Robot-assisted approach to cervical cancer (RACC) : An international multi-center, open-label randomized controlled trial

1 Robot-assisted Approach to Cervical Cancer (RACC) – an international multicenter, open-label randomized controlled trial Henrik Falconer1, Kolbrún Palsdóttir1, Karin Stålberg2, Pernilla Dahm-Kähler3, Ulrika Ottander4, Evelyn Lundin5, Lena Wijk6, Rainer Kimmig7, Pernille Tine Jensen8, Ane Gerda Zahl Eriksson9, Johanna Mäenpää10, Jan Persson11, Sahar Salehi1 1Theme Cancer, Karolinska University Hospital and Department of Women’s and Children’s Health, Division of Obstetrics and Gynecology, Karolinska Institutet, Stockholm, Sweden. 2Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden. 3Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden 4Department of Clinical Sciences/Obstetrics and Gynaecology, Umeå University, Umeå, Sweden 5Children and Women's Health, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden 6Department of Obstetrics and Gynaecology, Örebro University Hospital, Sweden; School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Sweden. 7Department of Gynecology and Obstetrics, University Hospital of Essen, Germany 8Department of Gynecology and Obstetrics, Aarhus University Hospital and Faculty of Health Science, Aarhus University, Denmark This is the accepted manuscript of the article, which has been published in International Journal of Gynecological Cancer. 2019, 29(6), 1072-1076. http://dx.doi.org/10.1136/ijgc-2019-000558 2 9Department of Gynecologic Oncology, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway 10Department of Gynaecology and Obstetrics, Tampere University Hospital and Faculty of Medicine and Medical Technology, Tampere University, Tampere, Finland. 11Department of Obstetrics and Gynecology, Skane University Hospital and Lund University, Lund, Sweden Word count abstract: 323 Word count manuscript: 2957 Key words: cervical cancer, radical hysterectomy, survival, minimally invasive surgery Trial registration: Registered at ClinicalTrials.gov (identifier NCT03719547) Corresponding author: Henrik Falconer, MD., Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden. E-mail: [email protected]. Telephone: +46851776303 3 ABSTRACT Background: Radical hysterectomy with pelvic lymphadenectomy represents the standard treatment for early stage cervical cancer. Results from a recent randomized controlled trial demonstrate that minimally invasive surgery is inferior to laparotomy with regards to disease-free and overall survival. Primary objective: To investigate the oncologic safety of robot-assisted surgery for early stage cervical cancer as compared to standard laparotomy. Study hypothesis: Robot-assisted laparoscopic radical hysterectomy is non-inferior to laparotomy in regards to recurrence free survival with the advantage of less postoperative complications and superior patient reported outcomes. Trial design: Prospective, multi-institutional, international, open-label randomized clinical trial. Consecutive women with early stage cervical cancer will be assessed for eligibility and subsequently randomized 1:1 to either robot-assisted laparoscopic surgery or laparotomy. Institutional Review 4 Board approval will be required from all participating institutions. The trial is coordinated from Karolinska University Hospital, Sweden. Major inclusion/exclusion criteria: Women over 18 with cervical cancer FIGO (2018) stages IB1, IB2 and IIA1 squamous, adenocarcinoma, or adenosquamous will be included. Women are not eligible if they have evidence of metastatic disease, serious comorbidity or a secondary invasive neoplasm in the past five years. Primary endpoint: Recurrence-free survival at 5 years between women who underwent robot-assisted laparoscopic surgery versus laparotomy for early stage cervical cancer. Sample Size: The clinical non-inferiority margin is in this study defined as a 5-year recurrence-free survival not worsened by more than 7.5%. With an expected recurrence-free survival of 85%, the study needs to observe 127 events with a one-sided level of significance (α) of 5% and a power (1-β) of 80%. With 5 years of recruitment and 3 years of follow-up, the necessary number of events will be reached if the study can recruit a total of 768 patients. Estimated Dates for Completing Accrual and Presenting Results: Trial launch is estimated to May 2019 and is estimated to finally close in May 2027 with presentation of data short thereafter. 