Research Article
Local and Systemic Therapies for Liver Metastases
Qiang Gao*, Zhenggang Ren, Jia Fan and Diyang Xie
1Department of Liver Surgery, Liver Cancer Institute, Fudan University, China
*Corresponding author: Qiang Gao, Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, P.R. China
Published: 07 Dec, 2016
Cite this article as: Gao Q, Ren Z, Fan J, Xie D. Local
and Systemic Therapies for Liver
Metastases. Clin Surg. 2016; 1: 1225.
Abstract
Liver metastases are accountable for a high mortality and morbidity in patients with metastatic diseases. The majority of liver metastases are derived from colorectal, gastric and neuroendocrine primary tumors. Resection is the only potentially curative approach to selected colorectal liver metastases (CRLM) and neuroendocrine liver metastases (NELM). Improvements in systemic therapies and operative technologies have succeeded in converting some borderline unresectable cases to resectable, resulting in a more favorable overall survival. For unresectable CRLM or NELM because of the size, location or comorbidities, other locoregional treatments including ablation, intraatrial therapy and stereotactic body radiotherapy can serve as an alternative with proved efficacy and safety. Evidences on locoregional strategies for non-colorectal, non-neuroendocrine liver metastases (NCNELM) are scarce and warrant large randomized controlled trials for verification. Resection has been indicated as a curative attempt for highly selected gastric liver metastases in Eastern centers. Systemic therapy remains the cornerstone for metastatic diseases. The optimal management of liver metastases requires a multidisciplinary team to form an individualized therapeutic approach. This article evaluates current evidences on the management of liver metastases, with an emphasis on liver-directed local treatment.
Introduction
The liver is one of the most common sites for metastatic diseases. The majority of liver metastases are derived from gastrointestinal neoplasms based on the filter role of the portal circulation. Colorectal liver metastases (CRLM) afflict 35% to 60% of the patients with colorectal cancer (CRC), representing the leading type of liver metastases [1-3]. Neuroendocrine tumors (NET) also present a high affinity to the liver and the liver metastases of NET (NELM) affect approximately 40% to 75% of the patients during the disease course [4]. Non-colorectal, non-neuroendocrine liver metastases (NCNELM) derived from a heterogeneous group of primary tumors are always associated with a more disseminated status and a poorer prognosis. Although chemotherapy and molecular targeted therapy remain the cornerstone for metastatic diseases, surgical resection serves as a potentially curative approach to selected patients with CRLM and NELM [2,5]. On the other hand, resections of NCNELM have still been undefined. Recently, improved molecular understanding of the primary tumors and the development of targeted therapies as well as immunotherapy have not only gained better overall survival (OS) but also provided more chances for local therapies of hepatic metastases. Meanwhile, the advancement in the operative technologies has succeeded in expanding resectability standard. Besides surgical resection, other local therapies including ablative therapy, intra-atrial therapy (IAT) and the use of radiotherapy to the liver have also evolved. Herein, we briefly explored recent advances in the treatment of liver metastases with an emphasis on the local therapies.
Surgical Resection
Surgical resection remains the only potentially curative option for patients with resectable
CRLM. The 5-year OS rate for patients undergoing hepatic resection has exceeded 50% [6-7].
