SarcoSIGHT- A randomised controlled trial of fluorescence guided sarcoma surgery versus standard of care

Research Question

Does fluorescence guided surgery significantly reduce the unexpected positive margin rate compared to standard of care surgery in patients undergoing open surgery for sarcoma? Background

Sarcomas are rare malignant tumours accounting for 1% of all cancers with around 5300 patients diagnosed annually in the UK (1). Sarcomas affect a wide age range of the population with an increased overall prevalence in younger age groups compared to other cancers. The median age of patients at diagnosis is 56-years (2).

There is a five-year survival rate of approximately 65%, reducing to 50% in higher grade sarcomas, with little improvement in survival outcomes over the last 30-years (3). Surgery is the mainstay of treatment, with the goal being complete resection of the tumour while leaving as much normal tissue as possible to maximise functional outcomes. Currently, surgeons use pre-operative imaging to plan the resection of the tumour and operate by eye and palpation.

This often leads to uncertainty during the operation, particularly in difficult anatomical locations, as to where the tumour ends, and normal tissue begins (4). Margins

The most important prognostic factor is the resection margin. Margins are assessed post-operatively by a pathologist. A clear margin, known as a negative margin, means that the resected tumour is surrounded by normal tissue, which implies there is no disease left in the patient.

By contrast, a positive margin means that sarcoma cells are visible at the edge of the tumour. Positive margins can be either macroscopic or microscopic. Positive margins significantly correlate with a higher rate of local recurrence, reduced time to local recurrence and poorer overall survival.

Given that the positive margin rate remains considerable and has such clear associations with poor oncological outcomes, there is a need for technologies that will assist sarcoma surgeons to achieve lower positive margins rates to improve short- and long-term outcomes for patients. Fluorescence Guided Surgery

The most promising technology to reduce the positive margin rate in sarcoma surgery is fluorescence guided surgery (FGS). FGS is an established method, which involves the intravenous administration of fluorescent dye (indocyanine green; ICG) followed by intra-operative visualisation of the fluorescence with a near-infrared (NIR) camera.

ICG has been used for decades to assess cardiac output (5) and hepatic function (6). ICG is approved by the European Medicines Agency (EMA) and considered safe (7, 8). More recently ICG has been used for tissue perfusion assessments intra-operatively in other surgical fields, allowing surgeons to identify healthy tissue more accurately from tissue that is diseased or poorly vascularised (9, 10).

The most recent application of FGS using ICG is for tumour margin identification of solid cancers (11-15). ICG is administered 12-24 hours prior to the operation, allowing time for uptake of the dye in the tumour and clearance from the peritumoral tissue, prior to imaging intra-operatively. Findings have shown that tumour margin identification using FGS could have the potential to greatly improve patient outcomes but requires further investigation (16).

Rationale

In November 2020, the National Cancer Research Institute Sarcoma Research Group (UK) reached a consensus that trials in surgery are a priority to assess new technologies that may improve surgical performance (17). To date there have been no randomised sarcoma trials with a surgical intervention. Recently published case series data suggested that the use of FGS using ICG for high grade sarcoma resection may reduce the UPM rate (16).

As such, undertaking this randomised control trial of FGS in sarcoma is well-timed. This trial will be exclusive to sarcoma patients, but inclusive of all ages and subtypes except low grade sarcomas because they do not fluoresce. Delivery of this trial will provide the sarcoma community, nationally and internationally, with crucial insights into performing more effective surgery, developing improvements to the current standard surgical techniques as well as the histopathological assessment of resection specimens.

It also aims to provide answers to questions on functional outcomes and the optimal timing of adjuvant therapies in sarcoma patients. With UPMs clearly linked to inferior oncological outcomes in the short term (e.g., decreased time to local recurrence) and longer term (e.g., poorer overall survival), this randomised surgical trial represents an important step towards improving these outcomes for sarcoma patients.

