Review article 1
Hepatic resection for metastatic melanoma: a systematic review Ahmer M. Hameeda, E-Ern I. Nga, Emma Johnstona,b, Michael J. Hollandsa,b, Arthur J. Richardsona,b, Henry C. Pleassa,b and Vincent W.T. Lama,b Melanoma metastatic to the liver has a very poor prognosis, and has traditionally been treated using systemic chemotherapy with limited efficacy. Surgery is increasingly being explored as a therapeutic option for melanoma liver metastases, with varying levels of success. A systematic review was undertaken to explore the short-term and long-term outcomes associated with hepatectomy for melanoma metastases, in addition to identifying prognostic factors favouring increased survival. All eligible studies were identified through an electronic search of Medline and Embase (January 1990–March 2013). Each study was independently analysed by two reviewers, with relevant data extracted and tabulated according to predetermined criteria. Thirteen studies were selected that fulfilled the selection criteria, with a total of 551 patients undergoing hepatic resection for melanoma metastases. Metastases to the liver occurred at a median interval of 54 months. The median perioperative morbidity and mortality were 10% (range 0–28.6%) and 0% (range 0–7.1%), respectively. The median overall survival for operative patients was 24 months, with median survival being greater in the R0 resection group (25 months; range
9.5–65.6 months) compared with the R1/2 resection group (16 months; range 11.7–29 months). Overall median 1-, 3- and 5-year survival rates were 70% (range 39–100%), 36% (range 10.2–53%) and 24% (range 3–53%), respectively. Positive prognostic factors may include single hepatic metastases, a longer time to development of hepatic metastases and R0 resection. Hepatic resection for metastatic melanoma might confer a distinct survival benefit in a select group of patients, although disease c 2014 recurrence is the norm. Melanoma Res 24:1–10 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Introduction
considered inappropriate for surgery because of the lack of survival benefit with this approach. A few groups have recently reported hepatic resections in malignant melanoma with long-term survival rates [7–9].
Patients who develop American Joint Committee on Cancer (AJCC) stage IV melanoma have a very poor prognosis, with a median survival of 7.5 months and an estimated 5-year survival of 6% [1]. The liver is the most common site of metastases in ocular melanoma, with 40% of patients developing hepatic metastases [2], whereas in cutaneous melanoma, only 15–20% will develop liver metastases [2,3]. To date, the mainstay of treatment for malignant melanoma has been systemic therapy. However, even the most active chemotherapy agent, dacarbazine, has only demonstrated a complete response in 3–5% of patients treated, with a median duration of response of just 4–6 months [4]. More recently, biologic therapy has shown some promise with a complete response rate of 7%, but a significant toxicity and side effect profile has limited its use [5]. The role of surgical resection is therefore coming into favour because of the fact that more than 80% of patients with metastatic melanoma initially have only one site of metastasis, of whom 10–20% have a solitary liver metastasis [1,6]. Traditionally, these patients have been c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0960-8931
Melanoma Research 2014, 24:1–10 Keywords: liver metastasis, melanoma, surgical resection a Department of Surgery, Westmead Hospital and bDiscipline of Surgery, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
Correspondence to Ahmer M. Hameed, MBBS (Hons), BSc (Med) (Hons), Department of Surgery, Westmead Hospital, University of Sydney, Cnr Hawkesbury and Darcy Rd, Westmead, Sydney, NSW 2145, Australia E-mail: [email protected] Received 15 July 2013 Accepted 24 September 2013
The objectives of our study are to determine the long-term outcome of hepatic resection in metastatic melanoma to the liver and identify prognostic factors associated with long-term survival.
Methods Eligibility criteria
For studies to be included in this systematic review, articles had to be published after 1990, and have more than 10 patients undergoing hepatic resection. Both Englishlanguage and non-English-language articles were reviewed. Case reports, conference abstracts or proceedings, and articles deemed to have insufficient data for the purposes of this review were excluded. Information sources
The Medline (1946 to March 2013) and Embase (1974 to March 2013) databases were searched using the keywords melanoma, hepatic metastases and surgical resection DOI: 10.1097/CMR.0000000000000032
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2 Melanoma Research 2014, Vol 24 No 1
(Appendix). Reference lists from all relevant articles were reviewed manually for additional articles applicable to the selection criteria. Data collection process
Data were extracted from each study using a standardized table. Information was collected with reference to: study author(s), study period, study centre(s), total number of melanoma patients in series, total number of melanoma patients undergoing hepatic resection, number of primary uveal and cutaneous melanomas, number of hepatic metastases, synchronous and metachronous disease, time between melanoma diagnosis and liver metastasis detection, type(s) of neoadjuvant and adjuvant therapy, presence of extrahepatic disease, margin status, number of major hepatectomies (resection of three or more hepatic segments), morbidity/ mortality, other procedure(s), median follow-up, median overall survival, median disease-free survival, 1-, 3- and 5-year overall survival and disease recurrence (in patients with no evidence of disease posthepatic resection). Synthesis of results
Qualitative measures were combined from each applicable study through the tabulation of all data items of interest. A formal meta-analysis was precluded by the absence of homogeneity between studies and an adequate control group within each study. PRISMA guidelines were adhered to in the completion of this systematic review [10].
Results Study selection and search strategy are described in Fig. 1. Thirteen studies fulfilled the selection criteria and underwent collective analysis. Study demographics are outlined in Table 1. The majority of studies were retrospective in nature. A total of 551 patients underwent hepatic resection for melanoma metastases, out of whom 113 had primary cutaneous melanoma and 370 had primary ocular melanoma; the primary source was unknown in 68 patients. We found that a median of 29.4% of patients underwent surgical exploration without subsequent hepatic resection. In studies that outlined the number of melanoma patients undergoing resection as a proportion of the total number of patients with melanoma liver metastases, a median of 22.7% of patients underwent surgical therapy (range 1.4–56.5%). Hepatic metastases and resection extent
Table 2 shows characteristics related to the hepatic metastases and how they were resected. The median time to the development of liver metastases was 53.6 months. Synchronous disease was present in a median of 9.8% of patients, with most patients undergoing hepatectomy having metachronous metastases. A single metastasis was resected in 28.4% of patients, whereas 71.6% of patients had more than one metastasis removed.
A significant proportion of patients underwent a major hepatectomy (median 59.7%). Importantly, R0 resection was achieved in a median of 92.5% of patients (range 29.8–100%), indicating that the vast majority of surgeries were approached with curative intent. Interestingly, a significant minority of patients also had resection of extrahepatic disease (median 14.9%). Further procedures and adjuvant and neoadjuvant therapies
The use of adjuvant and neoadjuvant therapies in addition to metastasectomy is outlined in Table 3. It can be seen that only a minority of patients had any form of neoadjuvant therapy (median 16.3%), whereas a marginally greater proportion were given adjuvant treatments (median 30.8%). There was great disparity in the specific form of treatment used, and thus it is difficult to analyse the therapies individually. The majority of patients within this subset received chemotherapy, either systemically or locally through an intra-arterial catheter. Other neoadjuvant and adjuvant treatments used included bioimmunotherapy, vaccine therapy, gene therapy and hepatic artery embolization. Additional procedures, such as resection of extrahepatic disease and radiofrequency ablation, among others, were also used as outlined in Table 3. Primary and secondary outcomes
Table 4 shows pertinent study outcome data. Hepatic resection in malignant melanoma was proven to be safe, with an overall mortality rate of 2.6% (median 0%); median morbidity was also acceptably low at 10%. After a median follow-up of 24 months, the median overall survival was 24 months (range 9.5–39 months). Median overall survival 1-year posthepatectomy was a respectable 70%, with survival declining to 36 and 24% after 3 and 5 years, respectively. Disease recurred in 74.8% of patients; the liver was the site of recurrence in 50% of patients. The median disease-free survival was 13 months (range 8.3–19.9 months). Comparative data
Although not directly comparable, series that reported survival data for both operative and nonoperative patients found median overall survivals of 24 and 7.4 months, respectively (Table 5). The extent of resection seemed to positively influence survival, with patients undergoing R0 resections having a median overall survival of 25 months compared with 16 months for palliative resections. Surgery for hepatic metastases from ocular melanoma primaries yielded a survival of 31.7 months, which was greater than that for primary cutaneous melanoma (median survival 24.3 months). This data are further supported by 1-, 3- and 5-year overall-survival data (Table 5).
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Hepatic resection for metastatic melanoma Hameed et al.
3
Identification
Fig. 1
Records identified through database searching (n = 967)
Additional records identified through other sources (n = 2)∗
Eligibility
Screening
189 duplicates removed
Records excluded (n = 755)
Records screened by abstract ± title (n = 780)
• Lack of relevance (n = 755)
Total full-text articles assessed for eligibility (n = 25)
Full-text articles excluded, with reasons (n = 12)
Included
Studies included in qualitative synthesis (n = 13)
Studies included in quantitative synthesis (meta-analysis) (n = variable)†
• Overlap series (n = 3) • < 10 patients undergoing potentially curative resection (n = 2) • Insufficient data + overlap series (n = 2) • Insufficient data (n = 5)
Study selection and search strategy. *From additional search using Embase and Medline. wDepending on parameter being analysed and how many studies it was reported in (see tables for results).
