Evaluation of robotic versus open partial pancreatoduodenectomy—study protocol for a randomised controlled pilot trial (EUROPA, DRKS00020407)

This exploratory trial aims to compare the two different operative approaches, OPD and RPD, with regard to postoperative morbidity within 90 postoperative days (POD), measured using the Comprehensive Complication Index (CCI).

EUROPA is an investigator-initiated, exploratory, open-label RCT with two parallel study groups.

The trial protocol was approved by the ethics committee of the University of Heidelberg (Ethikkommission Medizinische Fakultät Heidelberg; S-025/2020, 3 February 2020), and the trial was registered with the German Clinical Trial Register (DRKS), an approved primary registry in the WHO network (DRKS00020407, 9 March 2020; UTN U1111-1245-8931, 30 December 2019) before inclusion of the first patient. The trial will be conducted at the Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Germany, in accordance with the Good Clinical Practice (GCP) guidelines and the Declaration of Helsinki. More than 250 PDs are performed each year at the Department of General, Visceral and Transplantation Surgery, and it is certified as a centre of excellence for minimally invasive surgery by the German Society for General and Visceral Surgery (Deutsche Gesellschaft für Allgemein- und Viszeralchirurgie). Conservatively, five patients per month can be included in the trial. Thus, given the need to recruit 80 patients (see the “Sample size calculation” section), completion of recruitment is feasible within 18 months. The independent statistical analysis will be performed at the Institute of Medical Biometry and Informatics (IMBI) of the University of Heidelberg. All patient-related information is subject to medical confidentiality according to the European General Data Protection Regulation (Datenschutzgrundverordnung, DSGVO), the Federal Data Protection Act (Bundesdatenschutzgesetz) and the State Data Protection Act (Landesdatenschutzgesetz).

All patients scheduled for elective PD will be screened consecutively for eligibility and will be informed about the EUROPA trial during a pretreatment visit or on the day of hospitalisation. Eligible for participation are all adult patients planned for elective PD for any indication who are judged suitable for both RPD and OPD by the treating pancreatic surgeon. Patients must provide written informed consent to the responsible study physician and must be able to understand the individual consequences of the clinical trial. The following exclusion criteria have been defined: (1) borderline or unresectable carcinoma of the pancreatic head as defined in the National Comprehensive Cancer Network guidelines [19], (2) distant metastases, (3) American Society of Anesthesiologists (ASA) score > 3, (4) participation in another interventional trial interfering with the intervention and outcome of this trial and (5) anticipated language problems or lack of compliance.

Participants may withdraw from the trial at their own request at any time without giving reasons. If PD cannot be performed (e.g. because of technical irresectability or metastatic disease), the patient concerned will leave the trial early. The latter category will be included in the final report of the trial to ensure complete transparency.

In order to avoid the risk of learning-associated bias, only surgeons with sufficient proficiency will be allowed to perform the randomised interventions. Proficiency in the open group will be defined as having performed 40 or more OPDs, and in the robotic group, 40 or more RPDs. The requirement for a minimum of 40 RPDs is based on the results of research into learning curves for RPD [12, 20, 21].

In both groups, after exclusion of hepatic and peritoneal metastases, PD is performed by conventional resection and reconstruction with pancreato-jejunostomy, hepatico-jejunostomy and duodeno-jejunostomy/gastro-jejunostomy according to local standards [22].

Resection or preservation of the pylorus, the extent of lymphadenectomy, additional vascular resections, abdominal drain placement and abdominal wall closure at the end of the procedure are left to the surgeon’s discretion and will be documented in the electronic case report form (eCRF).

OPD, the current institutional standard procedure, will be performed as described before [22].

RPD was introduced at the Department of General, Visceral and Transplantation Surgery in November 2016, accompanied by a tutoring and proctoring programme. The procedure has been standardised and is performed as described in the Intuitive® surgical procedure guide, written by the members of our department [23]. Key components of the RPD procedure are defined and will be adhered to in this trial in order to provide consistent, reproducible results. The surgeon can decide to convert from RPD to OPD due to intraoperative circumstances or technical problems, and the reasons for conversion will be documented.

