Comparative Trial Between Open and Single-port Robotic-assisted Groin Lymphadenectomy in Vulvar Cancer

Background and rationale Vulvar cancer accounts for less than 1% of cancers in women and approximately 5% of cancers of the female genital tract. About 90% of vulvar cancers are squamous cell carcinomas. Inguinofemoral lymph-node status is a major prognostic factor, and surgical assessment or treatment of the groins is an important component of care. Sentinel lymph-node biopsy has reduced treatment-related morbidity for eligible patients, but inguinofemoral lymphadenectomy remains indicated for patients with multifocal invasive disease, tumors measuring at least 4 cm, or suspected or confirmed inguinal lymph-node metastases.

The standard open approach to inguinofemoral lymphadenectomy is associated with substantial postoperative morbidity. Reported complications include wound infection, wound dehiscence, lymphocele or seroma, prolonged drainage, cellulitis, readmission, and lower-limb lymphedema. Video-endoscopic approaches have shown lower complication rates in small studies, but evidence on oncologic safety remains limited. A single-port robotic platform may facilitate minimally invasive dissection in the confined anatomical space of the groin. SP-RAIL is designed to assess whether single-port robot-assisted inguinofemoral lymphadenectomy is feasible and reduces early postoperative morbidity without compromising the adequacy of lymph-node retrieval or regional oncologic safety.

Study design SP-RAIL is an international, multicenter, randomized, controlled phase 2 treatment trial. The planned sample size is 64 participants, allowing for up to 10% non-evaluable participants and providing 58 evaluable participants. Recruitment is planned over four years. The study will initially be conducted at Karolinska University Hospital in Stockholm, Sahlgrenska University Hospital in Gothenburg, Copenhagen University Hospital, and Aarhus University Hospital. Additional centers with access to single-port robot-assisted surgery may be added if they meet the trial's eligibility and quality requirements.

Eligible participants will be randomized in a 1:1 ratio to single-port robot-assisted inguinofemoral lymphadenectomy or traditional open inguinofemoral lymphadenectomy. Randomization will be centralized through the Clinical Trials Unit at Karolinska University Hospital, use permuted blocks, and be stratified by participating center. Randomization will occur after eligibility has been verified, written informed consent has been obtained, and baseline health-related quality-of-life questionnaires have been completed.

Study population Participants must be at least 18 years old, have a primary diagnosis of histologically confirmed vulvar squamous cell carcinoma, and have an indication for inguinofemoral lymphadenectomy because of multifocal invasive disease, a tumor measuring at least 4 cm, or suspected or confirmed inguinal lymph-node metastases. Participants must have an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 and provide written informed consent.

Key exclusion criteria are histology other than squamous cell carcinoma, recurrent disease, a contraindication to surgery, previous pelvic or inguinal irradiation, and previous inguinofemoral lymphadenectomy. Preoperative imaging will be performed according to local practice.

Interventions In both treatment groups, inguinofemoral lymphadenectomy comprises superficial and deep removal of fatty and lymphatic tissue around the femoral and saphenous vessels within the anatomical boundaries of Scarpa's triangle. The inguinal ligament defines the cranial boundary, the sartorius muscle the lateral boundary, the adductor longus muscle the medial boundary, and approximately 1 to 4 cm along the great saphenous vein the caudal boundary. Superficial dissection includes lymphatic tissue above the cribriform fascia and around the saphenous vein. Deep dissection includes lymphatic tissue medial to the femoral vein. Preservation of the saphenous vein is preferred but is not mandatory and will be recorded. Placement of a drain is recommended in both groups, while drain management follows each center's local protocol.

In the experimental group, participants will undergo single-port robot-assisted inguinofemoral lymphadenectomy with sentinel lymph-node mapping using indocyanine green. Following injection around the vulvar tumor, the groin space is accessed through an incision at the edge of the triangle formed by the sartorius and adductor longus muscles. A da Vinci single-port access system is placed, carbon dioxide insufflation is established at 10 mmHg, and the femoral artery, femoral vein, saphenous vein, and inguinal ligament are identified. Lymphatic tissue is removed according to the protocol-defined boundaries. The sentinel lymph node is identified during dissection and submitted separately for pathological ultrastaging.

In the control group, participants will undergo traditional open inguinofemoral lymphadenectomy. The skin incision is made parallel and superior to the inguinal ligament, and lymphatic tissue is removed using the same anatomical boundaries. Sentinel lymph-node dissection is recommended but is left to the surgeon's discretion. The tracer, if used, may be indocyanine green, technetium, or blue dye.

Histopathological assessment of retrieved lymph nodes and ultrastaging of sentinel lymph nodes will follow international recommendations and each center's protocol. If lymph-node metastases are identified, adjuvant radiotherapy or radiochemotherapy will be delivered according to national guidelines.