Discussion Summary of evidence
This systematic review demonstrated that hepatic resection of melanoma metastases can be conducted safely while conferring significant survival advantage in a highly selected group of patients. Melanoma liver metastases have traditionally been managed nonoperatively, and overall survival tends to be very poor. In a combined analysis of multiple trials, Manola et al. [24] found an overall survival of 6.4 months in patients with metastatic melanoma; this was reduced to 3.9 months in those patients with hepatic metastases. A further large pooled database analysis by the AJCC showed a 1-year survival of B40% in patients with visceral, nonpulmonary melanoma involvement [25]. Hepatectomy in patients with colorectal cancer spread is well established as it is hypothesized that liver involvement reflects locoregional spread of disease through the portal circulation [26,27]. In contrast, melanoma liver metastases indicate systemic disease involvement, and as such hepatic resection in such
patients is much more controversial [26,27]. This systematic review provides some encouragement that melanoma liver metastasis resection can improve patient survival, with a 1-year survival of 70% and median overall survival of 24 months. In their meta-analysis of survival postmetastasectomy for colorectal cancer liver metastases, Kanas et al. [28] established a median 5-year survival of 38% and median overall survival of B43 months. A systematic review by Lam et al. [29] suggested that median survival after second hepatectomy for colorectal liver metastases was still as high as 35 months. Reddy et al. [30] directly compared survival for hepatectomy in noncolorectal nonneuroendocrine (NCNE) liver metastases, out of which melanoma was among the most common, with colorectal liver metastases. Median overall survival after resection of NCNE metastases was 44 months, which was equal to that for colorectal liver metastases, whereas survival in the subset of melanoma patients was 41 months [30]. Although overall survival from our review is not as high as that seen in studies on colorectal cancer, it can be seen
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4 Melanoma Research 2014, Vol 24 No 1
Table 1
Basic demographic characteristics of hepatic resection for melanoma metastases studies
References Caralt et al. [11] Chua et al. [12] De Ridder et al. [13] Frenkel et al. [14] Groeschl et al. [15]
Country(s) Spain
Hospital(s) or institution(s)
Study period
Type of analysis
Total number with hepatic resection (%)
NR
14 (NA)
Australia The Netherlands
Hospital val d’Hebron and Hospital Clinic, Barcelona St George Hospital, Sydney Nationwide, The Netherlands
2000–2009 Retrospective 1994–2010 Retrospective
Israel
Hadassah Medical Center, Jerusalem
1988–2007 Retrospective
USA
1990–2009 Retrospective
NR
1999–2005 Retrospective
1996–2003 Retrospective
Herman et al. [16]
Brazil
Kim et al. [17]
USA
Kodjikian et al. [18] Mariani et al. [19] Marshall et al. [20] Pawlik et al. [21]
France
Duke University Medical Center, Durham; John Hopkins Hospital, Baltimore; M. D. Anderson Cancer Center, Houston; University of Pittsburgh Medical Center, Pittsburgh A. C. Camargo Cancer Hospital and University of Sao Paulo Medical School, Sao Paulo John Wayne Cancer Institute, Santa Monica Croix-Rousse Hospital, Lyon
France UK USA, France and Italy
Ripley et al. [22] USA Rose et al. [23] USA and Australia
1994–2007 Retrospective
Total number of melanoma patients with liver metastases
Total number with ocular and cutaneous disease
Patients explored without resection (%) Cutaneous Ocular 8
6
NR
13 (56.5) 32 (NA)
8 16
b
3 12c
0 17 (34.7)
30 (40.5)
0
30
4 (11.8)
31 (NA)
NR
NR
NR
367
10 (2.7)
5
5
8 (44.4)
NR
27 (NA)
23
2d
NR
a
74
23 NR
1983–1996 Retrospective
63
28 (44.4)
0
28
0
Institut Curie, Paris
1991–2007 Retrospective
798
255 (32.0)
0
255
NR
Clatterbridge Cancer Centre, Bebington M. D. Anderson Cancer Center, Houston; Duke University Medical Center, Durham; Gustave Roussy Institute, Villejuif; Institute for Research and the Cure of Cancer, Candiolo National Cancer Institute, Bethesda John Wayne Cancer Institute, Santa Monica; Sydney Melanoma Unit, Sydney
2000–2010 Prospective
90
12 (13.3)
0
12
26 (68.4)
1988–2004 Retrospective
NR
40 (NA)
24
16
NR
1980–2008 Retrospective 1971–1999 Retrospective
539 1750
35 (6.5)e 24 (1.4)
29 NR
1f NR
NA 10 (29.4)
3704 23–1750 229
551 (14.9) 1.4–56.5% 22.7%
113 – –
370 – –
– 0–68.4% 29.4%
Total Range Median
– – –
– – –
NA, not applicable/unable to calculate; NR, not recorded. a Patients with liver and/or gastrointestinal tract metastases; exact number with liver metastases not specified. b Primary site unknown in two patients. c Primary site unknown in four patients. d Two patients had primaries in the gastrointestinal/genitourinary tracts. e Main purpose of hepatic resection here was tumour collection for tumour-infiltrating lymphocytes, not complete tumour resection. f Primary site unknown in five patients.
that melanoma hepatic resection still has the potential to provide significant survival advantage.
to be highly selective when surgery is considered as an option.
Disease recurrence posthepatic resection is unfortunately the norm in malignant melanoma, with a median diseasefree survival of 13 months and B75% of patients developing recurrence over 1–3 years (Table 4). In this sense hepatectomy for melanoma is rarely curative, but still seems to prolong survival in suitable cases.
In general, surgical selection criteria in the above studies were nonspecific and relied on the surgeon’s assessment of potential for curative resection [11–21]. The potential for curative surgery was largely ascertained by preoperative imaging and intraoperative evaluation, which in some cases included intraoperative liver ultrasound [16,18, 20,23]. Only Groeschl et al. [15] defined resectable lesions as those in which sufficient venous, arterial and biliary flow could be maintained and more than or equal to 20% of liver parenchyma would be preserved posthepatectomy. Marshall et al. [20] considered resection in the event of four or fewer hepatic metastases, while Kodjikian et al. [18] attempted resection when more than or equal to 30–40% of liver parenchyma could
Surgical selection criteria
In series where the total number of hepatic resections was reported as a proportion of total patients with hepatic metastases, the median rate of resection was only 22.7% (Table 1). In some of the larger studies, such as that by Rose et al. [23], only 1.4% of the patient population underwent hepatectomy. This clearly indicates the need
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Hepatic resection for metastatic melanoma Hameed et al.
