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Clinical trial
PARa-aOrtic LymphAdenectomy in locally advanced cervical cancer (PAROLA trial): a GINECO, ENGOT, and GCIG study
  1. Alejandra Martinez1,2,
  2. Fabrice Lecuru3,
  3. Nicolò Bizzarri4,
  4. Cyrus Chargari5,
  5. Anne Ducassou6,
  6. Anna Fagotti4,
  7. Francesco Fanfani4,
  8. Giovanni Scambia4,
  9. David Cibula7,
  10. Berta Díaz-Feijoo8,
  11. Antonio Gil Moreno9,
  12. Martina Aida Angeles9,
  13. Mustafa Zelal Muallem10,
  14. Christhardt Kohler11,
  15. Mathieu Luyckx12,
  16. Frederic Kridelka13,
  17. Agnieszka Rychlik14,
  18. KG Gerestein15,
  19. Viola Heinzelmann16,
  20. Pedro T Ramirez17,
  21. Michael Frumovitz17,
  22. Gwenael Ferron1,
  23. Sarah Betrian18,
  24. Thomas Filleron19,
  25. Christina Fotopoulou20 and
  26. Denis Querleu4
  27. the PAROLA Study group
    1. 1 Surgical Oncology Department, Institut Claudius Regaud, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France
    2. 2 Centre de Recherches en Cancérologie de Toulouse, INSERM UMR 1037, Toulouse, France
    3. 3 Breast, Gynecology and Reconstructive Surgery Unit, Institute Curie, Paris, France
    4. 4 Fondazione Policlinico Universitario A. Gemelli, IRCCS, UOC Ginecologia Oncologica, Dipartimento per la salute della Donna e del Bambino e della Salute Pubblica, Rome, Italy
    5. 5 Radiotherapy Department, Hôpital Pitié-Salpêtrière AP-HP, Paris, France
    6. 6 Radiotherapy Department, Institut Claudius Regaud, Institut Universitaire du Cancer Toulouse Oncopole, France, Toulouse, France
    7. 7 Gynecologic Oncology Center, Department of Obstetrics and Gynecology, First Faculty of Medicine, Charles University and General University Hospital (Central and Eastern European Gynecologic Oncology Group CEEGOG), Prague, Czech Republic
    8. 8 Institute Clinic of Gynecology, Obstetrics and Neonatology, Hospital Clinic de Barcelona, Institutd'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
    9. 9 Gynecologic Oncology, Department of Obstetrics and Gynecology, Vall d’Hebron University Hospital, Barcelona, Spain
    10. 10 Department of Gynecology with Center for Oncological Surgery, Charité—Universitätsmedizin Berlin, Berlin, Germany
    11. 11 Department of Special Operative and Oncologic Gynecology, Asklepios-Clinic Hamburg-Altona, Asklepios Hospital Group, Hamburg, Germany
    12. 12 Department of Gynecology-Andrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
    13. 13 Department of Obstetrics and Gynecology, University of Liège, Liege, Belgium
    14. 14 Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw, Warsaw, Poland
    15. 15 Department of Obstetrics and Gynaecology, University Medical Centre Utrecht, Utrecht, The Netherlands
    16. 16 Obstetric and Gynaecology, University of Basel Faculty of Medicine, Zurich, Switzerland
    17. 17 Department of Gynecologic Oncology and Reproductive Medicine, MD Anderson Cancer Center, Houston, Texas, USA
    18. 18 Medical Oncology Department, Institut Claudius Regaud, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France
    19. 19 Biostatistics & Health Data Science Unit, Institut Claudius Regaud, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France
    20. 20 Gynaecologic Oncology, Imperial College London Faculty of Medicine, London, London, UK
    1. Correspondence to Professor Alejandra Martinez, Surgical Oncology Department, Institut Claudius Regaud. Institut Universitaire du Cancer Toulouse Oncopole, France, Toulouse, France; martinez.alejandra{at}iuct-oncopole.fr

    Abstract

    Background Positron emission tomography/computed tomography (PET/CT) fails to detect approximately 25% of aortic lymph node metastasis in patients with PET/CT stage IIIC1 cervical cancer. Surgical staging could lead to treatment modification and to improved para-aortic and distant control.

