Liver resection for metastatic uveal melanoma – Experience from a supra-regional centre and review of literature

Authors
Mr Dharmadev B Trivedi1,2	MS, MMedEd, FRCS	dharmadevt@yahoo.com	
Ms Natasha Aldulaimi2	Medical Student	npa1g17@soton.ac.uk	
Dr Ioannis Karydis2	MB, BCh, DPhil	Ioannis.Karydis@uhs.nhs.uk	
Dr Matthew Wheater2	BM, PhD, FRCP	matthew.wheater@uhs.nhs.uk	
Dr Sachin Modi2		BSc, MBBS, FRCR, FRCR (IR)	sachin.modi@uhs.nhs.uk	
Dr Brian Stedman2	BSc, MBBS, FRCS, FRCR	brian.stedman@uhs.nhs.uk	
Mr Dimitrios Karavias2	MD, PhD	dimitrios.karavias@uhs.nhs.uk	
Professor John Primrose2	MD, FRCS	j.n.primrose@soton.ac.uk	
Mr Neil Pearce2	MD, FRCS	neil.pearce@uhs.nhs.uk	
Mr Arjun S Takhar2	PhD, FRCS	arjun.takhar@uhs.nhs.uk	

Institution
1 South Warwickshire NHS Foundation Trust
Lakin Road
Warwick CV34 5BW
Warwickshire, United Kingdom
2 University Hospitals Southampton NHS Foundation Trust
Tremona Road
Southampton SO16 6YD
Hampshire, United Kingdom

Corresponding author
Mr Arjun S Takhar
Department of HPB Surgery
Southampton General Hospital
Tremona Road
Southampton SO16 6YD
Email: arjun.takhar@uhs.nhs.uk
Telephone: +44 238 120 6796

Funding information
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Abstract	 (Word count 200)

Background

Management of liver metastases from uveal melanoma (LMUM) requires multimodal approach. This study reviews the role of and outcomes after liver resection for LMUM, reviewing current literature and institutional outcomes.

Methods

Records of all patients referred to the Melanoma MDT between February 2005 & August 2018 were reviewed. All publications describing surgery for LMUM were identified from PubMed, Embase, and Google Scholar.

Results

31 of 147 patients with LMUM underwent laparoscopic liver biopsy, and 29 (14 females) had liver resections. 19 liver resections were performed locally (7 major (≥ 3 seg), 14 laparoscopic) without major complications or mortality. Overall survival positively correlated with the time from UM to LMUM (Spearman’s rho rs = 0.859, p < 0.0001). Overall & Recurrence-free survivals were comparable following R1 or R0 resections (OS 25 Vs 28 months, p = 0.404; RFS 13 Vs 6 months, p = 0.596). R1 resection cohort had longer lead-time (median 100 Vs 24 months, p = 0.0408). Eleven publications describing liver resection for LMUM were identified and included in the narrative review. 

Conclusion

Surgery for LMUM is safe and complements multidisciplinary management. Despite heterogeneity in literature, time from diagnosis of UM to LMUM remains key factor affecting the survival after liver resection.

Key words

Uveal melanoma, liver metastases, surgery, multi-disciplinary management

Manuscript  (Word Count 1959)

Introduction

Uveal melanoma (UM) is the most common intraocular malignancy. There is a predilection for male sex and Caucasian ethnicity [1]. The incidence of uveal melanoma in Europe, varies between 2 to 8 per million population [2]. Nearly all (90%) of uveal melanoma arise from the choroid, followed by ciliary body (6%), and iris (4%). Risk factors for developing uveal melanoma are lighter eye colour, lack of tanning, naevus of the choroid or iris, ocular melanocytosis, and BRCA1-associated protein 1 mutation [3]. Almost 50% of uveal melanomas metastasize, and the liver is the most common site in up to 89% of patients [1, 4]. 

Management of the metastatic uveal melanoma requires multi-modal management guided by a dedicated multi-specialty team. A variety of systemic treatment options including chemotherapy and immunotherapy have been explored with some survival benefit [4, 5, 6]. Contrarily, liver resection or ablation of the metastases for the patients with LMUMs have shown significant survival advantage for a selective cohort of patients with oligometastatic disease [7-10]. More recently, isolated organ (liver) chemoperfusion has shown survival benefit for the patients with LMUMs, especially in association with other liver-directed treatments to reduce the tumour burden [11,12]. 