Table 2
Characteristics of hepatic metastases and extent of resection
References Caralt et al. [11] Chua et al. [12] De Ridder et al. [13] Frenkel et al. [14] Groeschl et al. [15] Herman et al. [16] Kim et al. [17] Kodjikian et al. [18] Mariani et al. [19] Marshall et al. [20] Pawlik et al. [21] Ripley et al. [22] Rose et al. [23] Total Range Median
5
Number of Median time to Median size of metastases resected development of liver resected in patients metastases metastases (months) 1 >1 (cm) 7a
7a
49
9
4
62c
18
14
9
e
49.1
37
22
NR
NR
NR
NR
4
6
NR
25 (1–2)
2.7 NR 2)
0–5
> 15 ( > 55.6)
27 (100)
NR
NR
NR
14 (50)
NR
77 (30.2)
76 (29.8)
179 (70.2)
NR
NR
12 (100)
0
NR
NR
NR
37 (92.5)l
3 (7.5)m
NR
NR
8 (20)n
NR
NR
NR
29
h
68
c
25
230
18h
NR
NR
63
24j
16j
17o
15
20
18
p
NR
15 (62.5)
q
–
–
–
–
–
–
–
– –
17.1–92.3% 59.7%
29.8–100% 92.5%
0–70.2% 7.5%
5.1–16.7% 9.8%
73.9–100% 89.6%
0–68.6% 14.9%
58 – 37–63 53.6
NR
129 (28.4%) – –
6
i
325 (71.6%) – –
4.2 NR
24 (60)k 6 (17.1)
21 (87.5)
14 (50)
13 (5.1)
NR n
3 (12.5)
4 (16.7)
18 (75)
24 (68.6) n
12 (50)
NR, not recorded. Ocular primary – 1: 1; >1: 5; cutaneous primary – 1: 6; >1: 2. For total data set of 23 patients. c Time to resection, and not diagnosis, of liver metastases. d Resection status unknown in two patients. e Six or more hepatic metastases resected in 12 patients. f Major hepatectomy here defined as resection of four or more liver segments (compared with three in the other studies). g This data were only available for 29 out of the 31 patients. h Not exclusive to patients undergoing hepatic resection. i Two to four metastases (51 patients); more than four metastases (179 patients). j Ocular primary – 1: 8; >1: 8; cutaneous primary – 1: 16; >1: 8. k Ocular primary (10 patients); cutaneous primary (14 patients). l Three patients unknown. m Ocular primary (14 R0 resections); cutaneous primary (23 R0 resections). n All of these patients had cutaneous primaries. o Time to diagnosis of metastases at any site. p Two metastases (four patients); more than two metastases (two patients). q Excluding Groeschl et al. [15], Kim et al. [17], Kodjikian et al. [18], and Marshall et al. [20]. a
b
be spared. The absence of extrahepatic disease was also a common selection criterion among the various studies [11,14,16,18]. Significantly, both Chua et al. [12] and Rose et al. [23] did not exclude all patients with extrahepatic disease, with many patients undergoing additional extrahepatic metastasectomies, including from the brain, gastrointestinal tract, diaphragm and local and distant lymph nodes. Unsurprisingly, many studies explicitly mentioned multidisciplinary team involvement in patient selection [12,15,18–20,22], which is absolutely essential considering there is still great uncertainty about the approach to disseminated melanoma. Some more specific selection criteria included the absence of disease progression in patients who received neoadjuvant systemic therapies, [15] and in Herman et al. [16] hepa-
tectomy was only attempted if hepatic metastases occurred more than or equal to 24 months after resection of the primary melanoma. There is little clear data regarding the timing of surgery in patients operatively managed for melanoma liver metastases. Reddy et al. [30] did, however, suggest that delaying hepatic resections by more than 6 months postdiagnosis of metastatic disease may help select out patients with aggressive disease who would not benefit from surgery. Prognostic factors and differences between studies
Prognostic factors from multiple studies in this review indicate that R0 resection is associated with increased
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6 Melanoma Research 2014, Vol 24 No 1
Table 3
Additional procedures and nonsurgical therapies used
References
Neoadjuvant therapy
Adjuvant therapy (%) (type)
Caralt et al. [11] Chua et al. [12]
0
4 (30.8) (C)
NR
0
De Ridder et al. [13]
NR
NR
Frenkel et al. [14] Groeschl et al. [15] Herman et al. [16] Kim et al. [17] Kodjikian et al. [18] Mariani et al. [19]
NR 14 (45.2) (C) NR NR 0 0
Marshall et al. [20] Pawlik et al. [21]
NR 13 (32.5) (C/HAE/BC/BI/IAC)c
NR 8 (25.8) (C) 0 26 (96.3) (NS) 25 (89.3) (IAC)a 149 (58.4) (IAC/C) NR 8 (20) (C/IAC/BI/VT)c
Ripley et al. [22]
34 (97.1) (C/BI/VT/GT)
Rose et al. [23]
NR
17 (48.6) (C/BI/GT)d NR
0–97.1% 16.3%
0–96.3% 30.8%
Range Median
Other procedures undertaken Axillary LN resection in 1 patient; adrenal metastasis resection in 1 patient Total omentectomy in 1 patient; splenectomy in 1 patient; adrenalectomy in 1 patient; porta hepatis clearance in 1 patient; craniotomy with radiosurgery in 1 patient Regional LN dissection for metastases in 16 patients (inguinal LNs in 5 patients, axillary LNs in 10 patients, cervical LNs in 1 patient) NR NR Nil NR Intra-arterial catheter insertion in 25 patients Intra-arterial catheter insertion in 154 patientsb RFA in 8 patients NR RFA in 3 patients (all with primary ocular disease); regional LN dissection in 12 patients (all with primary cutaneous disease); intra-arterial catheter placement (exact number not specified) Pulmonary metastasectomy in 1 patient (of the 11 patients who had NED postsurgery) Diaphragmatic metastasis resection in 1 patient; soft tissue metastasis resection in 2 patients; local/regional LN dissection in 4 patients (mesenteric LN in 2 patients, periportal LN in 1 patient, and unspecified LN in 1 patient); gastrointestinal metastasis resection in 1 patient – –
BC, biochemotherapy; BI, bioimmunotherapy; C, systemic chemotherapy; GT, gene therapy; HAE, hepatic artery embolization; IAC, intra-arterial chemotherapy; LN, lymph node(s); NED, no evidence of disease; NR, not recorded; NS, type of therapy not specified; RFA, radiofrequency ablation; VT, vaccine therapy. a This includes 11 out of the 14 patients who had R0 resections. b Not all of these patients received IAC. c Ocular primary (three patients had neoadjuvant and adjuvant therapy, each); cutaneous primary (10 patients had neoadjuvant therapy, five had adjuvant therapy). d All 17 of these patients had tumour-infiltrating lymphocyte therapy post-chemotherapy.
survival or disease-free survival compared with R1/2 resections or nonoperative management [13,14,19,23]. In most of these studies, limited hepatic disease also correlated with improved survival [12,14,18,19,22]. Kodjikian et al. [18] and Mariani et al. [19] set their respective ‘cut-offs’ for resection as less than or equal to 10 or four liver metastases, respectively. Complete resection afforded by limited hepatic disease at least partially explains these results. Alternatively, patients with limited disease may also have less aggressive or more indolent disease and thus would survive longer regardless of their primary mode of treatment. Most patients undergoing resection in the studies by Ripley et al. [22] and Rose et al. [23] tended to have no more than one to two hepatic metastases. Furthermore, Rose et al. [23] observed that operative patients in their series had a median disease-free interval (to development of liver metastases) of 58 months, compared with only 35 months for nonoperative patients. Accordingly, Adam et al. [31] showed in a study of 1452 patients with NCNE liver metastases, out of whom B10% had primary melanoma, that patients with disease-free intervals less than 12 months and patients requiring a major hepatectomy had significantly worse outcomes postresection. Similar conclusions were drawn by De Ridder et al. [13]. Operative morbidity and mortality
In general, hepatic resection for malignant melanoma is a safe operation. The median mortality and morbidity for
surgical patients in this review were 0 and 10%, respectively (Table 4), with an overall mortality of 2.6%. From this systematic review, we conclude that operative morbidity and mortality are low enough for surgery to be considered, especially in those patients in whom there may be a survival advantage upon resection of melanoma liver metastases. Our data compare favourably with those from other studies of hepatic resection. Belghiti et al. [32] found an overall operative mortality of 4.4% for hepatic resections for a variety of indications, whereas the corresponding value in a study of close to 2000 patients was 3.1% [33]. Systemic therapies: chemotherapy, biological and targeted therapies
Systemic and/or nonsurgical therapies in metastatic melanoma can either be utilized as the sole form of treatment, or as adjuvant or neoadjuvant therapy that complements surgical resection. In this systematic review, the use of nonsurgical therapies is outlined in Table 3. In general, adjuvant therapies were used more commonly than neoadjuvant options in a highly heterogeneous manner with varying levels of success. Systemic therapies are still the mainstay of treatment in metastatic melanoma. Radiotherapy is not commonly used because of a generally poor response in melanoma [34]. In contrast, chemotherapy provides better antitumour efficacy in stage IV melanoma. It can either be given systemically or locally, such as intra-arterial
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Hepatic resection for metastatic melanoma Hameed et al.
Table 4
7
Study outcomes
References
Median follow-up (months)
Caralt et al. [11] Chua et al. [12] De Ridder et al. [13] Frenkel et al. [14] Groeschl et al. [15] Herman et al. [16] Kim et al. [17] Kodjikian et al. [18] Mariani et al. [19] Marshall et al. [20] Pawlik et al. [21] Ripley et al. [22] Rose et al. [23] Range Median
26.6
Perioperative Perioperative mortality (%) morbidity (%) 1 (7.1)
Median overall survival (months)
4 (28.6)
1-year overall survival (%)
26.3
5-year overall survival (%)
Median disease-free survival (months)
Disease recurrence (%)
Liver recurrence as a proportion of disease recurrence (%)
77
49
NR
19.9
12 (92.3)
50
b
b
NR
b
11 (84.6)
54.5
24 (96)
NR
a
0
0
21
0
5 (15.6)
29
63
22
3
11
NR
0
0
23
78
34
29
NR
10 (76.9)
90
39
57
36
36
12
21 (72.4)
42.9
9
c
NR
b
3-year overall survival (%)
21
c
60
40
14
35
NR
25.4 (mean) NR
0
1 (10)
22
NR
NR
NR
15
5 (50)
60
1 (3.7)
NR
9.5
39
11.5
4
NR
NR
NR
NR
0
0
20.5
89
24
24
NR
NR
NR
NR
8 (3.1)
42 (16.4)
14
56.7
10.2
7
NR
NR
NR
NR
NR
NR
24
100
NR
NR
NR
11 (91.7)
NR
22.6
2 (5.0)
NR
28.2
85
37.6
10.9
8.3
30 (75)
40
NR
1 (2.9)d
NR
36
70
53
53
14e
4 (36.4)
NR
NR
0
NR
28
70
41
29
12
13 (72.2)
46.2
9–35 24
0–7.1% 0
0–28.6% 10%
9.5–39 24
3–53% 24%
8.3–19.9 13
36.4–96% 74.8%
40–90% 50%
39–100% 10.2–53% 70% 36%
NR, not recorded. a Includes all patients in series. b Includes two patients with gastrointestinal tract but no liver metastases. c Mortality and morbidity for whole data set were 1.9 and 20%, respectively. d By intention-to-treat (related to interleukin-2 treatment). e No evidence of disease group.
