Abstract
Surgical resection remains the primary curative treatment option for patients with colorectal liver metastases. While the majority of patients will develop tumor relapse within or outside of the liver after hepatic metastasectomy, a subset of these patients may be amenable to salvage surgical resection. However, outcomes for this approach are not well defined. In this article, we summarize the current evidence for the incidence, feasibility and outcomes of salvage resection for recurrence after initial resection of colorectal liver metastases.
Practice points.
Repeat partial hepatectomy for intrahepatic recurrence after resection of colorectal liver metastases is safe.
Approximately, 25–38% of patients with relapse after resection of colorectal liver metastases are potentially amenable to salvage surgery.
Long-term outcome after salvage resection of recurrent disease in selected patents is comparable to that of patients undergoing initial hepatectomy for colorectal liver metastases.
The use of ablation techniques can extend the limits of salvage treatment in patients with intrahepatic relapse that is not amenable to surgical treatment after a previous partial hepatectomy.
While a single site of extrahepatic disease is not an absolute contraindication to salvage resection, surgical salvage of multiple-site recurrence is associated with poor outcome and should be used in only highly selected cases.
A node-positive primary, short disease-free interval from the date of initial hepatectomy, multiple metastases, bilobar and large metastases (> 5 cm) and a positive resection margin at the second hepatectomy are associated with unfavorable outcome after salvage resection of recurrent colorectal liver metastases.
The liver is the most common metastatic site in patients with colorectal cancer (CRC) [1]. Approximately 20–25% of patients present with liver metastases at the time of CRC diagnosis and an additional 25% will develop liver metastases during the course of their disease [2,3]. In the majority of patients, in particular in those with synchronous metastases, the liver is the only site of distant spread [4,5]. Treatment of patients with metastatic CRC has improved markedly over the past three decades. In the 1980's, the median survival of all patients with metastatic CRC rarely exceeded 12 months [6,7]. In recently published studies the median survival of patients with widespread, unresectable disease ranges between 20 and 31 months [8,9] and exceeds 60 months in patients with limited, resected metastases [10]. It has indeed been demonstrated that resection of limited colorectal liver metastases (CRLM) is associated with prolonged survival with 5-year survival rates in excess of 50% and cure rates of approximately 20–25% [11]. The introduction of effective cytotoxic chemotherapy agents together with targeted antibodies have contributed significantly to patients’ long-term outcomes. At present, objective response rates of 50–68% are observed in patients who received first-line combination chemotherapy for metastatic CRC [8,12–13]. In addition to prolonging disease control, the improved response rates of modern chemotherapy regimens have rendered a higher proportion of patients amenable to potentially curative resection. There is evidence that partial hepatectomy in the context of perioperative chemotherapy is generally safe, even in patients requiring complex, extended or staged resections for complete tumor clearance [14,15].
The outcomes of hepatic resection for patients with CRLM have encouraged attempts to surgically salvage recurrent disease after hepatectomy with repeat resection and/or ablation. Several retrospective case series have provided data on the outcomes of patients who undergo repeat resections for recurrent disease after resection of CRLM [16,17]. The majority of these studies report solely the results of the patients who underwent repeat resection and lack information on the complete denominator of patients who underwent initial resection and the number of patients diagnosed with recurrence. While the results of repeat resection have been encouraging, it has remained unclear if the documented outcomes truly reflect the therapeutic impact of resection for recurrence or rather simply reflect the effect of selection bias.
In this review, we summarize the current evidence for the incidence, feasibility and outcomes of salvage resection for recurrence after initial resection of CRLM. We included studies on salvage resection of recurrence after resection of CRLM that were published between January 2000 and January 2017 and provided information on the denominator of patients who underwent the initial resection of CRLM. Studies that included patients with salvage resection of extrahepatic disease were eligible as were studies including ablation techniques with curative intent (Table 1) [18–30].
Table 1. . Recent studies on salvage resection for recurrence after curative treatment of colorectal liver metastases.
| Study (year) | Inclusion period | Denominator (n) | Recurrence (n) | Salvage (n) | Follow-up (months) | Site of salvage (Li/Lu/multiple/other) | Ref. |
|---|---|---|---|---|---|---|---|
| Studies on salvage of liver-only or liver-predominant relapse | |||||||
| Joönsson et al. (2012) | 1995–2009 | 240 | – | 32 | – | 32/–/–/– | [19] |
| Kulik et al. (2013) | 1994–2010 | 1026 | – | 94 | – | 94/0/0/0 | [20] |
| Wicherts et al. (2013) | 1990–2010 | 1036 | – | 288 | 45 | 288/–/–/– | [21] |
| Yamazaki et al. (2013) | 2004–2011 | 232 | – | H2 37 H3 22 |
– | H2 35/0/2/0 H3 21/0/1/0 |
[22] |
| Battula et al. (2014) | 1998–2011 | 1027 | – | 53 | 32 | 47/0/6/0 | [23] |
| Ali et al. (2015) | 2001–2013 | 136 | 50 | 30 | 30/–/–/– | [25] | |
| Lee et al. (2015) | 1994–2009 | 461 | 281 | 55 | 39 | 55/–/–/– | [27] |
| Fukami et al. (2017) | 1994–2015 | 282 | 193 | 78 | 48 | 78/–/–/– | [28] |
| Studies on salvage of intra- and extrahepatic relaps (including patients with extrahepatic only relapse) | |||||||
| Mise et al. (2010) | 1994–2004 | 211 | 166 | 98 | 60 | 60/21/ 9/8 | [18] |
| Saiura et al. (2014) | 1999–2008 | 287 | 211 | 102 | 63 | 73/18/6/5 | [24] |
| Butte et al. (2015) | 1994–2004 | 952 | 594 | 160 | 59 | 49/70/29/12 | [26] |
| Hof et al. (2016) | 2000–2013 | 431 | 305 | 160 | 39 | 103/47/–/10 | [29] |
| Oba et al. (2016) | 1996–2010 | 263 | 198 | 108 | 88.8 | 61/29/16/2 | [3] |
Studies published 2010 and after that provided the denominator, in other words number of patients who underwent primary hepatectomy for CRLM, were included.