Specialist management of metastatic uveal melanoma has been offered at a supra-regional centre for more than 17 years. This study aims to evaluate the role, safety, and oncological effectiveness of liver surgery for patients with LMUM in the context multidisciplinary management. Secondly, a comprehensive literature review is presented to highlight the current evidence for liver resection for LMUMs. A multi-disciplinary treatment pathway developed upon the prevalent national guidelines [13], and novel treatment options is presented. 

Patients and Methods

All consecutive patients referred to the Uveal Melanoma Multi-Disciplinary Team (MDT) between February 2005 and August 2018, were identified from the oncology and hepato-biliary surgery database. Patients with documented evidence of surgical intervention for LMUM were identified. Demographic data, MDT outcome letters, operative records, clinic letters, letters from referring hospitals, discharge summaries, radiology reports, and histology findings were reviewed. Patients were treated in line with UK guidelines [13] and offered local, regional, and systemic therapies according to an agreed algorithm (Figure 1). Major liver resection was defined as resection of three or more anatomical segments of liver, and minor liver resection was defined as 2 or less anatomical segments in accordance with the established Brisbane 2000 system [14]. Postoperative complications were documented according to the Clavien-Dindo classification [15]. Resection was considered as R0 if a microscopic clearance of 1 mm was achieved. Only cases that underwent surgery locally were included in the final analysis. The work was approved by the institutional clinical governance department.
For the purpose of a narrative literature review, all English language publications describing surgical intervention for the LMUM patients were identified from the PubMed, Embase, and Google Scholar repositories. Due to the rarity of this condition, articles likely to describe same patient cohorts were also included. 	

Data analysis	

Descriptive data analysis was performed using Microsoft™ Excel (version 2010, Microsoft Corporation, Washington) for quantitative data in the form of median, range, and percentage as appropriate. Non-parametric data sets were compared using Log rank, and Mann-Whitney U tests. Spearman correlation coefficient was calculated to identify relationships between variables. Missing data was excluded from the statistical analysis. A p-value of <0.05 was considered to be statistically significant. 

Results

Identifying the cohort

Of 341 total patients discussed in the uveal melanoma MDT, 193 had metastatic uveal melanoma. During the follow period up to August 2020, 32 patient had received no treatment due to advanced disease or significant comorbidities making them unfit for any form of treatment. 147 out of 161 patients had either radiologically or histologically confirmed liver metastases. Survival data for one patient was not available. The CONSORT diagram (figure 1) summarises the cohort identification for the study, and table 1 describes the demographics and surgical outcomes data for the study cohort.

Figure 1. CONSORT diagram showing selection of the study cohort

Table 1.	Demographics and focused outcomes among patients undergoing liver resection with curative intent locally
Total liver resections = 19 (N=17)	Median (range)	
Age at diagnosis of UM	57 (30, 76)	
Age at diagnosis of LMUM	61 (40, 79)	
Time (Months) from Diagnosis of UM to LMUM	37 (13, 320)	
Major (> 2 seg) / Minor (<3 seg) resection	7 / 12	
Laparoscopic / Open	14 / 5	
Postoperative hospital stay	6 (4, 10)	
Post-operative complications	2 / 19 (CD grade II) (10.5%)	
Perioperative mortality	0 / 19	
Repeat surgery at Southampton	2/19	
R0 resection rate	10/ 19 (52.6%)	
Subsequent Treatment After surgery with curative intent 	
Percutaneous selective hepatic chemo-saturation
Immunotherapy
No Treatment
Radio Frequency Ablation (RFA)
- Subsequent surgery
Selective Internal Radio Therapy	3
9
2
3
2
1	
Survival data

At the end of the follow up, seven patients were still alive. Median overall survival (range) from the diagnosis of UM, surgery for LMUM, and recurrence free survival after curative liver resection was 83 (25, 204), 27 (8, 66), and 6 (0, 47) months, respectively. Time from the diagnosis of UM to LMUM (lead time) correlated positively with overall survival (Spearman’s rho rs = 0.859, p < 0.0001). No correlation between age at diagnosis of UM or at LMUM was observed. The type of liver resection (major Vs minor) did not influence overall, post-liver resection, or recurrence free survival. Similarly, R0 or R1 resection margin status did not significantly influence survival outcomes (median survival post-surgery 28 Vs 25 months, p = 0.470; median recurrence free survival 6 Vs 13 months, p = 0.108).  However, we acknowledge that patients who had R1 resection had significantly longer lead time (median 100 Vs 24 months, p = 0.0408).	

