Frontiers of Minimally Invasive Surgery in Ovarian Cancer

(MIRRORS Study Concept)

Miss Radwa Hablase MBBch MRCOG PGCert

Senior Clinical Research Fellow in Gynaecological Oncology

The Royal Surrey NHS Foundation Trust

Guildford, UK

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Principal investigator of MIRRORS-FROZEN (Pilot) – RCT

The trial is funded by intuitive foundation

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Guildford experience:

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• The department has by far the greatest experience in

robotic Gynaecology surgery in the UK.

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• Guildford is the only robotic Gynaecology Epicentre for

training in the UK.

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• Over 2000 cases of Robotic Surgery

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• Published Exenterations , radical hysterectomy

Enhanced recovery .

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MIRRORS – Trial : Role of Robotic Surgery IN

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Chief Investigator : Mr : Simon Butler – Manuel

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IDS

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1. MIRRORS – MIRRORS study: a prospective cohort study assessing the

feasibility of robotic interval debulking surgery for advanced-stage ovarian cancer.

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2. MIRRORS RCT (randomised controlled trial (RCT) of robotic

interval cytoreductive surgery for advanced ovarian,

fallopian tube and peritoneal cancer (EOC) following MIRRORS-protocol vs

standard open interval cytoreductive surgery

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PI: Christina Uwins

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Complex Adnexal Lesions

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3. MIRRORS- FROZEN (Pilot )-RCT -A pilot randomised controlled trial (RCT) comparing open Vs robotic surgery in the management of women with complex pelvic adnexal masses ≤ 8cm.

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PI: Radwa Hablase

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• The incidence rate of ovary, fallopian tube and primary peritoneal carcinomas in England has remained stable since 2001 , with around 7,500 women diagnosed each year.

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https://digital.nhs.uk/ndrs/data/data-outputs/cancer-publications-and-tools/ovarian-cancer-audit-feasibility-pilot-ocafp---disease-profile-in-england/stage

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IDS

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• Mortality rates for ovarian cancer in the UK are highest in females aged 85 to 89 (2017-2019).

https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/ovarian-cancer#heading-One

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https://digital.nhs.uk/ndrs/data/data-outputs/cancer-publications-and-tools/ovarian-cancer-audit-feasibility-pilot---geographic-variation/treatment-variation-by-stage-age-tumour-morphology-and-charlson-comorbidity-score

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Our Data:

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• A retrospective audit study of patients aged 80-year-old and over, who underwent robotic assisted gynaecology surgery, over the period from October,2009 till March ,2021 – 113 patient .

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Our Data:

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Rationale :

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• There has been a move towards increasingly more radical procedures, in the treatment of ovarian cancer, to attain removal of all visible disease as this is associated with the best prognosis.

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• Ultra-radical surgery is associated with increased patient morbidity and reduced numbers of patients put forward for surgery and increased 30-day mortality (1).

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• Women not suitable for such procedures may benefit both symptomatically and from a prognostic point of view, from a reduction in their tumour burden. This group of women have the potential to gain the most from a robotic approach.

1. Falconer H, Joneborg U, Krawiec K, Palsdottir K, Bottai M, Salehi S. Ultra-radical upfront surgery does not improve survival in women with advanced epithelial ovarian cancer; a natural experiment in a complete population. Gynecol Oncol. 2020;159: 58-65.

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1. Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a metaanalysis. J Clin Oncol. 2002;20: 1248-59.
2. Hunter RW, Alexander NDE, Soutter WP: Meta-analysis of surgery in advanced ovarian carcinoma: Is maximum cytoreductive surgery an independent determinant of prognosis? Am J Obstet Gynecol 166:504-511, 1992

Hunter et al in 1992. This study, involving 6,962 patients with advanced ovarian carcinoma treated between 1967 and 1989, found that each 10% increase in maximal cytoreductive surgery was associated with a 4.1% increase in median survival time.

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The feasibility of Robotic Surgery in Interval debulking setting :

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. Retrospective studies have confirmed the feasibility of robotic interval debulking.