CRLM: Colorectal liver metastasis; H2: Second hepatectomy; H3: Third hepatectom; Li: Liver; Lu: Lung.
Safety of repeat hepatic resection
Perioperative complications are threatening to patients’ lives, impact recovery from surgery and can compromise long-term outcomes after surgery for malignancy including CRLM [31,32]. Data on perioperative safety have therefore been required to establish salvage repeat liver resection as an accepted treatment option for patients with recurrent CRLM. This is of particular importance as these patients may have undergone previous major hepatectomy and commonly have received multiple lines of chemotherapy with potential hepatotoxicity. Repeat hepatectomy is challenging due to adhesions, distortion of anatomy and abnormalities of the liver parenchyma after previous resection and chemotherapy. Several studies have reported that repeat hepatectomy for recurrent CRLM is safe in experienced hands (Table 2). These reports include resections beyond the second hepatectomy and up to the fourth repeat resection as well as repeat resections after previous extended hepatectomies [21,33]. Morbidity and mortality rates after repeat partial hepatectomy are in the range of 8–71% and 0–2.4%, respectively. Even though these numbers have not been demonstrated to be increased compared with those after primary hepatectomy, one should note that the number of repeat hepatectomies is inversely correlated with the extent of resection. Therefore, repeat hepatectomies are associated with less extensive resections, which tend to be lower risk operations at least if performed at experienced centers [21,34]. This should be taken into account when the outcomes of primary and repeat hepatectomies are compared. Furthermore, this highlights the importance of patient referral to high-volume hepatobiliary centers for surgical evaluation as well as resection with the aim to minimize morbidity and maximize resection rates.
Table 2. . Characteristics and perioperative outcomes of index single hepatectomy and repeat second hepatectomy for metastastic colorectal cancer.
| Study (year) | Bilobar metastases | Number of metastases | Metastases size (cm) | Major hepatectomy | Operative time | Blood loss | Morbidity | Mortality | Ref. | |
|---|---|---|---|---|---|---|---|---|---|---|
| Joönsson et al. (2012) | H1 (n = 240) | – | – | – | – | – | 1000 ± 1786 | 65† | – | [19] |
| H2 (n = 32) | – | – | – | – | – | 1850 ± 1833 | 71 | – | ||
| Kulik et al. (2013) | H1 (n = 932) | 29 | 46‡ | 43§ | 49 | – | – | 16.5 | 1.4 | [20] |
| H2 (n = 94) | 40 | 58 | 37 | 32 | – | – | 9 | 0 | ||
| Wicherts et al. (2013) | H1 (n = 288) | – | 72‡ | 36 (33) | 34 | – | – | 27 | 0 | [21] |
| H2 (n = 288) | – | 53 | 31 (28) | 17 | – | – | 32 | 2.4 | ||
| Yamazaki et al. (2013) | H1 (n = 173) | – | 2 (1–24) | 3.5 (0.8–13.6) | – | 359 (115–579) | 280 (25–3.093) | 27¶ | 0 | [22] |
| H2 (n = 37) | – | 2 (1–13) | 3.0 (1.6–16.1) | – | 395 (178–740) | 307 (15–1.492) | 25 | 0 | ||
| H3 (n = 22) | – | 1 (1–6) | 4.0 (1.9–6.5) | – | 472 (195–616) | 286 (66–1.053) | 33 | 0 | ||
| Battula et al. (2014) | H (n = 916) | – | 1 (1–9) | 3.5 (1.0–18.5) | 82 | – | – | 21 | 4.9 | [23] |
| H1 (n = 53) | – | 1 (1–8) | 3.0 (1–11) | 47 | – | – | 13 | 0 | ||
| H2 (n = 53) | – | 1 (1–3) | 3.0 (1.0–7.5) | 19 | – | – | 8 | 0 | ||
| Ali et al. (2015) | H1 (n = 86) | 27 | 46‡ | 3.5 (2.5–6) | 52 | 200 (160–240) | – | – | 0 | [25] |
| H2 (n = 30) | 20 | 60 | 3.5 (2.5–5.6) | 27 | 228 (189–261) | – | – | 0 | ||
| Lee et al. (2015) | H1 (n = 406) | – | 1 (1–8) | 2.4 (0.2–7.5) | – | 276 (± 101) | – | 17 | – | [27] |
| H2 (n = 55) | – | 1 (1–4) | 2.4 (1.0–7.5) | – | 264 (± 59) | – | 11 | – | ||
| Fukami et al. (2017) | H1 (n = 282) | 29 | 49‡ | 3.5 ± 3.7 | 32 | 204 (± 85) | 616 ± 720 | 17 | 0.4 | [28] |
| H2 (n = 78) | 10 | 31 | 2.5 ± 1.5 | 13 | 188 (± 93) | 694 ± 721 | 12 | 1.3 | ||
Studies published in 2010 and thereafter that provided the denominator of patients initially treated (i.e. initial number of patients who underwent hepatectomy) were included.
†Clavien grade II+ complications.
‡Percentage of patients with >1 metastases.