5 Trial registration: The trial is registered at ClinicalTrials.gov (NCT03719547) INTRODUCTION Cervical cancer has become a rare disease in the industrialized world but remains one of the most common cancers in developing countries.1 Radical hysterectomy with pelvic lymphadenectomy represents the standard of care for patients with early stage disease. The procedure can be performed either by laparotomy or minimally invasive techniques. Laparoscopic radical hysterectomy was first described in 1992 and is widely recognized as one of the most challenging surgical procedures in gynecologic oncology.2 In 2005, robot-assisted laparoscopic surgery was approved by the Food and Drug Agency for gynecological indications and the technique gained rapid popularity and has replaced conventional laparoscopy in many institutions. In the Nordic countries, laparoscopic radical hysterectomy never gained acceptance and in 2018, more than 80 % of radical hysterectomies were performed with robot-assisted laparoscopic surgery in Sweden. Several studies suggest that the learning curve is significantly shorter for robot-assisted laparoscopic surgery compared to conventional laparoscopy, which may be related to improved instrumentation in the robotic platform.3 In addition, retrospective analyses including two meta-analyses suggest that the oncologic safety is comparable between open surgery and robot-assisted laparoscopic surgery.4,5 However, results from a recent randomized trial have questioned the safety of minimally invasive surgery for cervical cancer. In the international LACC-trial, the final study population comprised 631 women with early stage cervical cancer, randomized to either open radical hysterectomy or minimally invasive surgery.6 In the minimally invasive surgery group, the majority of women were operated by conventional laparoscopy (84 %) whereas only 16% of the women underwent robot-assisted laparoscopic 6 surgery. After a median follow-up of 30 months, minimally invasive surgery was inferior to laparotomy with a hazard ratio of 3.7 (95% CI 1.63-8.58) for recurrence and 6.0 (95% CI 1.7720.3) for overall survival. The authors speculate that the use of intrauterine manipulators, the CO2 gas or intra-corporeal colpotomy may account for the surprising outcomes. The results from the LACC-trial were in part supported by population-based data from the United States, demonstrating that minimally invasive surgery was associated with significantly worse survival outcomes than women treated by open access.7 In contrast to the LACC-trial, a majority of women in the minimally invasive group were operated with robot-assisted laparoscopic surgery. In Sweden, treatment of cervical cancer is centralized to seven university hospitals and data from all radical hysterectomies are entered into a national quality registry since 2011 (Swedish Quality Register for Gynecologic Cancer, SQRGC). Based on 822 cases of radical hysterectomies 20112017, no difference in either disease-free survival or overall survival could be observed in the Swedish cohort (submitted for publication). Similar results have been obtained from the Danish quality register (personal communication). In summary, the LACC trial does not reflect current practice in many countries including the Nordic countries. The health care systems have gradually adopted robot-assisted laparoscopic surgery and the perceived safety is supported by data from Nordic population-based quality assurance databases. However, the LACC trial is currently the only randomized controlled trial exploring the oncologic safety of minimally invasive surgery and to establish the safety of current practice, a new randomized controlled trial is needed. Given the excellent outcomes in the open arm in the LACC trial, it is unlikely that robot-assisted laparoscopic surgery can generate superior outcomes. In the RACC-trial, we hypothesize that robot-assisted laparoscopic surgery is non-inferior to laparotomy but associated with less morbidity, shorter hospitalization 7 and superior patient reported quality of life. In addition, we will investigate if sentinel lymph node biopsy using indocyanine green as tracer, has sufficient diagnostic accuracy to replace conventional lymphadenectomy in women with early stage cervical cancer. METHODS Trial Design The RACC-trial is a prospective, international, multi-institutional, open-label randomized controlled trial. Figure 1 gives the study schema of the RACC-trial (Fig 1). Women with early stage cervical cancer will be assessed for eligibility and subsequently randomized 1:1 to either robot-assisted laparoscopic surgery or laparotomy. Informed consent is required from all participating women. The surgical procedure comprises total radical hysterectomy according to the Querleu-Morrow classification (type B or C) and pelvic lymphadenectomy.8 The use of intrauterine manipulators is not allowed, closure of the vagina prior to colpotomy is recommended but not mandatory. In addition, the sensitivity and negative predictive value of pelvic sentinel lymph node biopsy will be investigated using cervical injection of indocyanine green. To avoid any imbalance in the detection of low-volume disease based on ultrastaging between the arms, sampling (with subsequent ultrastaging) will be performed in non-mapped hemi-pelvises according to the most frequent sites of nodal metastases.9 Intraoperative complications will be classified according to Kaafarani et al and the CLASSIC