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Overall, 19 (66%) patients underwent an R0 cytoreduction, 8 (28%) an optimal (<1 cm) cytoreduction, and 2 (7%) a suboptimal cytoreduction. The median overall survival was 39.7 months and median progression-free survival was 21.2 months. Interval robotic cytoreduction following NAC is feasible and may be preferable to open interval cytoreductive surgery, in specific patients, to minimize morbidity and length of hospital stay.

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The feasibility of Robotic Surgery in Interval debulking setting :

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. Retrospective studies have confirmed the feasibility of robotic interval debulking.

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The findings of CILOVE support the feasibility of laparoscopic IDS with a conversion rate of 9.4%. Up to 10 ports were used to achieve a high rate of R=0 of 97%. No benefit in reducing LOS or time to chemotherapy was however demonstrated

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• All patients achieved R<1 (robotic R0=47.4%, open R0=0%).
• No patients had conversion to open.
• Median estimated blood loss was 50 mL for robotic (range 20–500 mL), 2026 mL for open (range 2000–2800 mL) (p=0.001).
• Median intensive care length of stay was 0 days for robotic (range 0–8) and 3 days (range 3–13) for MIRRORS Open (p=0.012).
• The median length of stay was 1.5 days for robotic (range 1–17), 6 days for open (range 5–41) (p=0.012).
• The time to chemotherapy was as follows 18.5 days for robotic (range 13–28), 25 days for open (range 22–28) (p=0.139).

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MIRRORS – FROZEN ( Pilot)

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A feasibility pilot randomised controlled trial (RCT) comparing open Vs robotic surgery in the management of women with complex pelvic adnexal masses ≤ 8cm.

Background & Rationale

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The research questions : In selected patients, minimally invasive robotic surgery is safe and acceptable approach in managing complex pelvic masses and is associated with similar or improved patient outcomes compared to the conventional open approach ?

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MIRRORS-FROZEN : To assess the feasibility of a large, adequately powered multicentre RCT by estimating patients’ recruitment pool, measuring recruitment rates and randomization acceptability.

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Background & Rationale

Complex adnexal lesions span a spectrum of pathologies from benign to cancer and multiple risk prediction models are used in clinical practice to triage patients as being low or high risk of cancer.

Risk of Malignancy 1 (RMI1) , Risk of Malignancy Algorithm (ROMA) , IOTA Assessment of Different Neoplasias in the Adnexa (ADNEX) ,IOTA Simple Rules (malignant vs benign, or inconclusive), and Ovarian Adnexal and Reporting Data System (ORADS).

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Background & Rationale

ORADS had a sensitivity of 76·4% (95% CI 70·1–82·0) and a specificity of 78·3% (75·3–81·0).

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Background & Rationale

CA-125 at threshold ≥ 35 IU/ml has sensitivity of 86·0% (80·6 to 90·3) 77·6% (74·6 to 80·3) ·

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HE 4 , Additional tumour markers (as in the ROMA test) have failed to improve significantly the discrimination between benign and malignant masses compared with CA 125 alone.

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Background & Rationale

Minimally invasive surgery (MIS) for staging complex ovarian masses has been demonstrated to be feasible in small retrospective and case-control studies. Survival data lack high-quality long-term follow-up data and the large variation in these studies design and patients' selection criteria.

Although ESGO and NCCN guidelines mention the potential use of minimally invasive approach, there is no clear standardization of patient selection and laparotomy remains the recommended approach in the two guidelines .

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Background & Rationale

A Laparoscopic Adjusted Model Able to Predict the Risk of Intraoperative Capsule Rupture in Early-stage Ovarian Cancer: Laparoscopic Ovarian Cancer Spillage Score (LOChneSS Study)

Tumours <6 cm – 7.7%

Tumours 6-9 cm – 18%

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The rates of port site metastasis are very low, especially in early-stage ovarian cancer. For instance, two reviews have reported a port-site metastasis rate as low as 0.18% and 0.4%

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MIRRORS-FROZEN TRIAL DESIGN

Key eligibility criteria

• Complex adnexal Pelvic mass/es ≤8 cm with no malignant disease outside the adnexae on CT or MRI.
• Radiological or histological or cytological evidence of stage III or IV disease.
• Any patient randomized to either of the study arms and found to have disease which appears greater than stage 1 will be withdrawn from the trial and treated according to the national guidelines.