    Primary Objective(s) To demonstrate if chemoradiation with tailored external beam radiation field based on surgical staging and pathologic examination of the para-aortic lymph node is associated with improved 3-year disease-free survival compared with patients staged with PET/CT staging only.

    Study Hypothesis Surgical staging followed by tailored chemoradiation will improve disease-free survival while avoiding unnecessary prophylactic extended-field chemoradiation in patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC1 cervical cancer.

    Trial Design This is an international multicenter, randomized, phase III study. Eligible patients will be randomized 1:1 between PET/CT staging followed by chemoradiation (control arm), or surgical staging followed by tailored chemo-radiation (experimental arm). Randomization will be stratified by tumor stage according to TNM classification, center, and adjuvant treatment.

    Major Inclusion/Exclusion Criteria Main inclusion criteria are histologically proven PET/CT FIGO stage IIIC1 cervical cancer. Main exclusion criteria include unequivocal positive common iliac or para-aortic lymph node at pre-therapeutic imaging PET/CT.

    Primary Endpoint(s) The primary endpoint is disease-free survival defined as the time from randomization until first relapse (local, regional, or distant), or death from any cause.

    Sample Size 510 eligible patients

    Estimated Dates for Completing Accrual and Presenting Results The estimated date for completing accrual will be Q2 2027. The estimated date for presenting results will be Q4 2030.

    Trial Registration Number NCT05581121.

    • cervical cancer
    • lymph nodes
    • radiotherapy, intensity-modulated

    Data availability statement

    No data are available.

    https://doi.org/10.1136/ijgc-2022-004223

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      Introduction

      Background

      Worldwide, cervical cancer is one of the most common malignant diseases. Although cervical cancer is often curable if detected early, more than one third of patients present with locally advanced disease at diagnosis (stages IB3-IVA).1 Para-aortic lymph node status is the most important prognostic factor in patients with locally advanced cervical cancer, and plays an important role in extra-abdominal lymph node and metastatic spread. The 5-year survival rate of patients with para-aortic lymph node metastasis remains below 40%, with a majority of patients presenting with distant failure.2 3 Lymph node extension to the para-aortic area is a key point for the therapeutic strategy since it defines the extension of radiation fields and allows for treatment intensification. In the RetroEMBRACE cohort of 731 patients, 30% experienced treatment failure. Of these, 9% were located in the para-aortic lymph nodes, and 24% were systemic and para-aortic lymph nodes. The study concluded a need to optimize the treatment strategy to eradicate micrometastasis in para-aortic lymph nodes and distant organs.4 An EMBRACE analysis on nodal failures demonstrated that pathological nodes at diagnosis are mainly located in the pelvis, while nodal failures are more often in the para-aortic lymph node. In the 11% of patients who have a nodal relapse, 68% are para-aortic lymph nodes.5 A recent review including 850 patients from three randomized controlled trials concluded that prophylactic extended field chemoradiation significantly reduces para-aortic lymph node recurrence, distant failure, and overall survival.6 A bicentric retrospective study including 198 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC1 cervical cancer showed improved 5-year cancer-specific survival and para-aortic lymph node recurrence-free survival in patients with common iliac lymph nodes and three or more pelvic positive lymph nodes treated with prophylactic extended field chemo-radiotherapy.7 8 One approach might be to prescribe extended field irradiation to all patients with radiologic findings of pelvic lymph node spread. However, extended-field irradiation is associated with increased incidence and persistence of high grade toxicity in the EORTC, RTOG, and CTAC studies.9–11 The high morbidity rates of extended-field chemoradiation associated with conventional radiotherapy reported in these trials have been largely reduced since the use of intensity modulated radiation therapy (IMRT) extended-field chemoradiation, with toxicity rates ranging from 4–10%.8 12 13 Reported high grade toxicity is even similar to pelvic chemo-radiation therapy (CRT) in several studies.7 12 However, there is still a lack of prospective data with IMRT extended-field chemo-radiation, there are different inclusion criteria in these studies, and there is still no consensus on delineation and dose prescription of IMRT extended-field chemoradiation.6