Comparison of survivals of operative and nonoperative patients, patients with primary ocular or cutaneous disease, and R0 resections with R1/2 resections
Table 5
Median overall survival (months)
Operative patients (overall figures) Nonoperative patients R0 resection R1/2 resection Ocular primary Cutaneous primary
1-year overall survival (%)
3-year overall survival (%)
5-year overall survival (%)
Range
Median
Range
Median
Range
Median
Range
Median
9.5–39
24
39–100
70
10.2–53
36
3–53
24
4–11 [24–29]
7.4 [24–29]
3–8 [25,26]
5.5 [25,26]
0 [26]
0 [26]
34–40 [25,26,28] 35 [25,26,28]
9.5–65.6 [11,23,25–30] 25 [11,23,25–30] 81.6–100 [25–28] 96 [25–28] 11.7–29 [25–27,29,30] 16 [25–27,29,30] 46.4 [25–27] 78 [25–27] 24.6–66 [12,13,24,30] 31.7 [12,13,24,30] 83–100 [12,13] 91.5 [12,13] 11–26.9 [12,13,24,30] 24.3 [12,13,24,30] 75–80 [12,13] 77.5 [12,13]
18.4–61 [25–27] 48 [25–27] 48–51 [25,26] 49.5 [25,26] –a 0–14 [25–27] 6.7 [25–27] –a 43–56 [12,13] 49.5 [12,13] –b –b 34–60 [12,13] 47 [12,13] –b –b
a
Results available from only one study, Kodjikian et al. [18], in which 5-year survival was 0% in R1/2 resections. Results available from only one study, Pawlik et al. [21], in which 5-year survival for ocular disease was 20.5%, compared with 0% for cutaneous disease.
b
chemotherapy to the liver. Single-agent therapies most commonly include alkylating agents such as dacarbazine or temozolomide, or platinum compounds such as cisplatin, among others [34,35]. Dacarbazine is largely considered the chemotherapeutic agent of choice [36]. In one meta-analysis, dacarbazine monotherapy was found to produce only 15.3% response rates, with close to three-
quarters of these partial responses [37]. Combination therapies such as the Dartmouth regimen (dacarbazine with cisplatin, carmustine and tamoxifen) may also be used; this initially showed response rates close to 55%, with an overall survival of 13–14 months [38]. However, a later phase III trial showed only an 18.5% response rate with an overall survival of 7.7 months [39].
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8 Melanoma Research 2014, Vol 24 No 1
There is still no clear consensus as to the most efficacious approach when systemic therapies are employed secondary to surgery. Interestingly, Pawlik et al. [21] found that adjuvant systemic therapy in cutaneous melanoma patients significantly increased survival to 28.6 months compared with 4.9 months for patients having hepatic resections alone. The chemotherapeutic regimens used were heterogeneous in nature, and thus it is difficult to draw clear conclusions from this finding. Furthermore, Adam et al. [31] found increased survival in patients responsive to neoadjuvant chemotherapy. In contrast, Kodjikian et al. [18] found that the group treated with palliative resection and adjuvant intra-arterial chemotherapy did not have improved survival compared with the group undergoing systemic therapy or best supportive care without surgery.
studies exploring biological agents are still lower compared with those reported for surgical resection in this review. Perhaps even more pertinently, pivotal studies such as those by Hodi et al. [44] and Chapman et al. [46] only included patients with unresectable melanoma, and thus patient subsets in these studies cannot be directly compared with most of the patients undergoing hepatic resection for melanoma. The use of such targeted approaches in conjunction with surgery has not yet been explored.
Interestingly, systemic therapies may be used to select surgical candidates in hepatic metastatic melanoma. Groeschl et al. [15] excluded from hepatectomy patients who showed disease progression after receiving neoadjuvant therapy. O’Rourke et al. [40] similarly emphasized the emerging importance of neoadjuvant chemotherapy in selecting patients for potentially curative resections, including those with extrahepatic disease who may benefit from palliative hepatectomies.
Table 1 shows that the majority of patients in this systematic review had primary ocular melanoma as opposed to cutaneous primaries. This is a reflection of the different biological behaviours displayed by both types of primary. In comparison with primary cutaneous disease, ocular melanoma patients more commonly have liver metastases; the liver tends to be the first metastatic site in these patients, and may be the only metastatic deposit in 60–80% of cases [2,11,19]. Although multiple liver metastases are more common in ocular melanoma, the disease-free interval to development of liver metastases tends to be longer [11]. As such, it stands to reason that hepatic resection is more commonly undertaken in ocular melanoma metastases. Although our study shows possibly improved survivals after resection of ocular metastatic disease (Table 5), such a conclusion is difficult to make considering the heterogeneous patient populations and high proportions of noncurative resections in ocular melanoma liver metastases (Table 2).
More recently, biological/immune therapies have become prominent in the treatment of metastatic melanoma, including interleukin-2 (IL-2) and monoclonal antibodies [41]. IL-2 has been the most common such therapy used in the recent past [42]. A systematic review found an overall survival of 11.4 months on IL-2 treatment in metastatic melanoma [43]. IL-2 has also been combined with cisplatin, vinblastine, dacarbazine and interferon-a in inoperable stage four melanoma patients with response rates of up to 60% [41]. The monoclocal antibody ipilimumab is recommended for use in metastatic melanoma if systemic therapies are used as the primary treatment modality [35]. An overall survival of 10.1 months has been reported in patients with unresectable melanoma; however, patients with ocular melanoma were excluded in this study [44]. The addition of dacarbazine to ipilimumab may increase overall survival to 11.2 months [45]. Vemurafenib is another biological agent, and is recommended for use in metastatic melanoma patients with the BRAF V600E mutation; it shows a response rate of up to 48%; however, very few of these are complete responses [35,46]. A more novel approach was investigated by Ripley et al. [22] whereby tumour-infiltrating lymphocytes were harvested from resected disease and given to the patients postoperatively; 40% of patients who received this therapy showed a response, including 13% with complete responses. Some important points should be drawn from the above studies. Importantly, reported overall survivals in the
Overall, it is still very difficult to ascertain the best treatment regimen with respect to systemic therapy and/ or surgery in stage IV melanoma. Decisions must be individualized to each patient and, in this regard, a multidisciplinary team decision is absolutely essential. Resection in ocular compared with cutaneous disease
Bias and study designs
Certain biases cannot be ignored when analysing the results of this systematic review. Most of the studies showed significant selection bias in that candidates undergoing hepatic resection tended to have more limited disease, which may indicate less aggressive tumour biology and thereby contribute to higher survivals. An element of lead and length-time bias was also evident in some studies, especially those using aggressive screening strategies. Furthermore, consideration must be given to the retrospective nature of the majority of studies here, and the fact that they were often conducted over long time periods (range 1971–2010) with significant changes in surgical techniques. Conclusion
In summary, hepatic resection in highly selected cases appears to offer a survival advantage over systemic chemotherapy alone. It has an acceptable morbidity and low operative mortality in the published series reviewed
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Hepatic resection for metastatic melanoma Hameed et al.
and should be considered as a treatment option in multidisciplinary discussions of patients with metastatic melanoma to the liver. Further studies are required that directly compare surgical and nonsurgical therapies in a uniform fashion.
Acknowledgements
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Conflicts of interest
There are no conflicts of interest.
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Appendix Search keywords Literature search (Embase 1974 to present and Medline 1946 to present with daily update) (search current as of 3 March 2013): [melanoma] AND [liver OR hepatic] AND [metastasis OR metastases] AND [hepatectomy OR (liver resection) OR (hepatic resection) OR (liver surgery) OR (hepatic surgery) OR surgery OR metastasectomy OR metastastectomy]. Additional search (Embase 1974 to present and Medline 1946 to present with daily update) (search current as of 3 March 2013):
[non-colorectal OR noncolorectal OR non-neuroendocrine OR nonneuroendocrine] AND [liver OR hepatic] AND [hepatectomy OR (liver resection) OR (hepatic resection) OR (liver surgery) OR (hepatic surgery) OR surgery OR metastasectomy OR metastastectomy].
Study selection Studies were screened by reviewing their titles and abstracts. If abstracts were not available, a full-text version of the article was sought and then reviewed. If any exclusion criterion was evident from the abstract, the study was excluded, for example, series with fewer than 10 melanoma patients, case reports and so on were excluded if evident from the abstract. In cases of equivocal study titles or abstracts, the full study was read with inclusion and exclusion criteria for our analysis in mind. When the same patient case series was utilized in more than one article, the publication containing the most complete data set was selected. Articles included in the final analysis were independently assessed by two reviewers.