Randomized ( n=40)

Open Surgery Arm

MIRRORS-FROZEN Protocol

initial laparoscopic phase, a thorough inspection of the abdomino-pelvic cavity should be performed to determine the feasibility of proceeding robotically. In patients randomized to the robotic arm and deemed suitable to proceed, peritoneal fluid or washings should be retrieved, followed by robotic excision of the mass(es) and its retrieval in a bag.

Follow up

6 weeks PROM

Primary Outcome :

• Recruitment Rate.
• Randomization acceptability
• Response rate to the trial questionnaires

Secondary Outcomes:

• Oncological outcomes (Rate of intra-operative cyst rupture with spillage within the peritoneal cavity , Time to chemotherapy if indicated.)
• Surgical outcomes ( Conversion rate , Blood loss during surgery, Surgical & post operative complications )
• Length of Hospital stay.
• Cost analysis of MIRRORS- FROZEN Protocol Vs Standard open surgical staging.
• Patient Reported outcomes ( Pain Assessment ,Quality of Life following Surgery using EORTC QLQ-C30 and QLQ-OV28 & EQ5D-5L, HDAS).
• Exploratory Analysis – Using liquid biopsy (body fluids) measurements to investigate potential diagnostic/prognostic and therapeutic biomarkers

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Surgical Protocol

At the initial laparoscopic phase, a thorough inspection of the abdomino-pelvic cavity should be performed to determine the feasibility of proceeding robotically. In patients randomized to the robotic arm and deemed suitable to proceed, peritoneal fluid or washings should be retrieved, followed by robotic excision of the mass(es) and its retrieval in a bag. The choice of specimen retrieval method, whether through a wound protector ring or vaginally, is left to the discretion of the individual surgeon. Following retrieval of the mass(es), it should be sent for frozen section analysis as per standard pathology department standards of practice to determine the extent of the surgery.

The surgery continues robotically; however, conversion to laparotomy can be considered at any point at the discretion of the individual surgeon, in the event of surgical difficulty where it is felt to be in the patient's best interest. For example, in situations of complex adhesions or to achieve intact removal of the cyst.

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Benign: After removing the pelvic mass, surgery may either end, or proceed to completion hysterectomy and removal of the remaining tube(s) and ovary/ies based on the patient's preference and agreed consent. If an omentectomy or omental biopsy is performed, the clinical rationale should be documented.

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Borderline: Surgical staging should be performed and includes:

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1.Peritoneal biopsies of normal surfaces, including from the under

surface of the right hemidiaphragm, bladder reflection, Pouch of

Douglas, right and left paracolic gutters, and both pelvic sidewalls.

2.Infracolic omentectomy

3.Hysterectomy and contralateral salpingo-oophorectomy unless preservation of fertility is desired.

4.Appendicectomy for mucinous tumours .

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Malignant: Surgical staging should be performed and includes:

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1.Peritoneal biopsies of normal surfaces, including from the under surface of the right hemidiaphragm, bladder reflection, Pouch of Douglas, right and left paracolic gutters, and both pelvic sidewalls. (4-6) biopsies.

2.Supracolic omentectomy.

3.Retroperitoneal lymph node assessment of pelvic and para-aortic nodes, with removal of enlarged lymph nodes as a minimum. (May be omitted in mucinous tumours).

4.Hysterectomy and contralateral salpingo-oophorectomy apart from cases of apparent Stage 1 A disease where fertility preservation is desired

5.Appendicectomy if abnormal

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Trial Questionnaires

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These self-administered questionnaires should not take longer than 30 minutes on average to complete.

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EORTC QLQ-C30 & OV 28

The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30. The ovarian cancer module (EORTC QLQ-OV28)

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HADS

The Hospital Anxiety and Depression Scale (HADS).

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EQ5D-5L

EQ5D is a standardized instrument for use as a measure of health outcome.

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Pain Scale

Simple 11-point scale (0-10)

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The Trial has opened for recruitment on the 10/10/2024

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For two years with the intended trial recruitment closure 12/12/2026

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