§Percentage of patients with metastases >5 cm.
¶Clavien grade III+ complications.
H1: Single hepatectomy; H2: Second hepatectomy; H3: Third hepatectomy.
Incidence of salvage repeat resection
A few recent studies have provided data on the initial number of patients who underwent a potentially curative resection for CRLM, the total number of patients who subsequently developed recurrence and the proportion of those who underwent salvage repeat resection. Some of the studies focused solely on liver recurrence while others included all recurrences regardless of the organ of involvement. This accounting of the complete denominator of initial resections, all recurrences as well as salvage resections speaks to the level of selection and is of critical importance in interpreting these studies.
In a multi-institutional study on 1706, patients who underwent curative intent initial hepatic resection, 645 (37.8%) developed intrahepatic recurrence (with or without concurrent extrahepatic recurrence) and 246 (38.1%) of these underwent salvage liver resection [35]. In this study that excluded patients with isolated extrahepatic recurrence, the presence of extra-hepatic disease was similar among patients with initial (22.8%), second (15%), third (19.6%) and fourth (33.3%) resections that included complete resection of intra- and extrahepatic disease. These numbers are similar to another study that documented a repeat hepatectomy rate of 35% for patients with liver-only or liver-predominant recurrence; of whom 30% had extrahepatic disease resected at the time of repeat hepatectomy [36]. The outcome of patients with isolated extrahepatic disease recurrence was not reported in this study. However, extrahepatic disease in those patients with resected recurrent CRLM included limited and resectable peritoneal or locoregional colorectal recurrence, lung, adrenal, or lymph node metastases and was associated with worse overall survival after repeat hepatectomy [36]. Considering the most recently published studies, 20–60% of patients with liver-only or liver predominant relapse will be subjected to salvage resection [18,24–30].
There are less data available on the incidence of salvage resection of extrahepatic recurrence. A recent study from Japan on 198 patients with intra- and extrahepatic recurrence after initial hepatectomy, reported salvage resections in 108 (54.5%) patients. The first repeat resection included the liver only in 57%, lung only in 27%, liver and lung in 12%, liver plus other organs in 2% and other organs only in 2% [30]. The largest study on this topic included 952 patients who underwent initial hepatic resection with a median follow-up of 59 months for survivors. In this study, 594 (62%) patients experienced recurrence at any site and 160 (27%) underwent salvage resection as well as four patients who were treated with ablation. Out of patients who received salvage resection in this study, 42% had lung-only, 31% liver only, 12% other single-site only and 17% multiple site recurrence [26].
Predictors of salvage treatment after curative liver resection
In a multivariate analysis of all patients with recurrence after initial hepatic resection, Butte et al. demonstrated that young age, negative margin initial liver resection, maximum tumor diameter < 5 cm, and pattern of recurrence with liver or lung only disease were independently associated with salvage resection [26]. There are also treatment-related factors associated with the possibility of future salvage therapy that should be taken into consideration at the time of initial therapy for metastatic disease. The use of systemic chemotherapy should be critically evaluated in the context of its potential hepatotoxicity and lack of a documented survival benefit as adjuvant therapy after complete resection of CRLM. Butte et al. demonstrated a trend toward a lower likelihood of salvage resection in patients who received adjuvant therapy after resection of liver metastases [26]. These data must be interpreted carefully as the patients who received adjuvant chemotherapy were likely a higher risk group of patients.
There is also evidence that the extent of initial partial hepatectomy may impact the rate of salvage resection after the diagnosis of intrahepatic recurrence. Butte et al. reported a trend toward lower rates of salvage hepatic resection for recurrent disease in patients with a previous major resection compared with patients with a minor resection (25 vs 30%; p = 0.1). This may simply reflect differences in patients’ initial extent of disease or be a result of the amount of residual hepatic parenchyma and vasculature [26]. In this light, it is noteworthy that several studies from various high-volume institutions have demonstrated that parenchymal-sparing surgery for CRLM, when feasible, is associated with comparable intrahepatic recurrence rates and disease-specific survival compared with major hepatectomies [37–39]. A recently published study on 300 patients with a solitary CRLM ≤ 30 mm demonstrated similar outcomes for parenchymal-sparing and nonparenchymal-sparing surgery with respect to overall, recurrence-free and liver-only recurrence-free survival. In an interesting subgroup analysis of patients who developed liver-only relapse, there was an associated superior 5-year overall survival from the date of initial hepatectomy (72.4 vs 47.2%) and from the date of liver recurrence (73.6 vs 30.1%) for patients who received parenchymal-sparing surgery [40]. Importantly, there was no difference for patients in this subgroup analysis with and without parenchymal-sparing resection with respect to prognostic clinicopathologic variables. On multivariate analysis, parenchymal-sparing surgery was found to be independently associated with a higher rate of repeat hepatectomy. Furthermore, a parenchymal-sparing approach has been shown to lower the risk of perioperative complications and mortality [39].
Taken together, the available data suggest that certain patient, treatment and disease-related factors are associated with differing rates of salvage resection after relapse. We recommend that whenever possible a parenchymal-sparing approach should be favored, as it is associated with lower perioperative morbidity and may render a patient more amenable to repeat liver resection at the time of recurrence.