      International guidelines differ in staging modalities to assess para-aortic lymph node status in locally advanced disease cervical cancer.14 18- Fluorine fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is the most accurate imaging exam to assess para-aortic lymph node involvement. However, PET/CT underestimates para-aortic lymph node metastasis, and fails to detect small volume disease <5 mm and between 10–15% of cases with aortic lymph node involvement, that will remain undertreated.15 Pelvic lymph node metastasis is the most important factor associated with extension to the para-aortic lymph nodes. Indeed, PET/CT false-negative results in the para-aortic area have been recorded in <5% of patients without pelvic lymph node involvement, and in 20–30% of patients with pelvic lymph node uptake.16–18 For this reason, the European Society of Gynaecologic Oncology (ESGO) and National Cancer Comprehensive Network (NCCN) guidelines consider para-aortic lymph node dissection as an option for staging purposes in patients with positive pelvic nodes and negative para-aortic lymph nodes on pre-treatment FDG-PET/CT.19 20 In contrast, prophylactic extended-field chemoradiation may be considered to overcome the PET/CT false negative rate in para-aortic lymph nodes. The latter option could result in overtreatment and unnecessary toxicity in approximately 75% of patients with positive pelvic lymph nodes and negative para-aortic lymph nodes on pre-treatment PET/CT.

      Rationale

      The survival benefit of surgical staging has been assessed in several retrospective and prospective studies with controversial results.15 Some studies suggest that survival benefit of surgical staging is associated with removal of small volume disease. Several studies report similar survival data between patients with negative para-aortic lymph nodes and metastatic para-aortic lymph nodes <5 mm in diameter after surgical staging and tailored extended-field chemoradiation.16 21 Gold et al performed a post-hoc analysis of three randomized trials from the Gynecologic Oncology Group (GOG) evaluating different chemoradiation strategies.22 Even if patients in the radiological staging group had less advanced disease, smaller tumor size, and better performance status, disease-free and overall survival were significantly improved in the surgical staging group in multivariate analysis. There were also more para-aortic and extra-pelvic recurrences in the radiologically staged group. Methodology of this study was limited by a possible selection bias due to a combination of randomized arms from three different trials. There are two available randomized phase III trials comparing radiologic to surgical staging in locally advanced disease cervical cancer. The study performed by Lai et al was the first to address this question 20 years ago.23 A total of 61 patients were randomized to surgical or clinical staging using CT imaging. This study was closed prematurely due to survival differences favoring the clinical staging arm. This study has been largely criticized because of an imbalance between both study arms: patients in the surgical arm had more advanced disease with more stage III-IV and more >6 cm tumors, more unfavorable histology, and less frequent CRT. Finally, two patients with para-aortic lymph node involvement did not receive extended field radiotherapy, and the eight deaths in the surgical group were not related to disease progression but to treatment related complications. High grade toxicity was also reported in >40% of patients. The second randomized phase III study is the recent UTERUS 11 trial performed by the AGO group.3 This study included 240 patients with stage IIB-IVA locally advanced disease cervical cancer and negative para-aortic nodes on pre-treatment CT imaging. Authors found a non-significant 10% increase in disease-free survival, the primary endpoint, in favor of surgical staging. In an ad-hoc analysis, authors reported that surgical staging led to a significant increase in cancer-specific survival, and a significant disease-free survival benefit in patients with stage IIB. Importantly, surgical staging was not associated with a significant increase in delay to chemo-radiation and peri-operative complications were only reported in 7.3% of patients. This trial has been criticized by its methodology, mainly by the sample size population calculation, which can explain the uncertain conclusions.24

      The rationale of surgical staging is based on treatment modification of patients with positive pelvic nodes and occult para-aortic lymph node metastasis on pre-treatment PET/CT imaging to improve para-aortic and distant control.

      Hypothesis

      Current diagnostic tools underestimate a wide range of patients with microscopic and macroscopic para-aortic lymph node involvement.25 We hypothesize that surgical staging followed by tailored chemoradiation will improve disease-free survival while avoiding unnecessary prophylactic extended-field chemoradiation in patients with stage IIIC1 cervical cancer.