Regardless of the number, the size, and the distribution of metastases in the liver, CRLM are
deemed as resectable when RO margins (microscopic negative) can be obtained with adequate
functional future liver remnant (FLR) [8]. If the initial target FLR of 30% to 50% dependent on
the degree of underlying liver disease can’t be achieved, preoperative portal vein embolization
(PVE) or two-stage hepatectomy can be adopted to induce hypertrophy of the FLR [7,9]. More
recently, associating liver partition with portal vein ligation for staged hepatectomy (ALLPPS)
has been advocated to achieve a more favorable oncological outcome in patients with advanced
CRLM load [10,11]. The presence of synchronous resectable porta-hepatis node or extra hepatic
metastases like resectable pulmonary metastases are no longer deemed as contradictions to tumor
resections in highly selected patients [12-13]. On the other hand, for solitary small CRLM(≤ 30 mm
in size) , parenchymal-sparing hepatectomy has been recommended as it didn’t increase recurrence
in the liver remnant but more importantly improved 5-year survival
in case of recurrence (salvageability) [14]. However, approximately
80-90% of patients have unresectable CRLM at initial diagnosis
[15-16]. For those with liver-limited unresectable lesions because of
involvement of critical structures, an attempt to downsize CRLM
via chemotherapy alone or in combination with epidermal growth
factor receptor (EGFR) inhibitors has successfully converted some
responders from unresectable to resectable status [17-19]. Compared
to chemotherapy alone, the addition of EGFR inhibitors cetuximab
or panitumumab significantly increased the response rate and the
RO resection rate in CRLM patients with wild-type KRAS. Due to
the risk of developing liver steatohepatitis and sinusoidal liver injury
associated with modern chemotherapy, the neoadjuvant period is
limited to 2 to 3 months [20]. For a small percent of patients who have
a complete radiological response to neo-adjuvant systemic treatment,
surgical resection of the disappearing CRLM, if accessible, has still
been recommended [21-22]. In fact, local residual disease at the site
of the disappearing CRLM could still be found in 11-67% of patients
at laparotomy and in 80% of the resected specimens microscopically,
resulting in recurrences in more than 19% of patients under
conservative management [23-26]. For patients presenting with
synchronous CRLM, resection of the primary tumor and CRLM can
be performed in a simultaneous or staged approach [27-28]. The usual
practice of the staged practice is to resect the primary tumor followed
by chemotherapy and delayed hepatic resection. A new liverfirst
approach to prevent liver disease progression in patients with
advanced CRLM has been suggested by recent studies, which resulted
in a comparable morbidity and mortality to the traditional strategy
[6,29,30]. Repeated resections for successively recurrent CRLM have
been verified to continue to provide survival benefit [31].
Hepatic resection represents the mainstay of treatment for
patients with grade 1 or grade 2 NELM whereas grade 3 carcinoma is
candidate for systemic treatment [32]. The 5-year OS rate of patients
with NELM after resection has exceeded 60%, indicating a prolonged
survival compared to those with conservative management [33-34].
Selected patients with primarily unresectable NELM might be
amendable to conversion therapy via PVE or radiation lobectomy
with 90Y-radiolabeled microspheres [35-36]. Despite the apparent
benefit of surgical resection in NELM, the majority of patients develop
intrahepatic recurrence during the disease course, partly resulting
from an underestimation of the true extent of disease burden on
preoperative imaging [37]. As it is unlikely to render durable disease
control, repeated surgery should be undertaken only in a selected
group of patients [33]. Unlike CRLM with surgical resection for a
curative intent, debulking of NELM that required resecting at least
90% of the tumor burden was warranted to help alleviate significant
paraneoplastic symptoms and prolong overall survival [38].
The benefit of surgical resection for NCNELM remains
controversial. Recent retrospective studies have justified hepatic
resection of NCNELM with the reported 5-year OS rate ranged from
19% to 42% (Table 1) [39-45]. The significant difference in OS was
partly attributed to the great variety of the origin of the primary
tumor. Histologically, resection of NCNELM derived from breast
cancers and stromal tumors provided far more benefit than those
from melanoma and squamous tumors. Other negative prognostic
factors included shorter disease-free interval between the primary
tumor diagnosis and NCNELM, positive resection margin, poor
response to chemotherapy or hormone therapy, the presence of
extrahepatic diseases and large liver disease extent (Table 1). Notably,
although current treatment protocols in Western centers do not
recommend patients with gastric carcinoma to receive surgical
resection of hepatic metastases, patients with a small number of
hepatic metastases and no other non-curative factor have been
indicated for hepatectomy in the East [46-47]. Despite the fact that
patients with hepatic metastases from gastric carcinoma are liable to
develop multiple nodules distributed to both hepatic lobes as well as
outside of the liver, the median 5-year survival rate of highly-selected
patients following resection reached 27% according to a recent metaanalysis
of retrospective studies [48]. The survival benefit needs to
be further demonstrated by prospective randomized controlled trials
[49]. Nonetheless, both intrahepatic and extrahepatic recurrences are
common for patients with gastric carcinoma, indicating far worse
prognosis than those with CRLM. Considering the complexity of
NCNELM and lack of well-established treatment paradigm, surgical
resection should generally be reserved for patients with liver-limited
lesion and more importantly relatively favorable tumor biology.