Long-term outcome after salvage treatment
The majority of studies on long-term outcome after salvage resection of recurrent disease with curative intent report favorable long-term survival rates, though the impact of extreme selection bias has to be considered. Several meta-analyses have confirmed comparable or even superior long-term survival after repeat compared with initial hepatectomy after statistical aggregation of results from individual studies [16–17,41]. The 5-year overall survival rates measured from the date of salvage resection for recurrent liver-only or liver predominant disease have been reported to range from 30 to 45% and exceed 50% in more recent series [24,26,28,30]. In studies providing data on the complete denominator of patients with disease recurrence, these outcomes were significantly better than the 5-year overall survival rates of patients who were not amenable to salvage resection (Table 3). Multiple authors have documented similar or even better 5-year survival rates after each consecutive salvage resection compared with that after the index operation for metastatic disease. However, the available studies differ significantly with respect to the kind of analyses performed and the control groups applied. In some studies, long-term outcome of patients undergoing salvage resection of recurrence was compared with the entire cohort of patients who underwent the initial partial hepatectomy (i.e., including those patients with salvage resection for subsequent relapse). In other studies, it was compared with patients who only underwent the initial hepatic resection and did not undergo repeat resections for relapse). It is critical that readers consider the fact that those patients who are able to undergo a salvage resection, inherently have better underlying tumor biology which may, in and of itself (regardless of the salvage resection) account for the better survival.
Table 3. . Long-term outcome of salvage for recurrence after curative treatment of colorectal liver metastases.
| Study (year) | Groups | Median survival (months) | 3-year OS (%) | 5-year OS (%) | Ref. |
|---|---|---|---|---|---|
| Studies on salvage of liver-only or liver-predominant relapse | |||||
| Jonsson et al. (2012) | H1 (n = 240) | – | 76† | – | [19] |
| H2 (n = 32) | – | 86 | – | ||
| Kulik et al. (2013) | H1 (n = 932) | 48 | – | – | [20] |
| H2 (n = 94) | 61 | – | – | ||
| Wicherts et al. (2013) | H1 (n = 645)‡ | – | 58 | 45 | [21] |
| H2 (n = 288) | – | 76 | 54 | ||
| Yamazaki et al. (2013) | H1 (n = 173)‡ | – | 58 | 42 | [22] |
| H2 (n = 37) | – | 52 | 36 | ||
| H3 (n = 22) | – | 49 | 34 | ||
| Battula et al. (2014) | H1 (n = 916) | – | 58 | 43 | [23] |
| H1 (n = 53) | 53 | 83 | 59 | ||
| H2 (n = 53) | 45 | 61 | 52 | ||
| Ali et al. (2015) | H1 (n = 69)§ | – | 66 | 49 | [25] |
| H2 (n = 30) | – | 56 | 45 | ||
| Lee et al. (2015) | H1 (n = 406) | – | 63 | 53 | [27] |
| H2 (n = 55) | – | 59 | 43 | ||
| Fukami et al. (2017) | H1 (n = 282) | – | – | – | [28] |
| H2 (n = 62) | 80 | 80 | 57 | ||
| Studies on salvage of intra- and extrahepatic relaps (including patients with extrahepatic only relapse) | |||||
| Mise et al. (2010) | H1 (n = 211) | 43 (28–125) | – | – | [18] |
| S1 (n = 98) | Li: 48 (4–155) Lu: 55 (26–183) Li + Lu: 38 (20–85) |
– | – | ||
| Saiura et al. (2014) | H1 (n = 287) | – | – | 56 | [24] |
| S1 (n = 102) | – | – | 70 | ||
| Butte et al. (2015) | H1 (n = 952) | 61 | – | 50 | [26] |
| S1 (n = 160) | 87 | – | 65 | ||
| Hof et al. (2016) | H1 (n = 270) | 50 | – | 45 | [29] |
| S1 (n = 91) | 50 | – | 44 | ||
| S2 (n = 69) | 65 | – | 62 | ||
| Oba et al. (2016) | H1 (n = 263) | 60 | – | 54 | [30] |
| S1 (n = 108) | – | – | 63 | ||
Studies published in 2010 and after that provided the denominator of patients initially treated were included. Survival is reported from the time of initial hepatectomy.
†2-year survival.
‡Patients with 1 hepatectomy only.
§Patients with 1 hepatectomy without recurrent colorectal liver metastases.
H1: First hepatectomy; H2: Repeat hepatectomy; OS: Overall survival; S1: First salvage treatment; S2: Second salvage treatment.
Ablation techniques can also be used as salvage treatment in patients with intrahepatic relapse that is not amenable to surgical treatment after a previous partial hepatectomy. The available evidence on perioperative and long-term outcomes of patients treated with ablation supports its use for intrahepatic recurrence after previous hepatectomy for CRLM [42,43]. In a study from the Memorial Sloan–Kettering Cancer Center, there was no statistically significance in recurrence-free survival or overall survival in patients who underwent resection and ablation compared with patients with resection alone despite higher tumor burden and clinical risk score in the combination group [42]. In line with these data, increased use of intraoperative ablation techniques with the number of repeat hepatectomies has been reported [21,35].
The impact of salvage resection of recurrent disease at extrahepatic sites on patients’ long-term survival has remained controversial. Hof and colleagues demonstrated a significant association of the location of recurrence with survival after potentially curative therapy of CRLM. In this study 5-year overall survival of patients with isolated lung-recurrence, isolated liver-recurrence and recurrence elsewhere including recurrence in liver and lung was 55, 41.1 and 14.8%, respectively [29]. Mise et al. showed no survival difference between patients who underwent repeated resections for isolated hepatic or pulmonary recurrences, whereas survival was significantly shorter for patients with resection of both hepatic and pulmonary metastases [18]. Although, the differences did not reach statistical significance, Butte et al. showed a trend toward higher rates of effective salvage therapy in patients with lung-only recurrence (28.1%), compared with patients with liver-only recurrence (22.7%), other single site-only recurrence (23.1%) and multiple-site recurrence (18.2%) [26].