      Methods

      Trial Design

      This is an international multicenter, randomized, phase III study which aims to demonstrate that tailored CRT based on surgical staging and pathologic examination of the para-aortic lymph nodes is associated with increased disease-free survival compared with patients staged with PET/CT only without surgical staging. Secondary objectives include overall survival, metastasis and para-aortic free survival, quality of life, morbidity, evaluation of infra-mesenteric and infrarenal lymph node metastasis rate, survival in patients with small volume para-aortic lymph node disease, and cost-utility analysis. Ancillary studies will include radiomics, biologic, and the SENTI-PAROLA ancillary study, to evaluate the feasibility and accuracy of the para-aortic sentinel lymph node approach.

      All eligible patients will be equally randomized between the two following treatment groups.

      Control Arm

      Standard chemo-radiotherapy and brachytherapy will be conducted according to EMBRACE II and the European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology (ESGO/ESTRO) guidelines. Patients with ≥3 positive pelvic lymph nodes will have prophylactic para-aortic chemoradiation.

      Experimental Arm

      Pre-therapeutic para-aortic lymphadenectomy followed by tailored chemo-radiotherapy and brachytherapy will be undertaken according to EMBRACE II and ESGO/ESTRO guidelines. Pre-therapeutic lymphadenectomy will be performed no later than 3 weeks after PET/CT via the laparoscopic extraperitoneal or transperitoneal approach using either traditional laparoscopy or robotically-assisted laparoscopy. Lymph node dissection will be performed from the common iliac bifurcation to at least the inferior mesenteric artery, according to international recommendations. Lympho-fatty tissue from and including the common iliac vessels, the aorta, aorto-caval space, and the vena cava will be completely removed to at least the level of the inferior mesenteric artery. Chemo-radiation will start 7 to 10 days after surgery and a maximum 3 weeks after surgical staging.

      Exploratory Cohort for Equivocal Lymph Nodes

      Patients with equivocal common iliac or para-aortic lymph nodes will be included in an exploratory cohort and treated with surgical staging followed by tailored chemo-radiation.

      The PAROLA (PARa-aOrtic LymphAdenectomy in locally advanced cervical cancer) trial has been funded by the French National Cancer Institute, Program Hospitalier de Recherche Clinique Cancer (PHRC-K PHRC-22–161). The trial is also supported by ARCAGY-GINECO, Swiss GO, BGOG (Belgium and Luxembourg Gynaecological Oncology Group), ENGOT (European Network of Gynaecological Oncological Trial groups), GCIG (Gynecological Cancer InterGroup), MITO (Multicenter Italian Trials in Ovarian Cancer and gynecological malignancies) and GEICO (Grupo Español de Investigacion en Cancer de Ovario) cooperative groups.

      Participants

      Main inclusion criteria are histologically proven PET/CT FIGO stage IIIC1 cervical cancer. Main exclusion criteria include unequivocal positive common iliac or para-aortic lymph node at pretherapeutic imaging PET/CT. Detailed inclusion and exclusion criteria are summarized in Table 1.

      View this table:
      Table 1

      Inclusion and exclusion criteria

      Outcomes

      The primary endpoint is disease-free survival, defined as the time from randomization until first relapse (local, regional, or distant) or death from any cause. Patients still alive at the time of analysis without documented event (including lost to follow-up) will be censored at the last valid disease assessment. Secondary endpoints include overall survival, cancer specific-survival, metastasis-free survival, surgical and radiation morbidities, quality of life, and cost analyses.

      Sample Size

      PAROLA is a superiority trial powered to detect an improvement in 3-year disease-free survival from 60% to 70%. This study hypothesis corresponds to detect a hazard ratio of 0.70. A total of 257 events is necessary for 80% power to detect this difference if it is true, using a one-sided log rank test at the 2.5% significance level and a 1:1 randomization. Based on an estimated accrual rate of approximately 10 patients per month for the randomization of 510 patients and a fixed follow-up of 5 years by patient, we can expect to see this number of events 100 months after the start of the study.

      Interim Analyses and Stopping Guidelines

      An interim analysis for both futility (O’Brien-Fleming boundary) and efficacy (O’Brien-Fleming boundary) will be performed after observation of 129 events. An independent data monitoring committee will review the pre-planned interim analyses (futility and efficacy).