Discussion

Evolution of liver directed therapy for LMUM

Liver directed therapies for LMUM have continued to evolve over past two decades. Of these, surgical resection has emerged as a promising option for patients with potentially resectable liver metastases, and a favourable disease biology [4]. Patients who are able to receive liver resection with curative intent are found to have significant survival benefit as compared to those receiving systemic treatments [5]. Concurrently a variety of non-surgical liver directed therapies such as Hepatic Artery Infusion (HAI), Selective internal Radiotherapy (SIRT) / Radioembolization, Percutaneous selective hepatic perfusion (PHP), and Trans-Arterial Chemoembolization (TACE) have also shown somewhat favourable impact on the patient survival outcomes [16].

This study demonstrates that liver resection with curative intent for a selected group of patients with LMUM is feasible, safe, and provides survival benefit similar to previously published studies (Tables 2 & 3). As evident from the current literature the time from the development of uveal melanoma to the development of liver metastases (lead time) is consistently identified as a favourable prognostic factor [7, 17,19,20,24]. Most studies report a lead time of more than 24 months providing survival benefit for the patients who are able to receive curative (R0) surgery [17, 19, 24].  However, in a selected cohort of patients, complete (R0) surgical resection has also been found to provide a significant survival benefit over the patients who do not receive surgical resection for the LMUM despite similar lead times [21]. 

Table 2. 	Description of current literature and main outcomes (in chronological order of the publication year)

	Study centre	Study period
(years)	Sample (cohort) size (n)	Median survival post liver resection (months)	Recurrence free survival (months)	Morbidity
n (%)	Mortality	Favourable prognostic factors	
Ayoma et al  [7]	Philadelphia, US	22	9 (2 liver + omental nodule, 1 liver + Rt hemicolectomy)	27 (11-86)	19 (6 – 78)	0	0	Longer lead time
Complete surgical resection	
Hsueh et al [20]	California, US	28	24 (5 liver, 19 other sites)	38δ	nr	nr	nr	Lead time  45 months
< 5 metastatic lesions
Surgical resection	
Rivoire et al [18]	Lyon, France	14	28	R0 = 25 (11-110)
R2 = 16 (3-35)	nr	nr	nr	Age < 70 
R0 resection
  liver lesions	
Kodjikian et al [25]	Lyon, France	10	28	R0 = 25 (11-110)
R2 = 16 (3-35)	nr	nr	nr	Age < 70 
R0 resection
  liver lesions	
Pawlik et al [23]	Texas, US	16	16	29.4	8.8	nr	nr	none	
Adam et al [17]	Villejuif, France	21	104	19	nr	nr	nr	Age < 30 years
Lead time > 24 months
No extrahepatic disease
R0 resection	
Mariani et al [19]	Paris, France	16.5	255	14
R0 = 27 
R1 = 17 
R2 = 11	nr	nr	nr	Lead time > 24 months
R0 Resection
 4 liver lesions
Absence of miliary disease	
Frenkel et al [21]	Jerusalem, Israel	19	35
(Wedge sampling = 4)	23
R0 = 65.6
R1/2 = 16.6	7.4	0	0	< 6 liver lesions
operable disease
R0 resection (not statistically significant)	
de Ridder et al [22]	Netherlands	16	LMUM 12
[LMCM 16
Unknown 4]	34	8	4 (15)@	0	Solitary liver metastasis
Unilobar distribution
Resection of ≤ 3 segments@	
Gomez et al [8]	Liverpool, UK	9	18	27 (14 – 90)	13	4 (23.5)	0	nr	
Mariani et al [9]	Paris, France	13	72	27 (Surgery)
28 (Surg + RFA)	8	4 (6)	0	nr	
Akyuz et al [24]	Ohio, US	12	16	35	10	3 (19)	0	Lead time > 24 months
< 4 liver metastases
Pts receiving surgery	
Servois et al [10]	Paris, France	14	14	~94	20	0	0	nr	

δ Combined survival including extrahepatic resection patients, nr Not Reported, * R0 was removal of all visible disease, R2 was visible disease left in situ, ~ Same patient cohort as Rivoire et al, # Cumulative prognostic factors including non-melanomatous hepatic metastases, LMCM Liver metastases from Cutaneous Melanoma, @ Combined figures for the whole cohort, RFA Radio-Frequency Ablation, Sx Surgery

