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. Author manuscript; available in PMC: 2022 Jan 1.
Published in final edited form as: Surg Oncol Clin N Am. 2020 Oct 28;30(1):189–204. doi: 10.1016/j.soc.2020.08.008

Systemic Therapy Improvements Will Render Locoregional Treatments Obsolete for Cancer Patients with Liver Metastases

Satya Das 1, Jordan Berlin 2
PMCID: PMC7684942  NIHMSID: NIHMS1627383  PMID: 33220805

Background

Systemic therapies across the spectrum of cancer have improved dramatically over the last decade, largely driven by the development of more potent therapeutics and a greater understanding of molecular drivers of disease. Still, liver metastases and downstream complications of hepatic infiltration remain a major driver of mortality in this patient cohort. In rare circumstances, such as oligometastatic disease in colorectal cancer (CRC), a defined role for resection (metastectomy) exists, whereas in most other circumstances, practice patterns pertaining to management of hepatic disease vary dramatically. Locoregional treatments, or liver-directed therapies and debulking surgery, are used routinely in patients without clear evidence of any survival benefit. Herein, using gastrointestinal malignancies as our backdrop, we argue that systemic treatment advances will render locoregional hepatic therapies obsolete within the next decade. In the following paragraphs, we canvass the evidence used to justify locoregional approaches in neuroendocrine tumors (NETs), hepatobiliary cancer and CRC, discuss the landmark studies which define the current state of systemic therapy for these diseases and highlight pending advances which build the case for systemic treatment being the preferred approach over locoregional treatment in patients with liver metastases in the near future.

NETs

Hepatic debulking has been thought to be most optimal in NET patients with liver-limited metastatic disease (1,2). Its role in patients with unresectable extrahepatic disease is more controversial. We will describe briefly the primary studies which have been cited as justification for hepatic debulking prior to providing perspective on more recent studies which suggest systemic treatment approaches may be equally effective. In a 15-year single-center experience from Gustave-Roussy, 47 patients with well differentiated NETs underwent hepatectomies for liver metastases (3). Of these patients, 51% had non-pancreatic NETs while 49% had pancreatic NETs. In addition to undergoing hepatic tumor resections, 77% also underwent extra-hepatic disease resection. An R0 resection was achieved in 53% of patients though 97% of tumors were removed in each patient. Median survival was 91 months with a 5-year survival rate of 71%. At 10 years, 75% of patients had recurred in the liver. A retrospective analysis of cases collected from a multicenter database compared outcomes in well differentiated NET patients with hepatic metastases who underwent surgical cytoreduction versus hepatic embolization (4). Of the 120 patients, 61 underwent surgical cytoreduction while 59 underwent embolization. The patients who underwent surgery experienced a mean survival of 43 ± 26 months compared to 24 ± 16 months in patients who underwent embolization (p < .001). Of the surgical patients, 62% were able to undergo R0 resections while the remaining patients had incomplete resections. When separating outcomes by completeness of resection, patients with both R0 and incomplete resections demonstrated improved survival compared to patients undergoing embolization; patients with R0 resections demonstrated the best overall survival (50 ± 28 months) followed by patients who underwent incomplete resections (32 ± 19 months).

In another large multi-center retrospective analysis, outcomes in 339 NET patients who underwent hepatic resection between 1985–2009 were analyzed (5). Of these patients, 52.2% had low or intermediate grade tumors, 15% had high grade tumors and 32.7% had tumors of unknown grade. Most patients (83.8%) had liver-limited disease while the remainder had extrahepatic disease. Among all patients who underwent initial resections, 53.7% achieved R0 resections. The median time to first recurrence post-resection was 15.2 months in the entire cohort. The 1-,3- and 5-year PFS of included cases were 56.9%, 24.2% and 5.9%, respectively. No difference in recurrence rates were identified between patients who did and did not undergo R0 resections. Median overall survival (OS) of patients with extrahepatic disease was 85.1 months compared to 148 months in patients with liver limited disease (p < .001). On multivariate analysis, extra-hepatic disease presence was the strongest negative prognostic influence for patients.

Focusing solely on embolization in patients with hepatic metastases from NETs, only one small randomized study comparing between modalities (chemo-, bland-) has been reported to date (6). In this study, 26 well differentiated G1 or G2 small intestinal NET patients with progressive disease were randomized to bland embolization or chemoembolization. No differences in PFS were seen between the two arms (23.6 months versus 19.2 months; p = .9). A larger prospective study comparing between embolization modalities is ongoing however will not report findings until at least 2023 [NCT02724540].