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Hepatic resection for metastatic melanoma: a systematic review Ahmer M. Hameeda, E-Ern I. Nga, Emma Johnstona,b, Michael J. Hollandsa,b, Arthur J. Richardsona,b, Henry C. Pleassa,b and Vincent W.T. Lama,b Melanoma metastatic to the liver has a very poor prognosis, and has traditionally been treated using systemic chemotherapy with limited efficacy. Surgery is increasingly being explored as a therapeutic option for melanoma liver metastases, with varying levels of success. A systematic review was undertaken to explore the short-term and long-term outcomes associated with hepatectomy for melanoma metastases, in addition to identifying prognostic factors favouring increased survival. All eligible studies were identified through an electronic search of Medline and Embase (January 1990–March 2013). Each study was independently analysed by two reviewers, with relevant data extracted and tabulated according to predetermined criteria. Thirteen studies were selected that fulfilled the selection criteria, with a total of 551 patients undergoing hepatic resection for melanoma metastases. Metastases to the liver occurred at a median interval of 54 months. The median perioperative morbidity and mortality were 10% (range 0–28.6%) and 0% (range 0–7.1%), respectively. The median overall survival for operative patients was 24 months, with median survival being greater in the R0 resection group (25 months; range
9.5–65.6 months) compared with the R1/2 resection group (16 months; range 11.7–29 months). Overall median 1-, 3- and 5-year survival rates were 70% (range 39–100%), 36% (range 10.2–53%) and 24% (range 3–53%), respectively. Positive prognostic factors may include single hepatic metastases, a longer time to development of hepatic metastases and R0 resection. Hepatic resection for metastatic melanoma might confer a distinct survival benefit in a select group of patients, although disease c 2014 recurrence is the norm. Melanoma Res 24:1–10 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Introduction
considered inappropriate for surgery because of the lack of survival benefit with this approach. A few groups have recently reported hepatic resections in malignant melanoma with long-term survival rates [7–9].
Patients who develop American Joint Committee on Cancer (AJCC) stage IV melanoma have a very poor prognosis, with a median survival of 7.5 months and an estimated 5-year survival of 6% [1]. The liver is the most common site of metastases in ocular melanoma, with 40% of patients developing hepatic metastases [2], whereas in cutaneous melanoma, only 15–20% will develop liver metastases [2,3]. To date, the mainstay of treatment for malignant melanoma has been systemic therapy. However, even the most active chemotherapy agent, dacarbazine, has only demonstrated a complete response in 3–5% of patients treated, with a median duration of response of just 4–6 months [4]. More recently, biologic therapy has shown some promise with a complete response rate of 7%, but a significant toxicity and side effect profile has limited its use [5]. The role of surgical resection is therefore coming into favour because of the fact that more than 80% of patients with metastatic melanoma initially have only one site of metastasis, of whom 10–20% have a solitary liver metastasis [1,6]. Traditionally, these patients have been c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0960-8931
Melanoma Research 2014, 24:1–10 Keywords: liver metastasis, melanoma, surgical resection a Department of Surgery, Westmead Hospital and bDiscipline of Surgery, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
Correspondence to Ahmer M. Hameed, MBBS (Hons), BSc (Med) (Hons), Department of Surgery, Westmead Hospital, University of Sydney, Cnr Hawkesbury and Darcy Rd, Westmead, Sydney, NSW 2145, Australia E-mail: [email protected] Received 15 July 2013 Accepted 24 September 2013
The objectives of our study are to determine the long-term outcome of hepatic resection in metastatic melanoma to the liver and identify prognostic factors associated with long-term survival.
Methods Eligibility criteria
For studies to be included in this systematic review, articles had to be published after 1990, and have more than 10 patients undergoing hepatic resection. Both Englishlanguage and non-English-language articles were reviewed. Case reports, conference abstracts or proceedings, and articles deemed to have insufficient data for the purposes of this review were excluded. Information sources
The Medline (1946 to March 2013) and Embase (1974 to March 2013) databases were searched using the keywords melanoma, hepatic metastases and surgical resection DOI: 10.1097/CMR.0000000000000032
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2 Melanoma Research 2014, Vol 24 No 1
(Appendix). Reference lists from all relevant articles were reviewed manually for additional articles applicable to the selection criteria. Data collection process
Data were extracted from each study using a standardized table. Information was collected with reference to: study author(s), study period, study centre(s), total number of melanoma patients in series, total number of melanoma patients undergoing hepatic resection, number of primary uveal and cutaneous melanomas, number of hepatic metastases, synchronous and metachronous disease, time between melanoma diagnosis and liver metastasis detection, type(s) of neoadjuvant and adjuvant therapy, presence of extrahepatic disease, margin status, number of major hepatectomies (resection of three or more hepatic segments), morbidity/ mortality, other procedure(s), median follow-up, median overall survival, median disease-free survival, 1-, 3- and 5-year overall survival and disease recurrence (in patients with no evidence of disease posthepatic resection). Synthesis of results
Qualitative measures were combined from each applicable study through the tabulation of all data items of interest. A formal meta-analysis was precluded by the absence of homogeneity between studies and an adequate control group within each study. PRISMA guidelines were adhered to in the completion of this systematic review [10].
Results Study selection and search strategy are described in Fig. 1. Thirteen studies fulfilled the selection criteria and underwent collective analysis. Study demographics are outlined in Table 1. The majority of studies were retrospective in nature. A total of 551 patients underwent hepatic resection for melanoma metastases, out of whom 113 had primary cutaneous melanoma and 370 had primary ocular melanoma; the primary source was unknown in 68 patients. We found that a median of 29.4% of patients underwent surgical exploration without subsequent hepatic resection. In studies that outlined the number of melanoma patients undergoing resection as a proportion of the total number of patients with melanoma liver metastases, a median of 22.7% of patients underwent surgical therapy (range 1.4–56.5%). Hepatic metastases and resection extent
Table 2 shows characteristics related to the hepatic metastases and how they were resected. The median time to the development of liver metastases was 53.6 months. Synchronous disease was present in a median of 9.8% of patients, with most patients undergoing hepatectomy having metachronous metastases. A single metastasis was resected in 28.4% of patients, whereas 71.6% of patients had more than one metastasis removed.
A significant proportion of patients underwent a major hepatectomy (median 59.7%). Importantly, R0 resection was achieved in a median of 92.5% of patients (range 29.8–100%), indicating that the vast majority of surgeries were approached with curative intent. Interestingly, a significant minority of patients also had resection of extrahepatic disease (median 14.9%). Further procedures and adjuvant and neoadjuvant therapies
The use of adjuvant and neoadjuvant therapies in addition to metastasectomy is outlined in Table 3. It can be seen that only a minority of patients had any form of neoadjuvant therapy (median 16.3%), whereas a marginally greater proportion were given adjuvant treatments (median 30.8%). There was great disparity in the specific form of treatment used, and thus it is difficult to analyse the therapies individually. The majority of patients within this subset received chemotherapy, either systemically or locally through an intra-arterial catheter. Other neoadjuvant and adjuvant treatments used included bioimmunotherapy, vaccine therapy, gene therapy and hepatic artery embolization. Additional procedures, such as resection of extrahepatic disease and radiofrequency ablation, among others, were also used as outlined in Table 3. Primary and secondary outcomes
Table 4 shows pertinent study outcome data. Hepatic resection in malignant melanoma was proven to be safe, with an overall mortality rate of 2.6% (median 0%); median morbidity was also acceptably low at 10%. After a median follow-up of 24 months, the median overall survival was 24 months (range 9.5–39 months). Median overall survival 1-year posthepatectomy was a respectable 70%, with survival declining to 36 and 24% after 3 and 5 years, respectively. Disease recurred in 74.8% of patients; the liver was the site of recurrence in 50% of patients. The median disease-free survival was 13 months (range 8.3–19.9 months). Comparative data
Although not directly comparable, series that reported survival data for both operative and nonoperative patients found median overall survivals of 24 and 7.4 months, respectively (Table 5). The extent of resection seemed to positively influence survival, with patients undergoing R0 resections having a median overall survival of 25 months compared with 16 months for palliative resections. Surgery for hepatic metastases from ocular melanoma primaries yielded a survival of 31.7 months, which was greater than that for primary cutaneous melanoma (median survival 24.3 months). This data are further supported by 1-, 3- and 5-year overall-survival data (Table 5).
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Hepatic resection for metastatic melanoma Hameed et al.
3
Identification
Fig. 1
Records identified through database searching (n = 967)
Additional records identified through other sources (n = 2)∗
Eligibility
Screening
189 duplicates removed
Records excluded (n = 755)
Records screened by abstract ± title (n = 780)
• Lack of relevance (n = 755)
Total full-text articles assessed for eligibility (n = 25)
Full-text articles excluded, with reasons (n = 12)
Included
Studies included in qualitative synthesis (n = 13)
Studies included in quantitative synthesis (meta-analysis) (n = variable)†
• Overlap series (n = 3) • < 10 patients undergoing potentially curative resection (n = 2) • Insufficient data + overlap series (n = 2) • Insufficient data (n = 5)
Study selection and search strategy. *From additional search using Embase and Medline. wDepending on parameter being analysed and how many studies it was reported in (see tables for results).