Objectives and outcome assessments The primary objective is to determine whether single-port robot-assisted inguinofemoral lymphadenectomy is associated with fewer early postoperative complications than open inguinofemoral lymphadenectomy. The primary outcome is the proportion of participants with a Clavien-Dindo grade 2 to 5 complication within 30 days after surgery. Reoperations for vulvar wound dehiscence will not be counted as postoperative complications attributable to inguinofemoral lymphadenectomy.

Perioperative assessments include operative time in minutes, blood loss in milliliters, intraoperative complications classified using the CLASSIC system, conversion to another surgical approach, length of hospital stay in days, duration of drainage in days, and the number of lymph nodes removed per groin.

Oncologic assessments include inguinal recurrence within 24 months, recurrence-free survival at 24 months, and overall survival at 24 and 60 months. Recurrence-free survival is measured from randomization to recurrence or death; participants who are alive without recurrence are censored at the last clinical visit. Overall survival is measured from randomization to death from any cause; participants who are alive are censored at the last clinical follow-up or contact.

Long-term morbidity includes treatment-related morbidity assessed with the Common Terminology Criteria for Adverse Events and symptoms of leg and groin lymphedema assessed with the LYMQOL questionnaire. Health-related quality of life is assessed with the EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-VU34 questionnaires. The questionnaires are completed at baseline and at 1, 2, 6, 14, and 22 months after treatment, according to the trial schedule.

Health economic analyses will compare direct health-care costs and indirect productivity costs between treatment groups. Quality-adjusted life years will be derived from EQ-5D data, and cost utility may be expressed as an incremental cost-effectiveness ratio. Long-term cost effectiveness may be evaluated with decision-analytic models. The primary health economic analysis will reflect Swedish conditions; an international analysis may be performed if sufficiently comparable data are available.

Follow-up Participants will attend a study visit 30 days after surgery and visits four months after completion of treatment and every four months thereafter through 24 months. Visits include clinical examination of the vulva, vagina, anal region, and groins; inguinal ultrasound is optional. Postoperative complications are recorded and graded at the 30-day visit. Later treatment-related morbidity is classified using the Common Terminology Criteria for Adverse Events. A biopsy should be performed when recurrence is suspected, if possible. Confirmed inguinal recurrences must be reported to the coordinating center within seven days. The study ends when all participants have completed 60 months of follow-up, died, withdrawn, or been lost to follow-up.

Statistical considerations The sample-size calculation assumes a 54% postoperative complication rate with open inguinofemoral lymphadenectomy and targets an absolute reduction of 27 percentage points with the single-port robotic approach. With a one-sided alpha of 0.10 and 80% power, 58 evaluable participants are required; 64 participants will be enrolled to allow for up to 10% non-evaluable cases.

The primary outcome will be summarized by treatment group as counts and percentages and compared using Fisher's exact test. The protocol specifies a one-sided alpha of 0.10 and presentation of confidence intervals for observed complication rates and between-group differences. Continuous perioperative variables will be compared using t tests or Mann-Whitney U tests, as appropriate. Categorical outcomes will be analyzed using Fisher's exact test. Repeated assessments of lymphedema and other long-term morbidity will be analyzed using regression methods for dependent data, such as mixed-effects models. Recurrence-free survival and overall survival will be summarized using Kaplan-Meier methods, with exploratory treatment-group comparisons using log-rank tests.

Safety monitoring and quality assurance An interim feasibility and safety analysis will be conducted after the first 10 participants have been enrolled in the experimental group. The trial will stop if the median number of harvested lymph nodes per groin in that group is fewer than six. The trial will also stop for inadequate recruitment if fewer than 32 participants are enrolled within two years. Inguinal recurrences will be monitored continuously, and the trial may be stopped early if an abnormal recurrence rate is observed. The Trial Steering Committee may suspend recruitment at a center with a higher-than-average rate of major postoperative complications or evidence of poor surgical quality.

All procedures must be performed or supervised by an approved gynecologic oncology surgeon. Surgeons performing open surgery must have completed at least 10 standard inguinofemoral lymphadenectomies. Surgeons performing the experimental procedure must have completed at least 10 single-port hysterectomies and five single-port robot-assisted inguinofemoral lymphadenectomies. The coordinating investigators may review surgeon experience, annual case volume, operative videos, and on-site audits.

Data management and ethics Study data will be recorded in REDCap. Participants will be identified in the study database by a study-specific code rather than a national identification number. Written informed consent is required before enrollment. Participants may withdraw at any time without affecting subsequent care. The study will begin only after approval by the relevant ethics committees and will be conducted in accordance with the Declaration of Helsinki, applicable national law, the General Data Protection Regulation, and Good Clinical Practice.