The same perioperative and postoperative standard operating procedures are in place for both interventions, and patients in both groups will be accommodated on the same wards to ensure standardised postoperative care.

All consecutive patients will be screened, and reasons for non-inclusion must be documented in a screening list. In order to achieve comparable intervention groups for known and unknown risk factors, patients will be randomised before surgery using a centralised web-based tool (randomizer.at) provided by the Institute of Medical Informatics, Statistics and Documentation of the Medical University of Graz. Therefore, selection bias (biassed allocation to interventions) is minimised by sequence generation and allocation concealment. Randomisation will be conducted only by authorised trial personnel.

The primary endpoint of the EUROPA trial is cumulative morbidity within 90 days after PD, assessed by means of the CCI. The CCI is based on the established Clavien–Dindo classification of postoperative complications, which has gained widespread acceptance [24]. The Clavien–Dindo classification grades postoperative complications according to their sequelae, ranging from grade I (any deviation from the normal postoperative course without the need for pharmacological treatment) to grade V (death). The CCI score ranges from 0 (no complication of any kind during the postoperative course) to 100 (death of patient). The CCI permits objective assessment of cumulative postoperative morbidity even in an unblinded study setting. The CCI was developed jointly by surgeons and patients and considers the patient’s perspective as well as objective parameters of surgical effectiveness [25]. It is validated for the pancreatic surgical population and a difference of 10 is regarded as clinically relevant [26].

The secondary endpoints cover important oncological, clinical, economic and patient-relevant outcomes (Table 1).

Prespecified study visits are carried out by clinical investigators and study nurses from the clinical study centre to collect information on the primary and secondary outcome parameters and to identify any postoperative complications.

Blinding of participants, research assistants, operating surgeons, data collectors and outcome assessors to the treatment allocation is not feasible. Postoperative blinding of patients, e.g. by the use of large dressings, is barely possible, since unblinding would occur when wound dressings were changed prior to the assessment of the primary endpoint. Furthermore, given the objective nature of the primary endpoint (morbidity according to the Clavien–Dindo classification), complex blinding interventions are not justified. In addition, numerous endpoints (economic parameters, safety endpoints, etc.) are independent of blinding. However, some secondary endpoints may be affected by the lack of blinding, e.g. pain or patient-reported outcomes such as quality of life or quality of recovery. Outcome assessments will be conducted by trained study personnel who are not part of the surgical or ward team, to guarantee objectivity. Data analysts will be blinded to the intervention.

During the screening visit (1–14 days before surgery), inclusion and exclusion criteria are assessed (Table 2). After the patient has given informed consent, the demographic and baseline data, the ASA score, the updated Charlson Comorbidity Index [37], the health-related quality of life as measured by SF-36 [36], the quality of recovery as established using questionnaire QoR-15 [28] and the pancreas-specific medical history (indication for surgery, pre-existing diabetes mellitus, pre-existing exocrine insufficiency, neoadjuvant treatment, preoperative cholestasis, preoperative biliary drainage) are assessed and documented. Visit 2, including assessment of intraoperative and perioperative parameters as well as serious intraoperative complications, takes place on the day of surgery. Also documented during visit 2 are the type of pancreatic resection, extent of lymphadenectomy, additional organ resections, texture of the pancreas, size of the pancreatic duct at the transection site and drain insertion. Four inpatient follow-up visits on postoperative days (POD) 4, 8 and 12 and the day of discharge will be performed in person, and two telephone follow-up visits 30 and 90 days after surgery will be conducted to evaluate the primary and secondary outcome parameters (see Table 1). If a patient is discharged before POD 12, visit 5 can be omitted.

Recruitment of the EUROPA trial started in June 2020. Recruitment is expected to be complete in 2022. The current version of the protocol is version 1.1, finalised on 2 February 2020.