Table 3.	Characteristics and outcomes of liver directed surgery / ablation of the studies (in chronological order of the publication year)

	Laparoscopic	Open	Major (> 2 segments)	Minor (< 3 segments)	R0	R1	R2	Resection	Ablation	Study Characteristics	
Ayoma et al  [7]	nr	nr	5	4	nr	nr	nr	9	0	First study to report long survival for patients having surgical resection for metastatic uveal melanoma in detail	
Hsueh et al [20]	nr	nr	nr	nr	21	nr	nr	24	0	Study reporting resection for hepatic and extrahepatic metastases from UM	
Rivoire et al [18]	nr	nr	7	21	14	nr	14	24	0	R0 defined as removal of visible disease, R2 defined as residual visible disease	
Kodjikian et al [25]	do	do	do	do	do	do	do	do	do	Same patient cohort as Rivoire et al (2005)	
Pawlik et al [23]	nr	nr	10	6	14	2	0	16	3	Multi-institutional study comparing surgery for LMUM & LMCM
Advocated surgery within multidisciplinary management	
Adam et al [17]	nr	nr	nr	nr	nr	nr	nr	nr	nr	Cumulative results of 41 centres
Likely to include results from previous studies	
Mariani et al [19]	nr	nr	nr	nr	76	22	157	255	8	Largest cohort from single institute
RFA patients included in R0 surgery cohort
Unclear about R2 resection cohort (debulking or biopsy)	
Frenkel et al [21]	nr	nr	15	15	13	18	4	30	nr	No statistical difference in lead time (35 Sx Vs 37 Non-Sx)
Surgery provided survival benefit
Inclusion of patients having liver biopsy only in final survival analysis	
de Ridder et al [22]	nr	nr	11@	21@	23@	6@	1@	32@	0	National data from Netherlands including patients with LMUM, LMCM & unknown primary	
Gomez et al [8]	nr	nr	3	14	15	2	0	17	1	1st UK study reporting outcomes of resection with curative intention for LMUM patients	
Mariani et al [9]	nr	nr	30	40	72	0	0	70
(57 Sx,
13 Sx + RFA)	2	Study comparing outcomes of LMUM patient having surgery alone, RFA + Sx or RFA alone	
Akyuz et al [24]	16	0	0	2	nr	nr	nr	2	14	Study comparing laparoscopic resection (2) & laparoscopic RFA ablation to systemic therapy. Major liver resection was not considered appropriate	
Servois et al [10]	nr	nr	6 (primary)
0 (iterative)	8 (primary)
4 (iterative)	14	0	0	4 (+ RFA)	10	study reports iterative RFA +/- metastasectomy	

δ Combined survival including extrahepatic resection patients, nr Not Reported, * R0 was removal of all visible disease, R2 was visible disease left in situ, ~ Same patient cohort as Rivoire et al, # Cumulative prognostic factors including non-melanomatous hepatic metastases, LMCM Liver metastases from Cutaneous Melanoma, @ Combined figures for the whole cohort, RFA Radio-Frequency Ablation, Sx Surgery

The R0 conundrum

Achieving R0 (microscopic clearance of tumour) is considered ‘sine qua non’ in oncologic surgery. Despite the emphasis on complete microscopic clearance (R0 resection) of the LMUM in the literature, the definition and reporting of R status within the published literature remains ambiguous [7, 17-19, 21, 25]. The inconsistent reporting of oncological resection status (R), for example, including patients having liver biopsy alone with or without placement of intraarterial catheter [19] as R2, or reporting combined survival data of R1 and R2 cohort [22] makes it difficult to infer the exact survival benefit of surgical resection margin if any, and can overestimate the effect of cytoreduction. Gomez et al [8] defined R0 resection as a microscopic clearance of 1 mm or more. In agreement, in the present study, R0 resection was reported only if the microscopic clearance of 1 mm was achieved. Within the study, no patients were offered a cytoreductive surgery as advocated by Gomez et al [8].  Contrary to previous studies, we did not observe any difference in survival in the patients who had R1 or R0 resections; the lead time being significantly longer for R1 patients (100 Vs 24 months, p = 0.0408). In addition to a longer lead time in the R1 resection status cohort, there is one more possible reason for this observation. Like most other centres, the parenchymal dissection for liver resection was performed using Cavitron Ultrasonic Surgical Aspirator® (Integra CUSA® Excel; Integra Neurosciences Ltd, Andover, UK) for the study cohort. This can result in parenchymal ablation width of up to 7.1 ± 2.8 mm and tissue necrosis of up to 0.8 ± 0.2 mm [27], which may reduce the significance of R1 resection. 