In the study by Butte et al. 25% of patients who underwent salvage resection and 6% of patients with recurrence (regardless of salvage) remained free of disease with at least 36 months of follow-up from the time of last salvage. This suggests that salvage resection after initial resection of CRLM may be a potentially curative operation [26]. Even though, the available studies exclusively represent retrospective cohort studies, the published data on long-term survival in general justify salvage treatment including resection and ablation of recurrent disease with curative intent. Further data are required to evaluate the impact of salvage of extrahepatic disease on long-term survival. While the available data suggest a favorable outcome of patients with isolated lung recurrence, surgical salvage of multiple-site recurrence is associated with poor outcome and should be used in only highly selected cases.
Patient selection for salvage treatment
Aside from technical resectability, there are no established criteria to select patients for salvage treatment of recurrence after previous resection of CRLM. Adequate imaging is essential to guide decision-making in favor or against surgical salvage of recurrent disease. At present, routine staging of patients with recurrent disease considered for salvage therapy includes a computed tomography scan of the chest, abdomen and pelvis. This may be complemented by a contrast-enhanced magnetic resonance imaging (MRI) due to its higher sensitivity for detection of intrahepatic lesions compared with contrast-enhanced CT [44,45]. The role of positron emission tomography combined with computed tomography (PET-CT) for staging of patients with disease recurrence after previous resection of CRLM has remained controversial, in particular because of the results of a randomized controlled trial that failed to show frequent changes in surgical management using PET-CT [46]. However, in a recently published analysis of patients with recurrent CRLM, Vigano et al. demonstrated a higher sensitivity of PET-CT versus CT/MRI for detection of recurrences other than intrahepatic and pulmonary lesions. In this study, PET-CT was able to detect extrahepatic disease in 28.8% of patients with no detectable extrahepatic disease on CT/MRI and to avoid surgery in 20% of patients deemed resectable based on CT/MRI [47]. Based on these data the value of PET-CT should be re-evaluated for patients considered for salvage of recurrent metastatic CRC.
For patients with isolated intrahepatic recurrence without other sites of disease, several studies used similar selection criteria for repeat hepatectomy to those used for the initial resection (i.e., presence of resectable intrahepatic disease and absence of unresectable extrahepatic disease) [21,23,35]. Oba et al. proposed detailed selection criteria that were primarily based on the technical resectability of hepatic recurrence as well as the presence and extent of extrahepatic disease. Patients with technically resectable liver-only recurrence were referred immediately to repeat hepatectomy. Patients with isolated, resectable pulmonary recurrence were considered for metastasectomy, if the number of metastases was ≤3, metastases were confined to one lung and there was no thoracic lymphadenopathy. In this study, contraindications for salvage resection included extrahepatic, nonpulmonary metastases except for metastasis limited to an organ such as the primary tumor site, regional, celiac or para-aortic lymph nodes, the adrenal gland or the peritoneum [30]. However, these criteria in the context of present evidence are arbitrary and would require validation in further patient cohorts to provide outcome-based justification of these selection criteria.
There are clinicopathologic factors that have been repeatedly shown to be associated with poor long-term outcome after salvage resection of recurrent CRLM. A recent systematic review and meta-analysis summarized the prognostic variables for patients undergoing a second hepatectomy for recurrent CRLM. In this analysis a disease-free interval from the initial hepatectomy of <1 year, multiple metastases, bilobar and large metastases (>5 cm) and a positive resection margin at the second hepatectomy were associated with unfavorable outcome [48]. Butte et al. analyzed prognostic factors associated with disease-free survival ≥36 months after resection of any relapse. In this study, a node-negative primary tumor, single initial liver metastasis and low clinical risk score were significantly associated with this favorable disease-free survival [26]. While there is no consensus on contraindications to salvage therapy after hepatectomy for CRLM, the above data provide clinical factors to consider when patients are referred for possible salvage resection of recurrence.
The role of systemic chemotherapy to help in decision-making for selection of patients with potentially salvageable recurrence has not been well defined. The role of chemotherapy in converting patients with initially unresectable to resectable CRLM, even in the setting of recurrence after previous hepatectomy is well established. However, it's advantages for patients’ long-term outcome in the case of initially resectable (primary and recurrent) disease remains uncertain. In the absence of controlled clinical trials, some authors favor immediate resection without preoperative chemotherapy in cases of resectable recurrence [30], whereas others prefer preoperative chemotherapy even in patients with primarily resectable metastases to assess tumor ‘chemoresponsiveness’ and possibly to facilitate margin-free resections [21]. Another approach is the selective use of preoperative chemotherapy in patients with unfavorable disease characteristics at the time of presentation of recurrence such as a short disease-free interval after index hepatectomy, multi-site recurrence or bilobar recurrence. Owing to the lack of quality data on this topic, the decision for preoperative chemotherapy in patients with resectable recurrence should be made on an individual basis considering the known prognostic factors.
Conclusion
Salvage resection of recurrent disease after an initial complete resection of CRLM is feasible in about one quarter to one half of patients presenting with recurrent disease. This wide variation likely reflects the lack of standardized criteria to select patients for salvage resection. The available evidence suggests that salvage resection of limited recurrent colorectal metastases is safe in experienced centers. Furthermore, the prognosis of these resected patients compares favorably to those of patients not amenable to repeat resection and importantly is associated with outcomes similar to those after initial hepatectomy including the potential for cure. Based on these data, salvage treatment for limited and resectable recurrent disease after an initial complete resection of CRLM is recommended, however, careful patient selection considering the documented prognostic factors is essential to obtain optimal outcomes and to minimize treatment failures.