An important caveat of all these studies was they occurred prior to the regular utilization of the two most potent cytoreductive systemic options available to well differentiated NET patients: peptide receptor radionuclide therapy (PRRT) and capecitabine plus temozolomide (CAPTEM). Furthermore, most of the previously discussed studies do not mention the number of patients at baseline with progressive disease, making it difficult to discern the true benefit of the locoregional therapy employed. PRRT has been a transformative therapy for patients with metastatic or unresectable somatostatin receptor-avid neuroendocrine tumors. In a post-hoc analysis from the NETTER-1 study, which garnered 177Lu-DOTATATE its FDA approval, the hazard ratio (HR) for disease progression in small intestinal NET patients, regardless of hepatic tumor burden (< 25%, 25–50%, > 50%), was .19 (7,8). The 30-month progression-free survival (PFS) rate was > 75%. From a large Dutch registry study of 443 gastroenteropancreatic, bronchial and unknown primary NET patients treated with 177Lu-DOTATATE, median OS was 63 months (9). Of the patients included in the analysis, 53.9% had progressive disease at baseline. In patients with pancreatic NETs, median OS was the longest at 71 months while in small intestinal NETs, median OS was 60 months. Patients with liver or bone metastases had an inferior median OS of 57 months. The median PFS in the entire cohort was 29 months.

177Lu-DOTATATE employs a beta-emitting radionuclide which elicits objective response in 18–39% of NET patients. Though its biggest benefit is in preventing tumor progression, the extent of cytoreduction it can generate is modest. Newer generation PRRT agents utilizing alpha particles or somatostatin receptor antagonists have demonstrated the potential to create greater tumor death in pre-clinical studies (10). Alpha particles such as actinium-225 (225Ac) and bismuth-213 (213Bi) possess a higher linear energy transfer than beta-emitting particles and have a shorter range of action, suggesting they can generate greater amounts of double strand breaks and irreversible DNA damage (11). Clinical experience with 225Ac was reported in 32 patients with stable (44%) or progressive disease (56%) post-treatment with 177Lu-DOTATATE (12). Of the treated patients, 62.5% achieved a partial response and 100% achieved disease control. Somatostatin antagonists such as 177Lu-satoreotide tetraxetan have demonstrated increase uptake and retention in NET cells compared to agonists, suggesting the possibility they could lead to greater cell kill (13). This preclinical rationale has led to a phase I study with 177Lu-satoreotide tetraxetan, with initial results suggesting a response rate of 45% in treated patients (14).

CAPTEM has become another cornerstone systemic cytoreductive therapy for NET patients. In a randomized trial in well differentiated pancreatic NET patients with progressive disease within 12 months of study enrollment, PFS in patients who received the combination was 22.7 months (15). Median OS was not reached in the combination arm however > 80% of patients were alive at 50 months. In smaller series, CAPTEM demonstrated activity in small bowel NET patients with median PFS times > 22 months (16). Beyond, CAPTEM and PRRT, novel cytoreductive tyrosine kinase inhibitors such as cabozantinib and lenvatinib have demonstrated sustained PFS benefit in metastatic well differentiated NET patients along with promising cytoreductive potential. In a multi-cohort phase II study of well differentiated NET patients with baseline progressive disease, pancreatic NET patients and small intestinal NET patients treated with lenvatinib experienced a PFS of 15.5 months and 15.4 months, respectively (17). Similarly, in a phase II study of cabozantinib in progressive well differentiated NET patients, patients with pancreatic NETs and small intestinal NETs achieved PFS times of 21.8 months and 31.4 months, respectively (18).

Though in general, surgical debulking and embolization seem to elicit greater response rates in patients with NETs than systemic therapies, there do not appear to be differences in the more relevant endpoints of PFS and OS between the modalities (Table 1). Furthermore, recent systemic treatments such as 177Lu-DOTATATE prolong disease progression and survival in patients to a greater extent than has previously been observed with locoregional treatments. Newer iterations of PRRT (alpha emitting particles, somatostatin receptor antagonists) and emerging combinations with the more cytoreductive tyrosine kinase inhibitors offer the potential for even greater benefit and should replace locoregional therapy for NET patients with liver metastases within the next decade.