Ablation as an adjunct or alternative to surgery?

In recent years, ablation as an adjunct [9] or alternative [24] to surgical resection has been reported to provide similar safety and survival outcomes. Ablation with or without surgery, has also been identified as a valuable tool for iterative treatment following initial surgery, providing oncological benefit even in the absence of any systemic therapy [10]. As the liver directed therapies continue to evolve, future studies will be able to compare the impact of surgical resection and ablation with the intention to reduce the tumour burden (cytoreduction), on the liver directed oncological therapies [11, 12].  

Inherent limitations to the present study and previous literature
Recommendations regarding patient selection for liver resection for the LMUM have traditionally included younger patients [18, 19], lower tumour burden [20-23], and with minimal or no extrahepatic metastases [14, 18]. This inevitably leads to a selection bias which can exaggerate the beneficial effect of surgical resection [5]. Most of current evidence regarding role of surgical resection or ablation is derived from retrospective, small scale observation studies due to the rarity of the condition, and absence of prospective randomised trials.

The present study has similar limitations of having a single center, retrospective, and small patient cohort. There remains an additional possibility of selection bias in this study, since only the patients referred to the melanoma MDT at the study institute were able to receive surgical resection. Further, we have intentionally avoided comparing the patient who could not have surgery with those having surgery, since the beneficial effect of reducing disease burden by surgery or ablation is becoming more evident over past two decades, and non-surgical candidates are fundamentally incomparable to those able to receive a curative surgery. 

Nevertheless, due to the rarity of the pathology, and the paucity of strong evidence in the subject, this study provides a valuable addition to existing literature. Additionally, unlike previous studies, the patient having extrahepatic metastasectomy [7, 20], primary cutaneous melanoma [22] or the patients receiving ablative therapies with or without surgery [9, 10, 24] are carefully avoided from inclusion in this study. 

Future

The technique, feasibility, safety, and oncologic efficacy of liver resection for a selected group of patients with the LMUM have evolved significantly over past two decades [7-10, 17-25]. There is emerging evidence suggesting that low hepatic tumour burden is linked with better outcomes with both liver directed and systemic oncological strategies [12, 26]. The multimodal approach emphasized in this study integrates surgery within a stepwise approach for managing the LMUM. It involves local control with surgery (and/or ablation), regional treatment such as chemo-saturation with percutaneous hepatic perfusion (PHP), and systemic therapy, mainly with immunotherapy. Additionally, a pragmatic model founded on current national guidelines [13], for the management of the LMUM patients in the context of a multidisciplinary structure is presented in Figure 2.

Figure 2	The Southampton pathway for management of LMUM patients

Conclusion 

Management of the LMUM patients remains complex, and surgical resection is a valuable adjunct to the multimodal management of these patients. In a selected patient cohort with operable hepatic metastases (LMUM), and without extra-hepatic disease, liver resection seems to provide some survival benefit [4, 5, 7-9, 17-24]. Within the limitations of this study, we conclude that when the tumour biology is favourable (longer lead time), R1 resection status may not affect the survival outcomes. There remains significant heterogeneity in the current literature describing the role of liver resection for LMUM. This study highlights the issues related to reporting the outcomes of surgical intervention, that could be addressed in future studies. As evident from the current literature, liver directed treatments have continued to evolve along with the advancement of systemic therapies [6].  This work emphasizes on the need for developing a collaborative database, and a standard reporting toolkit for the treatments for LMUMs, at a national and international level. 

  

Disclosures (Conflict of Interest Statement)

Dharmadev Trivedi, Natasha Aldulaimi, Sachin Modi, Brian Stedman, Dimitrios Karavias, John Primrose, Neil Pearce, and Arjun Takhar have no conflicts of interest or financial ties to disclose. 
Matthew Wheater has received speaker fees from Pierre Fabre and consultancy fees from Bristol Myers Squibb.
Ioannis Karydis received funding in the form of honoraria and travel grants from Delcath Systems Inc.

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