Future perspective
In this review article, we describe the current evidence on effectiveness and safety of salvage treatment of recurrent disease after resection of CRLM. The results demonstrate the safety of salvage surgery in this patient cohort and, moreover, demonstrate that this treatment strategy offers potential long-term survival in approximately one quarter of these patients. These data reveal significant room for improvement of patient selection for surgical salvage. It remains to be investigated, if this may be achieved by tissue-based genetic analyses or circulating blood-based biomarkers. While these predictive biomarkers may help to tailor surgical salvage to patients who are likely to benefit from it, one might speculate that novel systemic therapeutics might provide more effective systemic control of disseminated disease making surgical salvage applicable to patients who previously were not considered adequate surgical candidates.
Footnotes
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
References
Papers of special note have been highlighted as: •• of considerable interest
- 1.Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet. 2014;383(9927):1490–1502. doi: 10.1016/S0140-6736(13)61649-9. [DOI] [PubMed] [Google Scholar]
- 2.Weiss L, Grundmann E, Torhorst J, et al. Haematogenous metastatic patterns in colonic carcinoma: an analysis of 1541 necropsies. J. Pathol. 1986;150(3):195–203. doi: 10.1002/path.1711500308. [DOI] [PubMed] [Google Scholar]
- 3.Manfredi S, Bouvier AM, Lepage C, Hatem C, Dancourt V, Faivre J. Incidence and patterns of recurrence after resection for cure of colonic cancer in a well defined population. Br. J. Surg. 2006;93(9):1115–1122. doi: 10.1002/bjs.5349. [DOI] [PubMed] [Google Scholar]
- 4.Van Der Pool AE, Damhuis RA, Ijzermans JN, et al. Trends in incidence, treatment and survival of patients with stage IV colorectal cancer: a population-based series. Colorectal Dis. 2012;14(1):56–61. doi: 10.1111/j.1463-1318.2010.02539.x. [DOI] [PubMed] [Google Scholar]
- 5.Kumar R, Price TJ, Beeke C, et al. Colorectal cancer survival: an analysis of patients with metastatic disease synchronous and metachronous with the primary tumor. Clin. Colorectal Cancer. 2014;13(2):87–93. doi: 10.1016/j.clcc.2013.11.008. [DOI] [PubMed] [Google Scholar]
- 6.Wilson SM, Adson MA. Surgical treatment of hepatic metastases from colorectal cancers. Arch. Surg. 1976;111(4):330–334. doi: 10.1001/archsurg.1976.01360220026004. [DOI] [PubMed] [Google Scholar]
- 7.Bengtsson G, Carlsson G, Hafstrom L, Jonsson PE. Natural history of patients with untreated liver metastases from colorectal cancer. Am. J. Surg. 1981;141(5):586–589. doi: 10.1016/0002-9610(81)90057-x. [DOI] [PubMed] [Google Scholar]
- 8.Yamazaki K, Nagase M, Tamagawa H, et al. Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G) Ann. Oncol. 2016;27(8):1539–1546. doi: 10.1093/annonc/mdw206. [DOI] [PubMed] [Google Scholar]
- 9.Schmoll HJ, Cunningham D, Sobrero A, et al. Cediranib with mFOLFOX6 versus bevacizumab with mFOLFOX6 as first-line treatment for patients with advanced colorectal cancer: a double-blind, randomized Phase III study (HORIZON III) J. Clin. Oncol. 2012;30(29):3588–3595. doi: 10.1200/JCO.2012.42.5355. [DOI] [PubMed] [Google Scholar]
- 10.Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, Phase 3 trial. Lancet Oncol. 2013;14(12):1208–1215. doi: 10.1016/S1470-2045(13)70447-9. [DOI] [PubMed] [Google Scholar]
- 11.Tomlinson JS, Jarnagin WR, Dematteo RP, et al. Actual 10-year survival after resection of colorectal liver metastases defines cure. J. Clin. Oncol. 2007;25(29):4575–4580. doi: 10.1200/JCO.2007.11.0833. [DOI] [PubMed] [Google Scholar]
- 12.Folprecht G, Gruenberger T, Bechstein WO, et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised Phase 2 trial. Lancet Oncol. 2010;11(1):38–47. doi: 10.1016/S1470-2045(09)70330-4. [DOI] [PubMed] [Google Scholar]
- 13.Cremolini C, Loupakis F, Masi G, et al. FOLFOXIRI or FOLFOXIRI plus bevacizumab as first-line treatment of metastatic colorectal cancer: a propensity score-adjusted analysis from two randomized clinical trials. Ann. Oncol. 2016;27(5):843–849. doi: 10.1093/annonc/mdw052. [DOI] [PubMed] [Google Scholar]
- 14.Masi G, Loupakis F, Pollina L, et al. Long-term outcome of initially unresectable metastatic colorectal cancer patients treated with 5-fluorouracil/leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) followed by radical surgery of metastases. Ann. Surg. 2009;249(3):420–425. doi: 10.1097/SLA.0b013e31819a0486. [DOI] [PubMed] [Google Scholar]
- 15.Tamandl D, Gruenberger B, Klinger M, et al. Liver resection remains a safe procedure after neoadjuvant chemotherapy including bevacizumab: a case-controlled study. Ann. Surg. 2010;252(1):124–130. doi: 10.1097/SLA.0b013e3181deb67f. [DOI] [PubMed] [Google Scholar]
