are found to be node positive intraoperatively will be evaluated. The protocol has been developed to be inclusive and reflect current clinical practice. All surgical approaches are eligible for the study. Lymph node infiltration can be detected either by intraoperative pathology assessment or by gross assessment (macroscopic suspicion has to be confirmed by the final histology). Sentinel or any other pelvic lymph nodes can be subject to intraoperative assessment. Any type of nodal metastasis (macrometastasis, micrometastasis, or isolated tumor cells) is considered a positive lymph node. All types of cervical procedures (such as conization, simple hysterectomy, trachelectomy, any type of radical hysterectomy, or radical trachelectomy) are eligible for the trial; administration of neoadjuvant chemotherapy is not an exclusion criterion.
The abandonment of a planned cervical procedure depends solely on the decision of the surgeon and on local institutional guidelines.
Data on patient characteristics, disease characteristics at diagnosis, primary treatment, adjuvant treatment, serious treatment related complications, and survival will be collected.
The ABRAX trial is a non-commercial trial that does not receive any support from the industry. Institutions will not receive any financial compensation for participation in the study. All trial related expenses (administrative center, statistics, electronic data capture system, and monitoring) are covered by research grants.
The basis for successful enrollment is collaboration within the leading collaborative group Central and Eastern European Gynecologic Oncology Group (CEEGOG, CEEGOG Cx2) and ENGOT (ENGOT Cx3).
By June 2019, there were 48 participating sites, including 13 CEEGOG sites and 29 sites from other ENGOT groups (see Figure 1).
Study design
Participants
Patients are enrolled in the study retrospectively if inclusion criteria are met. Inclusion criteria are: (i) histologically confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma; (ii) stage pT1a–pT2b; (iii) patient referred for primary surgery, including radical/simple hysterectomy or a fertility sparing procedure, with or without lymph node staging; (iv) intraoperative detection of lymph node involvement (macroscopic involvement=grossly involved lymph nodes (must be confirmed by final pathology)) or microscopic involvement (sentinel lymph node/lymph node intraoperative pathologic evaluation); (v) follow-up data available for ≥2 years; and (vi) surgery performed between January 2005 and December 2015.
Exclusion criteria are: (i) preoperative evidence of grossly involved lymph node; (ii) tumor types other than those noted in the inclusion criteria; (iii) negative pelvic lymph node; (iv) lymph node involvement reported by the final histology but not detected during the surgery; and (v) unavailability of follow-up data.
Primary Endpoints
The primary endpoint is progression free survival assessed separately in both subgroups. The prevalence of ≥G2 treatment related morbidity, and overall and pelvic progression free survival are secondary endpoints.
The oncological outcome will be stratified according to prognostic parameters such as tumor size, number of involved lymph nodes, type of lymph node metastases, presence of lymphovascular space invasion, tumor type, administration of neoadjuvant chemotherapy, and performance of systematic pelvic lymphadenectomy.
Statistical Methods and Sample Size
The power analysis was performed using PASS 138 and calculated for progression free survival as quantitative time to event primary endpoint with required standard measures. The recurrence rate is planned to be evaluated at the 24th month of follow-up to prove a non-inferiority of intraoperative abandonment of a radical cervical procedure to the reference value of 80% with a non-inferiority margin of 85%. With a hazard ratio of 0.728, power of 0.8, level for alpha error of 0.05, and an increase in progression free survival of 0.05, the target size is 359 cases per group (718 in total).
The null hypothesis for the secondary endpoint (prevalence of ≥G2 treatment related morbidity) assumes a significant difference in the prevalence of complications between the two study arms. Standard 95% confidence intervals for proportions will be estimated using the exact binomial distribution, and χ2 statistics will be used to compare the groups. A value of p=0.05 will be used as the limit of statistical significance in all of the analyses performed.
Discussion
According to the new European Society of Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology Guidelines for the Management of Patients with Cervical Cancer, management of early stage cervical cancer should aim for the avoidance of combining radical surgery and radiotherapy because of the high morbidity after a combined treatment.9 There are special types of complications associated with combined treatment, such as urinary fistulas or stenoses—intraoperatively dissected ureters and urinary bladder are further affected by pelvic radiation.
Adjuvant chemoradiation is currently recommended in 'high risk' patients. This category consists of patients after radical hysterectomy with positive pelvic lymph nodes, positive parametrial involvement, or a positive surgical margin. In the GOG 109 study, these patients experienced a significant improvement in disease free survival and overall survival with adjuvant chemoradiation.10
While both parametrial involvement and tumor extent can be assessed by imaging methods (magnetic resonance imaging and ultrasound) during preoperative clinical staging,11 12 the sensitivity of detecting lymph node metastases remains suboptimal due to the obvious limitations for detecting small lesions.13 Intraoperative pathologic lymph node evaluation represents an opportunity to identify patients with lymph node involvement before further radical surgery. The cervical procedure can be intraoperatively abandoned and the patient spared of receiving combined treatment.
However, data on this approach are scarce, and it remains controversial. According to a recently performed European Society of Oncology survey on current practice in the management of cervical cancer, the cervical procedure is abandoned in 61% of centers.14 In the analysis based on the Surveillance, Epidemiology, and End Results database, Richard and colleagues retrospectively analyzed a set of 218 patients who underwent a complete pelvic and para-aortic lymphadenectomy, and were found to have positive pelvic lymph nodes. All patients received postoperative radiotherapy. The cervical procedure was completed in 163 and abandoned in 55 patients. There was no significant difference in 5 year survival between these two groups.3
The primary endpoint of our trial is progression free survival of patients with no suspicious lymph nodes in clinical staging (cN0) and with intraoperatively reported lymph node metastasis. The performance or abandonment of the cervical procedure is the main stratification factor.
The retrospective nature is the trial’s major limitation. Taking into account a limited number of patients with intraoperative detection of lymph node involvement, a prospective design would be demanding, if not undoable. Moreover, randomization of patients would be difficult to conduct because individual institutions usually strongly prefer one of the two types of management tested in this trial.
Due to the long term study period, incomplete data might become another limitation, especially concerning radiotherapy or treatment related morbidity. Mandatory variables have been identified in the database, the completeness of the database is monitored, and cases with missing mandatory data will be excluded. One of the inclusion criteria is the requirement for the availability of at least 2 years of follow-up data.
References
Footnotes
Contributors LD: data curation; formal analysis; methodology; project administration; writing-original draft; writing-review and editing, investigation. IR: investigation. FR: investigation. IV: investigation. LD: data curation; formal analysis; methodology. JJ: data curation; formal analysis; methodology. DC: conceptualization; formal analysis; methodology; project administration; supervision; writing-review and editing; investigation.
Funding This work was supported by Charles University in Prague (UNCE 204065 and PROGRES Q28/LF1) and by a grant from the Czech Research Council (No 16-31643A, NV19-03-00023).
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 request