Aims and Objectives *To determine whether FGS using ICG reduces the UPM rate compared to the current standard of care (SoC). *Complications - Rates of intra- and postoperative complications as recorded in the clinical notes. *Length of index operation *Length of inpatient stay *Perceived impact of intervention of surgical decision making

*Local recurrence (LR) rate *Regional/distal recurrence rate *Overall survival (OS) rate *Identify rates of adjuvant and neo-adjuvant therapies *Quality of life (QoL) measurements *Recovery following resection Exploratory Objectives *To determine the role of ICG in the pathological assessment of resected sarcoma specimens

*To develop artificial intelligence algorithms to improve interpretation of fluorescence Methods, including justification of study design

Careful consideration was given to the trial design with input from our PPI group and sarcoma centres around the UK. The following was agreed: a prospective, 2 arm, randomised, open label, multi-centre trial to establish the efficacy of fluorescence guided surgery in reducing the unexpected positive margin rate in patients undergoing surgery for sarcoma.

Consenting patients who fulfil the eligibility criteria will be randomised to receive fluorescence guided resection (intervention arm) or standard resection (control arm) in a 1:1 ratio. Efficacy will be established using histopathological samples collected during surgery, and analysed in histopathology laboratories at participating centres to understand microscopic tumour infiltration into tissue (margin) beyond the tumour boundary.

Timelines for Delivery

Total duration is 58 months. Months 1-4 full protocol development, government approvals, contracting and site set up. Months 5-34, for 30 months recruitment. Data collection will close at the end of month 49. Months 50-58 data analysis, final report and dissemination. Anticipated Impact and Dissemination

Trial results will be shared widely, including with patient groups, charities and presented at national and international meetings. We will also publish the main trial findings and the results of the associated sub-studies in leading open access medical journals. We will undertake a series of PPIE meetings at the end of the trial to understand the experience of taking part for patients, and to ensure that our interpretation, and dissemination plan maintains its focus on patients.

References

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9. Holm C, Mayr M, Höfter E, Becker A, Pfeiffer UJ, Mühlbauer W. Intraoperative evaluation of skin-flap viability using laser-induced fluorescence of indocyanine green. Br J Plast Surg. Dec 2002;55(8):635-44. doi:10.1054/bjps.2002.3969

10. Moyer HR, Losken A. Predicting mastectomy skin flap necrosis with indocyanine green angiography: the gray area defined. Plast Reconstr Surg. May 2012;129(5):1043-1048. doi:10.1097/PRS.0b013e31824a2b02

11. Gotoh K, Yamada T, Ishikawa O, et al. A novel image-guided surgery of hepatocellular carcinoma by indocyanine green fluorescence imaging navigation. J Surg Oncol. Jul 1 2009;100(1):75-9. doi:10.1002/jso.21272

12. Bourgeois P, Veys I, Noterman D, et al. Near-Infrared Fluorescence Imaging of Breast Cancer and Axillary Lymph Nodes After Intravenous Injection of Free Indocyanine Green. Front Oncol. 2021;11:602906. doi:10.3389/fonc.2021.602906

13. Tummers QR, Hoogstins CE, Peters AA, et al. The Value of Intraoperative Near-Infrared Fluorescence Imaging Based on Enhanced Permeability and Retention of Indocyanine Green: Feasibility and False-Positives in Ovarian Cancer. PLoS One. 2015;10(6):e0129766. doi:10.1371/journal.pone.0129766

14. Okusanya OT, Holt D, Heitjan D, et al. Intraoperative near-infrared imaging can identify pulmonary nodules. Ann Thorac Surg. Oct 2014;98(4):1223-30. doi:10.1016/j.athoracsur.2014.05.026

15. Yokoyama J, Fujimaki M, Ohba S, et al. A feasibility study of NIR fluorescent image-guided surgery in head and neck cancer based on the assessment of optimum surgical time as revealed through dynamic imaging. Onco Targets Ther. 2013;6:325-30. doi:10.2147/ott.S42006

16. Brookes MJ, Chan CD, Nicoli F, et al. Intraoperative Near-Infrared Fluorescence Guided Surgery Using Indocyanine Green (ICG) for the Resection of Sarcomas May Reduce the Positive Margin Rate: An Extended Case Series. Cancers (Basel). Dec 14 2021;13(24)doi:10.3390/cancers13246284

17. NCRI Sarcoma Group. Annual Report 2019-2020. 2020. https://www.ncri.org.uk/wp-content/uploads/NCRI-Sarcoma-Group-Annual-Report-2019-20.pdf