Discussion Summary of evidence
This systematic review demonstrated that hepatic resection of melanoma metastases can be conducted safely while conferring significant survival advantage in a highly selected group of patients. Melanoma liver metastases have traditionally been managed nonoperatively, and overall survival tends to be very poor. In a combined analysis of multiple trials, Manola et al. [24] found an overall survival of 6.4 months in patients with metastatic melanoma; this was reduced to 3.9 months in those patients with hepatic metastases. A further large pooled database analysis by the AJCC showed a 1-year survival of B40% in patients with visceral, nonpulmonary melanoma involvement [25]. Hepatectomy in patients with colorectal cancer spread is well established as it is hypothesized that liver involvement reflects locoregional spread of disease through the portal circulation [26,27]. In contrast, melanoma liver metastases indicate systemic disease involvement, and as such hepatic resection in such
patients is much more controversial [26,27]. This systematic review provides some encouragement that melanoma liver metastasis resection can improve patient survival, with a 1-year survival of 70% and median overall survival of 24 months. In their meta-analysis of survival postmetastasectomy for colorectal cancer liver metastases, Kanas et al. [28] established a median 5-year survival of 38% and median overall survival of B43 months. A systematic review by Lam et al. [29] suggested that median survival after second hepatectomy for colorectal liver metastases was still as high as 35 months. Reddy et al. [30] directly compared survival for hepatectomy in noncolorectal nonneuroendocrine (NCNE) liver metastases, out of which melanoma was among the most common, with colorectal liver metastases. Median overall survival after resection of NCNE metastases was 44 months, which was equal to that for colorectal liver metastases, whereas survival in the subset of melanoma patients was 41 months [30]. Although overall survival from our review is not as high as that seen in studies on colorectal cancer, it can be seen
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4 Melanoma Research 2014, Vol 24 No 1
Table 1
Basic demographic characteristics of hepatic resection for melanoma metastases studies
References Caralt et al. [11] Chua et al. [12] De Ridder et al. [13] Frenkel et al. [14] Groeschl et al. [15]
Country(s) Spain
Hospital(s) or institution(s)
Study period
Type of analysis
Total number with hepatic resection (%)
NR
14 (NA)
Australia The Netherlands
Hospital val d’Hebron and Hospital Clinic, Barcelona St George Hospital, Sydney Nationwide, The Netherlands
2000–2009 Retrospective 1994–2010 Retrospective
Israel
Hadassah Medical Center, Jerusalem
1988–2007 Retrospective
USA
1990–2009 Retrospective
NR
1999–2005 Retrospective
1996–2003 Retrospective
Herman et al. [16]
Brazil
Kim et al. [17]
USA
Kodjikian et al. [18] Mariani et al. [19] Marshall et al. [20] Pawlik et al. [21]
France
Duke University Medical Center, Durham; John Hopkins Hospital, Baltimore; M. D. Anderson Cancer Center, Houston; University of Pittsburgh Medical Center, Pittsburgh A. C. Camargo Cancer Hospital and University of Sao Paulo Medical School, Sao Paulo John Wayne Cancer Institute, Santa Monica Croix-Rousse Hospital, Lyon
France UK USA, France and Italy
Ripley et al. [22] USA Rose et al. [23] USA and Australia
1994–2007 Retrospective
Total number of melanoma patients with liver metastases
Total number with ocular and cutaneous disease
Patients explored without resection (%) Cutaneous Ocular 8
6
NR
13 (56.5) 32 (NA)
8 16
b
3 12c
0 17 (34.7)
30 (40.5)
0
30
4 (11.8)
31 (NA)
NR
NR
NR
367
10 (2.7)
5
5
8 (44.4)
NR
27 (NA)
23
2d
NR
a
74
23 NR
1983–1996 Retrospective
63
28 (44.4)
0
28
0
Institut Curie, Paris
1991–2007 Retrospective
798
255 (32.0)
0
255
NR
Clatterbridge Cancer Centre, Bebington M. D. Anderson Cancer Center, Houston; Duke University Medical Center, Durham; Gustave Roussy Institute, Villejuif; Institute for Research and the Cure of Cancer, Candiolo National Cancer Institute, Bethesda John Wayne Cancer Institute, Santa Monica; Sydney Melanoma Unit, Sydney
2000–2010 Prospective
90
12 (13.3)
0
12
26 (68.4)
1988–2004 Retrospective
NR
40 (NA)
24
16
NR
1980–2008 Retrospective 1971–1999 Retrospective
539 1750
35 (6.5)e 24 (1.4)
29 NR
1f NR
NA 10 (29.4)
3704 23–1750 229
551 (14.9) 1.4–56.5% 22.7%
113 – –
370 – –
– 0–68.4% 29.4%
Total Range Median
– – –
– – –
NA, not applicable/unable to calculate; NR, not recorded. a Patients with liver and/or gastrointestinal tract metastases; exact number with liver metastases not specified. b Primary site unknown in two patients. c Primary site unknown in four patients. d Two patients had primaries in the gastrointestinal/genitourinary tracts. e Main purpose of hepatic resection here was tumour collection for tumour-infiltrating lymphocytes, not complete tumour resection. f Primary site unknown in five patients.
that melanoma hepatic resection still has the potential to provide significant survival advantage.
to be highly selective when surgery is considered as an option.
Disease recurrence posthepatic resection is unfortunately the norm in malignant melanoma, with a median diseasefree survival of 13 months and B75% of patients developing recurrence over 1–3 years (Table 4). In this sense hepatectomy for melanoma is rarely curative, but still seems to prolong survival in suitable cases.
In general, surgical selection criteria in the above studies were nonspecific and relied on the surgeon’s assessment of potential for curative resection [11–21]. The potential for curative surgery was largely ascertained by preoperative imaging and intraoperative evaluation, which in some cases included intraoperative liver ultrasound [16,18, 20,23]. Only Groeschl et al. [15] defined resectable lesions as those in which sufficient venous, arterial and biliary flow could be maintained and more than or equal to 20% of liver parenchyma would be preserved posthepatectomy. Marshall et al. [20] considered resection in the event of four or fewer hepatic metastases, while Kodjikian et al. [18] attempted resection when more than or equal to 30–40% of liver parenchyma could
Surgical selection criteria
In series where the total number of hepatic resections was reported as a proportion of total patients with hepatic metastases, the median rate of resection was only 22.7% (Table 1). In some of the larger studies, such as that by Rose et al. [23], only 1.4% of the patient population underwent hepatectomy. This clearly indicates the need
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Hepatic resection for metastatic melanoma Hameed et al.