Table 1
Table 2
Ablative Therapy
Ablative techniques including radiofrequency ablation (RFA) or microwave ablation (MWA) are parenchymal-sparing treatment for hepatic malignancies, especially effective for small lesions (preferably≤3cm) [50-51]. RFA can be performed during open surgery, laparoscopically or percutaneously with robust evidences of efficacy and safety [52]. MWA represents a relatively new generation of ablative techniques, taking its advantage over RFA in making larger ablation zones and less heat-sink effect. For patients with unresectable liver metastases because of comorbidities, location or inadequate FLR, ablation can be tried alone or in combination with resection. The concomitant ablation and resection approach taking advantage of destroying small tumors via frictional heating and resecting large ones resulted in a 5-year OS rate of approximately 37% to 80% in patients with extensive CRLM [53-56]. In one retrospective study, patients with even poorer prognosis and higher risk factors who underwent RFA plus resection achieved comparable 5-year OS rate (56%) to those (49%) who had resection alone [56]. On the other hand, the reported 5-year OS rate of patients who received ablation alone including those with initially resectable CRLM was merely 28% [57,58]. Another study, however, revealed comparable 5-year OS rate (51.9% vs. 53%) between ablation and resection for patients with CRLM whereas RFA therapy induced significantly more recurrences [59]. As such, current evidences don’t support the use of ablative therapy over resection in patients with potentially resectable CRLM. For patients with unresectable NELM, ablative technique can also serve as an effective anti-tumor treatment. Symptom relief was achieved in more than 90% of the patients and the 5-year OS rate exceeded 57% when RFA was applied alone or as an adjunct to resection [60]. Data on the use of ablation for NCNELM are scarce. A few retrospective studies presented the efficacy and safety of RFA performed on patients with breast cancer liver metastases [61-62]. In general, ablative therapy remains as an adjunct to resection, a salvage therapy for post-operation recurrences and an option for patients with unresectable lesions in terms of comorbidities and cancer specificfactors.
Regional Arterial Therapy
While systemic chemotherapy remains the first-line therapy for
liver dominant colorectal metastases, recent studies have suggested
a survival advantage for transarterial chemoembolization (TACE)
using drug-eluting bead irinotecan (DEBIRI) in such patients [63-64].
DEBIRI therapy functions through mechanical occlusion of the
feeding artery and direct delivery of high concentrations of irinotecan
to the metastatic lesions without systemic exposure, thus exerting
minimal side effects to the subjects. Not only can it serve as salvage
therapy for patients who have failed multiple lines of chemotherapy,
but also can deliver superior response when utilized in combination
with FOLFOX chemotherapy. Another promising alternative is
radioembolization that transfers Y-90 microspheres to the tumoral
and peritumoral vasculature and delivers a high radiation dose
(>100Gy) to CRLM [65]. Considering its nature of short-ranged beta
radiation, radioembolization is also referred to as selective internal
radiation therapy (SIRT). According to the recent SIRFLOX study,
an addition of SIRT to FOLFOX-based chemotherapy significantly
delayed disease progression in the liver [66]. Nevertheless, the
combination therapy did not improve progression-free survival
at any site due to increased incidence of progression in the lungs.
Thereby, it remains uncertain whether improved control of CRLM
delivered by addition of SIRT can translate to improve OS, the result
of which is proposed to publish in 2017. Conventional TACE, on
the other hand, remains a palliative therapy for patients with CRLM
refractory to systemic chemotherapy [67].