      Randomization and Blinding

      After verification of eligibility criteria, patients will be randomized by surgical or clinical staging in a 1:1 ratio (Figure 1). Randomization will be centrally processed by the IUCT-Oncopole cinical trials office using the TENALEA Clinical Trial Data Management System (online secure internet). Randomization will be stratified by tumor stage according to TNM classification (T1/2 vs T3), center, and adjuvant treatment (yes/no). Treatment allocation will be performed using the minimization method.

      Figure 1
      Figure 1

      Trial design and randomization scheme. ESGO, European Society of Gynaecologic Oncology; ESTRO, European Society for Radiotherapy and Oncology; FDG, fluorodeoxyglucose; FU, follow-up; PALN, para-aortic lymph node; PET/CT, positron emission tomography/computed tomography.

      Statistical Methods

      The primary endpoint will be analyzed on the intention-to-treat population when the required number of events has been reached. For each arm, disease-free survival rates will be estimated using the Kaplan-Meier method. The primary endpoint analysis will be a Cox regression analysis adjusted on stratification factors with 97.5% confidence intervals (one-sided). Planned subgroup analysis will be performed according to surgical extension (infra-mesenteric or infra-renal), T stage, number of pelvic lymph nodes, size of para-aortic lymph node metastasis, and specific populations (elderly, obese).

      Discussion

      The role of para-aortic lymph node surgical staging in locally advanced disease cervical cancer remains debatable. Several retrospective, prospective, and two phase III trials show conflicting results. However, the two phase III trials have several methodological flaws which limit their conclusions. The UTERUS-11 study showed a non-significant 10% increase in disease-free survival in patients with surgical staging; the main limitation of that study was the sample size calculation. The authors estimated a 5-year disease-free survival of 36.5% in the control arm which is lower than that reported on recent studies of chemo-radiation. Five-year disease-free survival is probably around 55–60%, as it finally resulted in this study and in other recent randomized phase III trials.3 26 27 The authors also estimated that surgical staging would improve 5-year disease-free survival from 36.5% to 55%, which is excessive, when considering the survival increase of adding chemotherapy to radiotherapy.26 Finally, the UTERUS-11 study was underpowered. UTERUS-11 included patients with both positive and negative pelvic lymph nodes. Pelvic extension is the main factor correlated with para-aortic extension. In the PAROLA trial only patients with FIGO stage IIIC1, at high risk of para-aortic lymph node disease, will be included. UTERUS-11 also performed clinical staging with CT, which is less accurate than PET/CT.28

      The key question remains as to whether surgical staging followed by tailored CRT can improve survival in patients with a high risk of para-aortic lymph node extension. We therefore propose a clinical trial with an adequate sample size and realistic hypotheses that will be performed thanks to a large national and international collaborative effort. Our proposal addresses patients with a high risk of para-aortic lymph node spread—patients with stage IIIC1 on pre-treatment PET/CT. The control arm will be treated following EMBRACE II and ESGO/ESTRO recommendations.29 This study aims to answer definitively the controversy between proponents and opponents of surgical staging.

      Data availability statement

      No data are available.

      Ethics statements

      Patient consent for publication

      Ethics approval

      Not applicable.

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      Footnotes

      • Twitter @Alejandra, @annafagottimd, @frafanfani, @Bertadiazfeijoo#, @AngelesFite, @ZMuallem, @pedroramirezMD, @frumovitz

      • Collaborators PAROLA Study Group: Stéphanie Motton, Elodie Chantalat, Yann Tanguy le Gac, Enora Laas, Fabrice Narducci, Eric Lambaudie, Sebastien Gouy, Charles André Philip, Catherine Uzan, Cyril Touboul, Cyrille Huchon, C Durdux, Frédéric Guyon, Agathe Crouzet, Hélène Costaz, Bruno Borghese, Pierre-Emmanuel Colombo, Nicolas Chopin, Cherif Akladios, Marcos Ballester, Catherine Ferrer.

      • Contributors All authors made the appropriate contributions, carefully compiling and analyzing data, reading the manuscript and giving their full approval. AM accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.

      • Funding This study was funded by French National Cancer Institute (Grant number: PHRC-22-161).

      • Competing interests None declared.

      • Provenance and peer review Not commissioned; internally peer reviewed.