Table 2
Characteristics of hepatic metastases and extent of resection
References Caralt et al. [11] Chua et al. [12] De Ridder et al. [13] Frenkel et al. [14] Groeschl et al. [15] Herman et al. [16] Kim et al. [17] Kodjikian et al. [18] Mariani et al. [19] Marshall et al. [20] Pawlik et al. [21] Ripley et al. [22] Rose et al. [23] Total Range Median
5
Number of Median time to Median size of metastases resected development of liver resected in patients metastases metastases (months) 1 >1 (cm) 7a
7a
49
9
4
62c
18
14
9
e
49.1
37
22
NR
NR
NR
NR
4
6
NR
25 (1–2)
2.7 NR 2)
0–5
> 15 ( > 55.6)
27 (100)
NR
NR
NR
14 (50)
NR
77 (30.2)
76 (29.8)
179 (70.2)
NR
NR
12 (100)
0
NR
NR
NR
37 (92.5)l
3 (7.5)m
NR
NR
8 (20)n
NR
NR
NR
29
h
68
c
25
230
18h
NR
NR
63
24j
16j
17o
15
20
18
p
NR
15 (62.5)
q
–
–
–
–
–
–
–
– –
17.1–92.3% 59.7%
29.8–100% 92.5%
0–70.2% 7.5%
5.1–16.7% 9.8%
73.9–100% 89.6%
0–68.6% 14.9%
58 – 37–63 53.6
NR
129 (28.4%) – –
6
i
325 (71.6%) – –
4.2 NR
24 (60)k 6 (17.1)
21 (87.5)
14 (50)
13 (5.1)
NR n
3 (12.5)
4 (16.7)
18 (75)
24 (68.6) n
12 (50)
NR, not recorded. Ocular primary – 1: 1; >1: 5; cutaneous primary – 1: 6; >1: 2. For total data set of 23 patients. c Time to resection, and not diagnosis, of liver metastases. d Resection status unknown in two patients. e Six or more hepatic metastases resected in 12 patients. f Major hepatectomy here defined as resection of four or more liver segments (compared with three in the other studies). g This data were only available for 29 out of the 31 patients. h Not exclusive to patients undergoing hepatic resection. i Two to four metastases (51 patients); more than four metastases (179 patients). j Ocular primary – 1: 8; >1: 8; cutaneous primary – 1: 16; >1: 8. k Ocular primary (10 patients); cutaneous primary (14 patients). l Three patients unknown. m Ocular primary (14 R0 resections); cutaneous primary (23 R0 resections). n All of these patients had cutaneous primaries. o Time to diagnosis of metastases at any site. p Two metastases (four patients); more than two metastases (two patients). q Excluding Groeschl et al. [15], Kim et al. [17], Kodjikian et al. [18], and Marshall et al. [20]. a
b
be spared. The absence of extrahepatic disease was also a common selection criterion among the various studies [11,14,16,18]. Significantly, both Chua et al. [12] and Rose et al. [23] did not exclude all patients with extrahepatic disease, with many patients undergoing additional extrahepatic metastasectomies, including from the brain, gastrointestinal tract, diaphragm and local and distant lymph nodes. Unsurprisingly, many studies explicitly mentioned multidisciplinary team involvement in patient selection [12,15,18–20,22], which is absolutely essential considering there is still great uncertainty about the approach to disseminated melanoma. Some more specific selection criteria included the absence of disease progression in patients who received neoadjuvant systemic therapies, [15] and in Herman et al. [16] hepa-
tectomy was only attempted if hepatic metastases occurred more than or equal to 24 months after resection of the primary melanoma. There is little clear data regarding the timing of surgery in patients operatively managed for melanoma liver metastases. Reddy et al. [30] did, however, suggest that delaying hepatic resections by more than 6 months postdiagnosis of metastatic disease may help select out patients with aggressive disease who would not benefit from surgery. Prognostic factors and differences between studies
Prognostic factors from multiple studies in this review indicate that R0 resection is associated with increased
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
6 Melanoma Research 2014, Vol 24 No 1
Table 3
Additional procedures and nonsurgical therapies used
References
Neoadjuvant therapy
Adjuvant therapy (%) (type)
Caralt et al. [11] Chua et al. [12]
0
4 (30.8) (C)
NR
0
De Ridder et al. [13]
NR
NR
Frenkel et al. [14] Groeschl et al. [15] Herman et al. [16] Kim et al. [17] Kodjikian et al. [18] Mariani et al. [19]
NR 14 (45.2) (C) NR NR 0 0
Marshall et al. [20] Pawlik et al. [21]
NR 13 (32.5) (C/HAE/BC/BI/IAC)c
NR 8 (25.8) (C) 0 26 (96.3) (NS) 25 (89.3) (IAC)a 149 (58.4) (IAC/C) NR 8 (20) (C/IAC/BI/VT)c
Ripley et al. [22]
34 (97.1) (C/BI/VT/GT)
Rose et al. [23]
NR
17 (48.6) (C/BI/GT)d NR
0–97.1% 16.3%
0–96.3% 30.8%
Range Median
Other procedures undertaken Axillary LN resection in 1 patient; adrenal metastasis resection in 1 patient Total omentectomy in 1 patient; splenectomy in 1 patient; adrenalectomy in 1 patient; porta hepatis clearance in 1 patient; craniotomy with radiosurgery in 1 patient Regional LN dissection for metastases in 16 patients (inguinal LNs in 5 patients, axillary LNs in 10 patients, cervical LNs in 1 patient) NR NR Nil NR Intra-arterial catheter insertion in 25 patients Intra-arterial catheter insertion in 154 patientsb RFA in 8 patients NR RFA in 3 patients (all with primary ocular disease); regional LN dissection in 12 patients (all with primary cutaneous disease); intra-arterial catheter placement (exact number not specified) Pulmonary metastasectomy in 1 patient (of the 11 patients who had NED postsurgery) Diaphragmatic metastasis resection in 1 patient; soft tissue metastasis resection in 2 patients; local/regional LN dissection in 4 patients (mesenteric LN in 2 patients, periportal LN in 1 patient, and unspecified LN in 1 patient); gastrointestinal metastasis resection in 1 patient – –
BC, biochemotherapy; BI, bioimmunotherapy; C, systemic chemotherapy; GT, gene therapy; HAE, hepatic artery embolization; IAC, intra-arterial chemotherapy; LN, lymph node(s); NED, no evidence of disease; NR, not recorded; NS, type of therapy not specified; RFA, radiofrequency ablation; VT, vaccine therapy. a This includes 11 out of the 14 patients who had R0 resections. b Not all of these patients received IAC. c Ocular primary (three patients had neoadjuvant and adjuvant therapy, each); cutaneous primary (10 patients had neoadjuvant therapy, five had adjuvant therapy). d All 17 of these patients had tumour-infiltrating lymphocyte therapy post-chemotherapy.
survival or disease-free survival compared with R1/2 resections or nonoperative management [13,14,19,23]. In most of these studies, limited hepatic disease also correlated with improved survival [12,14,18,19,22]. Kodjikian et al. [18] and Mariani et al. [19] set their respective ‘cut-offs’ for resection as less than or equal to 10 or four liver metastases, respectively. Complete resection afforded by limited hepatic disease at least partially explains these results. Alternatively, patients with limited disease may also have less aggressive or more indolent disease and thus would survive longer regardless of their primary mode of treatment. Most patients undergoing resection in the studies by Ripley et al. [22] and Rose et al. [23] tended to have no more than one to two hepatic metastases. Furthermore, Rose et al. [23] observed that operative patients in their series had a median disease-free interval (to development of liver metastases) of 58 months, compared with only 35 months for nonoperative patients. Accordingly, Adam et al. [31] showed in a study of 1452 patients with NCNE liver metastases, out of whom B10% had primary melanoma, that patients with disease-free intervals less than 12 months and patients requiring a major hepatectomy had significantly worse outcomes postresection. Similar conclusions were drawn by De Ridder et al. [13]. Operative morbidity and mortality
In general, hepatic resection for malignant melanoma is a safe operation. The median mortality and morbidity for
surgical patients in this review were 0 and 10%, respectively (Table 4), with an overall mortality of 2.6%. From this systematic review, we conclude that operative morbidity and mortality are low enough for surgery to be considered, especially in those patients in whom there may be a survival advantage upon resection of melanoma liver metastases. Our data compare favourably with those from other studies of hepatic resection. Belghiti et al. [32] found an overall operative mortality of 4.4% for hepatic resections for a variety of indications, whereas the corresponding value in a study of close to 2000 patients was 3.1% [33]. Systemic therapies: chemotherapy, biological and targeted therapies
Systemic and/or nonsurgical therapies in metastatic melanoma can either be utilized as the sole form of treatment, or as adjuvant or neoadjuvant therapy that complements surgical resection. In this systematic review, the use of nonsurgical therapies is outlined in Table 3. In general, adjuvant therapies were used more commonly than neoadjuvant options in a highly heterogeneous manner with varying levels of success. Systemic therapies are still the mainstay of treatment in metastatic melanoma. Radiotherapy is not commonly used because of a generally poor response in melanoma [34]. In contrast, chemotherapy provides better antitumour efficacy in stage IV melanoma. It can either be given systemically or locally, such as intra-arterial
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Hepatic resection for metastatic melanoma Hameed et al.
Table 4
7
Study outcomes
References
Median follow-up (months)
Caralt et al. [11] Chua et al. [12] De Ridder et al. [13] Frenkel et al. [14] Groeschl et al. [15] Herman et al. [16] Kim et al. [17] Kodjikian et al. [18] Mariani et al. [19] Marshall et al. [20] Pawlik et al. [21] Ripley et al. [22] Rose et al. [23] Range Median
26.6
Perioperative Perioperative mortality (%) morbidity (%) 1 (7.1)
Median overall survival (months)
4 (28.6)
1-year overall survival (%)
26.3
5-year overall survival (%)
Median disease-free survival (months)
Disease recurrence (%)
Liver recurrence as a proportion of disease recurrence (%)
77
49
NR
19.9
12 (92.3)
50
b
b
NR
b
11 (84.6)
54.5
24 (96)
NR
a
0
0
21
0
5 (15.6)
29
63
22
3
11
NR
0
0
23
78
34
29
NR
10 (76.9)
90
39
57
36
36
12
21 (72.4)
42.9
9
c
NR
b
3-year overall survival (%)
21
c
60
40
14
35
NR
25.4 (mean) NR
0
1 (10)
22
NR
NR
NR
15
5 (50)
60
1 (3.7)
NR
9.5
39
11.5
4
NR
NR
NR
NR
0
0
20.5
89
24
24
NR
NR
NR
NR
8 (3.1)
42 (16.4)
14
56.7
10.2
7
NR
NR
NR
NR
NR
NR
24
100
NR
NR
NR
11 (91.7)
NR
22.6
2 (5.0)
NR
28.2
85
37.6
10.9
8.3
30 (75)
40
NR
1 (2.9)d
NR
36
70
53
53
14e
4 (36.4)
NR
NR
0
NR
28
70
41
29
12
13 (72.2)
46.2
9–35 24
0–7.1% 0
0–28.6% 10%
9.5–39 24
3–53% 24%
8.3–19.9 13
36.4–96% 74.8%
40–90% 50%
39–100% 10.2–53% 70% 36%
NR, not recorded. a Includes all patients in series. b Includes two patients with gastrointestinal tract but no liver metastases. c Mortality and morbidity for whole data set were 1.9 and 20%, respectively. d By intention-to-treat (related to interleukin-2 treatment). e No evidence of disease group.