NLEM are classically hypervascular lesions with the majority of
blood supply derived from the hepatic artery, making them more
eligible for intra-arterial therapy. It has been illustrated that IAT
yielded improved radiological, biological and symptomatic response
for patients with extensive NELM [68,69]. Regardless of the variety
of the angiographic procedures, transarterial embolization (TAE)
showed comparable efficacy to TACE in NELM [70]. And increasing
evidences supported the use of radioembolization in NELM with
the median OS reaching approximately 35 months [71-73]. The
therapeutic effect of IAT on NCNELM has not been well established,
although there are some studies supporting its application as palliative
strategy for patient’s refractory to chemotherapy [73-74].
Stereotactic Body Radiation Therapy
External beam radiation therapy for treatment of hepatic metastases has long been frustrated by low tolerance of the normal liver parenchyma. Stereotactic body radiation therapy (SBRT) involves a direct and accurate delivery of highly ablative radiation doses to one or more discrete lesions, representing a new safe and effective strategy for liver metastases. When SBRT was applied to CRLM, 2-year local control rate of the lesions≤3cm was 100% [75]. The median OS of patients with CRLM≤6cm ranged from 20.5 to 29.2 months among studies with heterogeneous enrollment [75-76]. A recent study demonstrated a long-term survival benefit for patients with oligometastases after SBRT [77]. Meanwhile, the study identified a breast cancer history, a longer distant metastasis-free interval and a longer time from metastatic diagnosis to the end of SBRT as positive predictors of OS.
Systemic Therapy
Chemotherapy remains the cornerstone for patients with stage IV cancers. Besides the advent of new cytotoxic agents, the past decades have witnessed great improvements in targeted therapy and immunotherapy. Improved understanding of molecular profiling of tumors and novel technologies for identification of genetic alterations in patient tissue have led to a massive expansion of targeted agents (Table 2) [78]. Cetuximab or panitumumab targeting EGFR, or bevacizumab targeting vascular endothelial growth factor (VEGF) in combination with cytotoxic chemotherapy is considered as equivalent choice in the first-line, RAS wild-type, metastatic CRC [79-80]. VEGFR-2 monoclonal antibody ramucirumab in addition to FOLFIRI or irinotecan has demonstrated to be effective in the secondline setting [81]. Furthermore, multi-kinase inhibitor regorafenib serves as an additional line of therapy for patients with metastatic CRC refractory to all standard therapy [82]. For patients with HER2- positive gastric cancer, trastuzumab has been recommended to add to first-line chemotherapy to gain survival benefit [83]. Similar to metastatic CRC, ramucirumab alone or in combination with paclitaxel can be opted as second-line therapy for metastatic gastric cancer [84-85]. Although targeted therapy alone or in combination with conventional chemotherapy result in prolonged patient survival and improved disease control, resistance problem remains as tumor progresses. Recently, more attention has been attracted to immunotherapy, especially immune checkpoint inhibitors in solid tumors and chimeric antigen receptor (CAR)-modified T cell (CAR-T) therapy in hematologic malignancies. Ipilimumab is the only FDA-approved agent targeting cytotoxic lymphocyte–associated protein 4 (CTLA), demonstrating a significantly improved survival in patients with metastatic melanoma [86]. When ipilimumab fails in advanced melanoma, anti-programmed-death-receptor-1 (PD-1) treatment with pembrolizumab or nivolumab has been suggested [87-88]. More recently, nivolumab has also been approved for its use in NSCLC [89]. Treatments with checkpoint inhibitors in other tumors are still under clinical trials.
Conclusion
Regarding the complexity of treatment paradigm of liver metastases, optimal decision-making relies on a multidisciplinary team involving surgical, medical, interventional and radiation oncologists. While systemic therapy remains the cornerstone of management, complete surgical resection should given priority for resectable CRLM or NELM. The role of resection for NENLM is still controversial and warrants randomized controlled trials for verification. Other locoregional treatments including ablation, IAT and radiotherapy have also presented efficacy and safety in liver metastases, each with specific tumor-related requirements. Individualized approach for each patient demands an integrated consideration of the biology, location as well as disease burden of the liver metastases.
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