- 16.Yan TD, Sim J, Black D, Niu R, Morris DL. Systematic review on safety and efficacy of repeat hepatectomy for recurrent liver metastases from colorectal carcinoma. Ann. Surg. Oncol. 2007;14(7):2069–2077. doi: 10.1245/s10434-007-9388-6. [DOI] [PubMed] [Google Scholar]
- 17.Lam VW, Pang T, Laurence JM, et al. A systematic review of repeat hepatectomy for recurrent colorectal liver metastases. J. Gastrointest. Surg. 2013;17(7):1312–1321. doi: 10.1007/s11605-013-2186-5. [DOI] [PubMed] [Google Scholar]
- 18.Mise Y, Imamura H, Hashimoto T, et al. Cohort study of the survival benefit of resection for recurrent hepatic and/or pulmonary metastases after primary hepatectomy for colorectal metastases. Ann. Surg. 2010;251(5):902–909. doi: 10.1097/SLA.0b013e3181c9868a. [DOI] [PubMed] [Google Scholar]
- 19.Jonsson K, Grondahl G, Salo M, Tingstedt B, Andersson R. Repeated liver resection for colorectal liver metastases: a comparison with primary liver resections concerning perioperative and long-term outcome. Gastroenterol. Res. Pract. 2012:568214. doi: 10.1155/2012/568214. 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Kulik U, Bektas H, Klempnauer J, Lehner F. Repeat liver resection for colorectal metastases. Br. J. Surg. 2013;100(7):926–932. doi: 10.1002/bjs.9132. [DOI] [PubMed] [Google Scholar]
- 21.Wicherts DA, De Haas RJ, Salloum C, et al. Repeat hepatectomy for recurrent colorectal metastases. Br. J. Surg. 2013;100(6):808–818. doi: 10.1002/bjs.9088. [DOI] [PubMed] [Google Scholar]
- 22.Yamazaki S, Takayama T, Okada S, et al. Good candidates for a third liver resection of colorectal metastasis. World J. Surg. 2013;37(4):847–853. doi: 10.1007/s00268-012-1887-3. [DOI] [PubMed] [Google Scholar]
- 23.Battula N, Tsapralis D, Mayer D, et al. Repeat liver resection for recurrent colorectal metastases: a single-centre, 13-year experience. HPB. 2014;16(2):157–163. doi: 10.1111/hpb.12096. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Saiura A, Yamamoto J, Koga R, et al. Favorable outcome after repeat resection for colorectal liver metastases. Ann. Surg. Oncol. 2014;21(13):4293–4299. doi: 10.1245/s10434-014-3863-7. [DOI] [PubMed] [Google Scholar]
- 25.Ali MA, Di Sandro S, Lauterio A, et al. Repeat hepatectomy for recurrent colorectal liver metastases: is it worth the challenge? J. Gastrointest. Surg. 2015;19(12):2192–2198. doi: 10.1007/s11605-015-2939-4. [DOI] [PubMed] [Google Scholar]
- 26.Butte JM, Gonen M, Allen PJ, et al. Recurrence after partial hepatectomy for metastatic colorectal cancer: potentially curative role of salvage repeat resection. Ann. Surg. Oncol. 2015;22(8):2761–2771. doi: 10.1245/s10434-015-4370-1. [DOI] [PMC free article] [PubMed] [Google Scholar]; •• Single-institution study providing complete data on patients with initial hepatectomy and demonstrating potential salvage therapy in 27% of patients with recurrence and effective salvage therapy achievable in approximately one quarter of these patients.
- 27.Lee H, Choi SH, Cho YB, et al. Repeat hepatic resection in patients with colorectal liver metastases. World J. Gastroenterol. 2015;21(7):2124–2130. doi: 10.3748/wjg.v21.i7.2124. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Fukami Y, Kaneoka Y, Maeda A, Takayama Y, Onoe S. Postoperative complications following aggressive repeat hepatectomy for colorectal liver metastasis have adverse oncological outcomes. Surg. Today. 2017;47(1):99–107. doi: 10.1007/s00595-016-1340-6. [DOI] [PubMed] [Google Scholar]
- 29.Hof J, Wertenbroek MW, Peeters PM, Widder J, Sieders E, De Jong KP. Outcomes after resection and/or radiofrequency ablation for recurrence after treatment of colorectal liver metastases. Br. J. Surg. 2016;103(8):1055–1062. doi: 10.1002/bjs.10162. [DOI] [PubMed] [Google Scholar]
- 30.Oba M, Hasegawa K, Shindoh J, et al. Survival benefit of repeat resection of successive recurrences after the initial hepatic resection for colorectal liver metastases. Surgery. 2016;159(2):632–640. doi: 10.1016/j.surg.2015.09.003. [DOI] [PubMed] [Google Scholar]
- 31.Correa-Gallego C, Gonen M, Fischer M, et al. Perioperative complications influence recurrence and survival after resection of hepatic colorectal metastases. Ann. Surg. Oncol. 2013;20(8):2477–2484. doi: 10.1245/s10434-013-2975-9. [DOI] [PubMed] [Google Scholar]
- 32.Schiesser M, Chen JW, Maddern GJ, Padbury RT. Perioperative morbidity affects long-term survival in patients following liver resection for colorectal metastases. J. Gastrointest. Surg. 2008;12(6):1054–1060. doi: 10.1007/s11605-007-0438-y. [DOI] [PubMed] [Google Scholar]