classification.10,11 Postoperative complications are classified according to the Clavien-Dindo nomenclature.12 Patient Reported Outcomes will be assessed at baseline (prior to randomization), 1 month postop, 6 months postop, 1 year postop, 2 years postop and 5 years postop using four different instruments: the EORTC QLQ-C30, QLQ-CX24, EQ5D and LYMQOL. Objective assessment of lymphedema 8 will be performed using CTCAE 3.0. Finally, health care costs will be assessed for both modalities. To date, 16 sites from across Scandinavia and Germany are expected to participate in the RACCtrial with the potential to add additional sites as needed. The trial is funded by Stockholm County Council (Sweden). Participants Inclusion Criteria: Histologically confirmed primary adenocarcinoma, squamous cell carcinoma or adeno-squamous carcinoma of the uterine cervix Women with histologically confirmed FIGO stage IB (IB3 excluded) and IIA1 (with minimally tumor growth in the upper vagina) Women undergoing either a Type B or C radical hysterectomy according to Querleu Morrow classification ECOG Performance Status of ≤2 Age > 18 years Exclusion Criteria: Any histology other than adenocarcinoma, squamous cell carcinoma or adeno-squamous carcinoma of the uterine cervix Tumor size greater than 4 cm, estimated by either magnetic resonance imaging or clinical examination FIGO stage II-IV (except IIA1) 9 Women with a history of pelvic or abdominal radiotherapy Women who are pregnant Women with evidence of metastatic disease by conventional imaging studies, enlarged pelvic or aortic lymph nodes > 2cm; or histologically positive lymph nodes Serious concomitant systemic disorders incompatible with surgery (at the discretion of the investigator) Women unable to withstand prolonged lithotomy and steep Trendelenburg position Women with secondary invasive neoplasm in the past five years (except non-melanoma skin cancer, breast cancer T1 N0 M0 grade 1 or 2 without any signs of recurrence or activity) Women with iodine allergy cannot be part of the sentinel node part of the trial but are allowed randomization as to the primary outcome Primary endpoint Primary objective: This trial aims to compare the oncologic safety of robot-assisted laparoscopic surgery to standard laparotomy. Primary outcome measure: 5-year recurrence-free survival. Secondary Objectives: To evaluate overall survival, intraand postoperative outcomes 30 days after surgery, health care costs, quality of life and lymphoedema and the diagnostic accuracy of pelvic sentinel lymph node biopsy in women with early stage cervical cancer. In addition, a translational part exploring biomarkers for disease recurrence is planned. 16 robot-assisted laparoscopic surgery (or never implemented at all). Most surgeons would most likely agree that robot-assisted laparoscopic surgery provides substantial benefits compared to conventional laparoscopy, including the ability to better use wrist movements by the improved dexterity in the robotic platform. This notion is supported by several studies demonstrating shorter learning-curve for robot-assisted laparoscopic surgery compared to conventional laparoscopy.3,19,20 Today, the majority of minimally invasive surgery radical hysterectomies are performed by robot-assisted laparoscopic surgery in Nordic countries. Following the alarming results from the LACC-trial, data from the Swedish Quality Register for Gynecologic Cancer has been extracted. Entering data in the Swedish Quality Register for Gynecologic Cancer is mandatory in Sweden and the nation-wide coverage exceeds 99% of all procedures. Based on 852 women treated 2011-2017, no difference was observed for disease-free survival between minimally invasive surgery (n=628) and laparotomy (n=263). It should be noted that all women in the former group were treated with robot-assisted laparoscopic surgery since laparoscopic radical hysterectomy has never gained acceptance in Sweden. Similar data have been obtained from the Danish Gynecological Cancer Database. Although non-randomized, the population-based data derived from these quality registers are in contrast with the results from the LACC-trial. To establish the safety of robot-assisted laparoscopic surgery, a new randomized controlled trial is needed. In summary, the international RACC-trial will evaluate whether robot-assisted laparoscopic surgery is a safe alternative to laparotomy for the treatment of early stage cervical cancer. In addition, the RACC-trial will assess whether conventional lymphadenectomy can be replaced by a sentinel-node biopsy concept using indocyanine green as the tracer. The trial is anticipated to start accrual in May 2019. 17 AUTHOR CONTRIBUTION HF, KP, SS and JP are members of the RACC steering committee and designed the trial. AGZE, PTJ and JM are national coordinators and contributed to the final design of the trial. PDK, UO, LW, KS, EL, RK are local principal investigators. 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