Comparison of survivals of operative and nonoperative patients, patients with primary ocular or cutaneous disease, and R0 resections with R1/2 resections
Table 5
Median overall survival (months)
Operative patients (overall figures) Nonoperative patients R0 resection R1/2 resection Ocular primary Cutaneous primary
1-year overall survival (%)
3-year overall survival (%)
5-year overall survival (%)
Range
Median
Range
Median
Range
Median
Range
Median
9.5–39
24
39–100
70
10.2–53
36
3–53
24
4–11 [24–29]
7.4 [24–29]
3–8 [25,26]
5.5 [25,26]
0 [26]
0 [26]
34–40 [25,26,28] 35 [25,26,28]
9.5–65.6 [11,23,25–30] 25 [11,23,25–30] 81.6–100 [25–28] 96 [25–28] 11.7–29 [25–27,29,30] 16 [25–27,29,30] 46.4 [25–27] 78 [25–27] 24.6–66 [12,13,24,30] 31.7 [12,13,24,30] 83–100 [12,13] 91.5 [12,13] 11–26.9 [12,13,24,30] 24.3 [12,13,24,30] 75–80 [12,13] 77.5 [12,13]
18.4–61 [25–27] 48 [25–27] 48–51 [25,26] 49.5 [25,26] –a 0–14 [25–27] 6.7 [25–27] –a 43–56 [12,13] 49.5 [12,13] –b –b 34–60 [12,13] 47 [12,13] –b –b
a
Results available from only one study, Kodjikian et al. [18], in which 5-year survival was 0% in R1/2 resections. Results available from only one study, Pawlik et al. [21], in which 5-year survival for ocular disease was 20.5%, compared with 0% for cutaneous disease.
b
chemotherapy to the liver. Single-agent therapies most commonly include alkylating agents such as dacarbazine or temozolomide, or platinum compounds such as cisplatin, among others [34,35]. Dacarbazine is largely considered the chemotherapeutic agent of choice [36]. In one meta-analysis, dacarbazine monotherapy was found to produce only 15.3% response rates, with close to three-
quarters of these partial responses [37]. Combination therapies such as the Dartmouth regimen (dacarbazine with cisplatin, carmustine and tamoxifen) may also be used; this initially showed response rates close to 55%, with an overall survival of 13–14 months [38]. However, a later phase III trial showed only an 18.5% response rate with an overall survival of 7.7 months [39].
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8 Melanoma Research 2014, Vol 24 No 1
There is still no clear consensus as to the most efficacious approach when systemic therapies are employed secondary to surgery. Interestingly, Pawlik et al. [21] found that adjuvant systemic therapy in cutaneous melanoma patients significantly increased survival to 28.6 months compared with 4.9 months for patients having hepatic resections alone. The chemotherapeutic regimens used were heterogeneous in nature, and thus it is difficult to draw clear conclusions from this finding. Furthermore, Adam et al. [31] found increased survival in patients responsive to neoadjuvant chemotherapy. In contrast, Kodjikian et al. [18] found that the group treated with palliative resection and adjuvant intra-arterial chemotherapy did not have improved survival compared with the group undergoing systemic therapy or best supportive care without surgery.
studies exploring biological agents are still lower compared with those reported for surgical resection in this review. Perhaps even more pertinently, pivotal studies such as those by Hodi et al. [44] and Chapman et al. [46] only included patients with unresectable melanoma, and thus patient subsets in these studies cannot be directly compared with most of the patients undergoing hepatic resection for melanoma. The use of such targeted approaches in conjunction with surgery has not yet been explored.
Interestingly, systemic therapies may be used to select surgical candidates in hepatic metastatic melanoma. Groeschl et al. [15] excluded from hepatectomy patients who showed disease progression after receiving neoadjuvant therapy. O’Rourke et al. [40] similarly emphasized the emerging importance of neoadjuvant chemotherapy in selecting patients for potentially curative resections, including those with extrahepatic disease who may benefit from palliative hepatectomies.
Table 1 shows that the majority of patients in this systematic review had primary ocular melanoma as opposed to cutaneous primaries. This is a reflection of the different biological behaviours displayed by both types of primary. In comparison with primary cutaneous disease, ocular melanoma patients more commonly have liver metastases; the liver tends to be the first metastatic site in these patients, and may be the only metastatic deposit in 60–80% of cases [2,11,19]. Although multiple liver metastases are more common in ocular melanoma, the disease-free interval to development of liver metastases tends to be longer [11]. As such, it stands to reason that hepatic resection is more commonly undertaken in ocular melanoma metastases. Although our study shows possibly improved survivals after resection of ocular metastatic disease (Table 5), such a conclusion is difficult to make considering the heterogeneous patient populations and high proportions of noncurative resections in ocular melanoma liver metastases (Table 2).
More recently, biological/immune therapies have become prominent in the treatment of metastatic melanoma, including interleukin-2 (IL-2) and monoclonal antibodies [41]. IL-2 has been the most common such therapy used in the recent past [42]. A systematic review found an overall survival of 11.4 months on IL-2 treatment in metastatic melanoma [43]. IL-2 has also been combined with cisplatin, vinblastine, dacarbazine and interferon-a in inoperable stage four melanoma patients with response rates of up to 60% [41]. The monoclocal antibody ipilimumab is recommended for use in metastatic melanoma if systemic therapies are used as the primary treatment modality [35]. An overall survival of 10.1 months has been reported in patients with unresectable melanoma; however, patients with ocular melanoma were excluded in this study [44]. The addition of dacarbazine to ipilimumab may increase overall survival to 11.2 months [45]. Vemurafenib is another biological agent, and is recommended for use in metastatic melanoma patients with the BRAF V600E mutation; it shows a response rate of up to 48%; however, very few of these are complete responses [35,46]. A more novel approach was investigated by Ripley et al. [22] whereby tumour-infiltrating lymphocytes were harvested from resected disease and given to the patients postoperatively; 40% of patients who received this therapy showed a response, including 13% with complete responses. Some important points should be drawn from the above studies. Importantly, reported overall survivals in the
Overall, it is still very difficult to ascertain the best treatment regimen with respect to systemic therapy and/ or surgery in stage IV melanoma. Decisions must be individualized to each patient and, in this regard, a multidisciplinary team decision is absolutely essential. Resection in ocular compared with cutaneous disease
Bias and study designs
Certain biases cannot be ignored when analysing the results of this systematic review. Most of the studies showed significant selection bias in that candidates undergoing hepatic resection tended to have more limited disease, which may indicate less aggressive tumour biology and thereby contribute to higher survivals. An element of lead and length-time bias was also evident in some studies, especially those using aggressive screening strategies. Furthermore, consideration must be given to the retrospective nature of the majority of studies here, and the fact that they were often conducted over long time periods (range 1971–2010) with significant changes in surgical techniques. Conclusion
In summary, hepatic resection in highly selected cases appears to offer a survival advantage over systemic chemotherapy alone. It has an acceptable morbidity and low operative mortality in the published series reviewed
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Hepatic resection for metastatic melanoma Hameed et al.
and should be considered as a treatment option in multidisciplinary discussions of patients with metastatic melanoma to the liver. Further studies are required that directly compare surgical and nonsurgical therapies in a uniform fashion.
Acknowledgements
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Conflicts of interest
There are no conflicts of interest.
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References
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Appendix Search keywords Literature search (Embase 1974 to present and Medline 1946 to present with daily update) (search current as of 3 March 2013): [melanoma] AND [liver OR hepatic] AND [metastasis OR metastases] AND [hepatectomy OR (liver resection) OR (hepatic resection) OR (liver surgery) OR (hepatic surgery) OR surgery OR metastasectomy OR metastastectomy]. Additional search (Embase 1974 to present and Medline 1946 to present with daily update) (search current as of 3 March 2013):
[non-colorectal OR noncolorectal OR non-neuroendocrine OR nonneuroendocrine] AND [liver OR hepatic] AND [hepatectomy OR (liver resection) OR (hepatic resection) OR (liver surgery) OR (hepatic surgery) OR surgery OR metastasectomy OR metastastectomy].
Study selection Studies were screened by reviewing their titles and abstracts. If abstracts were not available, a full-text version of the article was sought and then reviewed. If any exclusion criterion was evident from the abstract, the study was excluded, for example, series with fewer than 10 melanoma patients, case reports and so on were excluded if evident from the abstract. In cases of equivocal study titles or abstracts, the full study was read with inclusion and exclusion criteria for our analysis in mind. When the same patient case series was utilized in more than one article, the publication containing the most complete data set was selected. Articles included in the final analysis were independently assessed by two reviewers.
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