- 33.Ziff O, Rajput I, Adair R, Toogood GJ, Prasad KR, Lodge JP. Repeat liver resection after a hepatic or extended hepatic trisectionectomy for colorectal liver metastasis. HPB. 2014;16(3):212–219. doi: 10.1111/hpb.12123. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Hallet J, Cunha AS, Adam R, et al. Outcomes of rehepatectomy for colorectal liver metastases: a contemporary multi-institutional analysis from the french surgical association database. Ann. Surg. Oncol. 2016;23(Suppl. 5):894–903. doi: 10.1245/s10434-016-5506-7. [DOI] [PubMed] [Google Scholar]
- 35.De Jong MC, Mayo SC, Pulitano C, et al. Repeat curative intent liver surgery is safe and effective for recurrent colorectal liver metastasis: results from an international multi-institutional analysis. J. Gastrointest. Surg. 2009;13(12):2141–2151. doi: 10.1007/s11605-009-1050-0. [DOI] [PubMed] [Google Scholar]
- 36.Jones NB, McNally ME, Malhotra L, et al. Repeat hepatectomy for metastatic colorectal cancer is safe but marginally effective. Ann. Surg. Oncol. 2012;19(7):2224–2229. doi: 10.1245/s10434-011-2179-0. [DOI] [PubMed] [Google Scholar]
- 37.Torzilli G, Donadon M, Marconi M, et al. Systematic extended right posterior sectionectomy: a safe and effective alternative to right hepatectomy. Ann. Surg. 2008;247(4):603–611. doi: 10.1097/SLA.0b013e31816387d7. [DOI] [PubMed] [Google Scholar]
- 38.Matsumura M, Mise Y, Saiura A, et al. Parenchymal-sparing hepatectomy does not increase intrahepatic recurrence in patients with advanced colorectal liver metastases. Ann. Surg. Oncol. 2016;23(11):3718–3726. doi: 10.1245/s10434-016-5278-0. [DOI] [PubMed] [Google Scholar]
- 39.Gold JS, Are C, Kornprat P, et al. Increased use of parenchymal-sparing surgery for bilateral liver metastases from colorectal cancer is associated with improved mortality without change in oncologic outcome: trends in treatment over time in 440 patients. Ann. Surg. 2008;247(1):109–117. doi: 10.1097/SLA.0b013e3181557e47. [DOI] [PubMed] [Google Scholar]; •• Single-institutional study demonstrating oncological safety of parenchymal-sparing surgery in patients with bilobar colorectal liver metastases.
- 40.Mise Y, Aloia TA, Brudvik KW, Schwarz L, Vauthey JN, Conrad C. Parenchymal-sparing hepatectomy in colorectal liver metastasis improves salvageability and survival. Ann. Surg. 2016;263(1):146–152. doi: 10.1097/SLA.0000000000001194. [DOI] [PubMed] [Google Scholar]
- 41.Antoniou A, Lovegrove RE, Tilney HS, et al. Meta-analysis of clinical outcome after first and second liver resection for colorectal metastases. Surgery. 2007;141(1):9–18. doi: 10.1016/j.surg.2006.07.045. [DOI] [PubMed] [Google Scholar]
- 42.Govindarajan A, Arnaoutakis D, D'Angelica M, et al. Use of intraoperative ablation as an adjunct to surgical resection in the treatment of recurrent colorectal liver metastases. J. Gastrointest. Surg. 2011;15(7):1168–1172. doi: 10.1007/s11605-011-1470-5. [DOI] [PubMed] [Google Scholar]
- 43.Van Der Pool AE, Lalmahomed ZS, De Wilt JH, Eggermont AM, Ijzermans JM, Verhoef C. Local treatment for recurrent colorectal hepatic metastases after partial hepatectomy. J. Gastrointest. Surg. 2009;13(5):890–895. doi: 10.1007/s11605-008-0794-2. [DOI] [PubMed] [Google Scholar]
- 44.Muhi A, Ichikawa T, Motosugi U, et al. Diagnosis of colorectal hepatic metastases: comparison of contrast-enhanced CT, contrast-enhanced US, superparamagnetic iron oxide-enhanced MRI, and gadoxetic acid-enhanced MRI. J. Magn. Reson. Imaging. 2011;34(2):326–335. doi: 10.1002/jmri.22613. [DOI] [PubMed] [Google Scholar]
- 45.Vreugdenburg TD, Ma N, Duncan JK, Riitano D, Cameron AL, Maddern GJ. Comparative diagnostic accuracy of hepatocyte-specific gadoxetic acid (Gd-EOB-DTPA) enhanced MR imaging and contrast enhanced CT for the detection of liver metastases: a systematic review and meta-analysis. Int. J. Colorectal Dis. 2016;31(11):1739–1749. doi: 10.1007/s00384-016-2664-9. [DOI] [PubMed] [Google Scholar]
- 46.Moulton CA, Gu CS, Law CH, et al. Effect of PET before liver resection on surgical management for colorectal adenocarcinoma metastases: a randomized clinical trial. JAMA. 2014;311(18):1863–1869. doi: 10.1001/jama.2014.3740. [DOI] [PubMed] [Google Scholar]
- 47.Vigano L, Lopci E, Costa G, et al. Positron Emission tomography-computed tomography for patients with recurrent colorectal liver metastases: impact on restaging and treatment planning. Ann. Surg. Oncol. 2017;24(4):1029–1036. doi: 10.1245/s10434-016-5644-y. [DOI] [PubMed] [Google Scholar]; •• Single-instutional study demonstrating a potential contribution of positron emission tomography combined with computed tomography in staging of patients with recurrent colorectal liver metastases.
- 48.Luo LX, Yu ZY, Huang JW, Wu H. Selecting patients for a second hepatectomy for colorectal metastases: an systemic review and meta-analysis. Eur. J. Surg. Oncol. 2014;40(9):1036–1048. doi: 10.1016/j.ejso.2014.03.012. [DOI] [PubMed] [Google Scholar]