Table 1.

Outcomes in NET Patients Treated with Systemic Therapy and Liver-Directed Therapy

Treatment Patient Population Sample Size Study Type Endpoint(s) (OS and PFS median unless otherwise specified)
177Lu-DOTATATE Plus Octreotide vs. High Dose Octreotide (7) Midgut NETs 229 Randomized Trial OS: NR vs. 27.4 months; PFS: HR .21 (95% CI .14.33)
177Lu-DOTATATE (9) Pancreatic NETs 133 Cohort Analysis OS: 71 months
Midgut NETs 181 OS: 60 months
CAPTEM vs. Temozolomide (15) Pancreatic NETs 144 Randomized Trial PFS: 22.7 months vs. 14.4 months (HR .58, p = .023); OS: NR vs. 38 months (HR .41, p = .012)
Cabozantinib (18) Pancreatic NETs 20 Single-Arm Prospective Trial PFS: 21.8 months (95% CI 8.5–32)
Midgut NETs 41 PFS: 31.4 months (95% CI 8.5-NR)
Lenvatinib (17) Pancreatic NETs 55 Single-Arm Prospective Trial PFS: 15.5 months (95% CI, 11.3-NR)
Midgut NETs 56 PFS: 15.4 months (95% CI, 11.5–19.4)
Chemoembolization vs. Bland Embolization (6) Progressive Small Intestinal NETs 26 Randomized Trial PFS: 23.6 months versus 19.2 months (p = .9)
Hepatic Debulking vs. Bland Embolization (4) Well Differentiated NETs 120 Retrospective Analysis Mean OS: 43 ± 26 months vs. 24 ± 15.8 months (p < .001)
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Abbreviations: NET, neuroendocrine tumor; 177Lu-DOTATATE, lutetium-177 DOTATATE, CAPTEM, capecitabine plus temozolomide; OS, overall survival; PFS, progression-free survival; 95% CI, 95% confidence interval; HR, hazard ratio; NR, not reached

Hepatobiliary Cancers

In hepatocellular carcinoma (HCC), locoregional therapies currently have a defined role for a small subset of patients. Apart from patients who are able to undergo resection (patients with liver-limited disease, no vascular invasion and adequate hepatic reserve), in whom there is potential for long term survival, the benefit from liver-directed therapies appears to be more modest (19). In an early study comparing chemoembolization to bland embolization, 112 Child-Pugh A and B HCC patients were randomized between the two treatments (20). The study was stopped early when a definitive survival benefit emerged in the chemoembolization arm (HR .47, p = .025). The survival probabilities at 1 and 2 years were 82% and 63%, respectively. Other subsequent studies suggested a similar benefit of radioembolization with selective internal radiation therapy (SIRT) in HCC (21). Based upon these findings, both modalities were combined with sorafenib and compared against sorafenib monotherapy in randomized trials. In the phase III SORAMIC study, 424 patients were randomized to sorafenib plus SIRT vs. sorafenib alone (22). No difference in OS was appreciated between the two arms (12.1 months for the combination arm vs. 11.4 months for the monotherapy arm, p = .953). Based on these data, there is no proven role for SIRT off a clinical trial in this disease. Grade 3/4 adverse events were reported in 64.8% of patients in the combination arm compared to 53.8% of patients in the sorafenib arm (p = .04). In the phase III STAH trial, 339 patients were randomized to chemoembolization plus sorafenib vs. sorafenib monotherapy (23). No difference in OS was appreciated between the two arms (12.8 months for the combination arm vs 10.6 months for the monotherapy arm, p = .29). Serious adverse events (≥ grade 3) occurred in 33.3% of the combination treated patients compared to 19.8% of patients in the sorafenib monotherapy arm (p = .006).

The systemic treatment armamentarium for HCC has changed dramatically over the last 5 years, with multiple FDA drug approvals and others pending. Sorafenib, which had been the gold standard of systemic therapy in this disease for several years, now faces significant competition from immunotherapy combinations and more potent tyrosine kinase inhibitors (24) (Table 2). Most recently, in the IMBrave150 randomized phase III study, atezolizumab plus bevacizumab demonstrated OS superiority compared to sorafenib in treatment naïve metastatic HCC patients (25). In this 501-patient study, patients who received atezolizumab plus bevacizumab had a HR of .58 (p = .0006) for OS compared to patients treated with sorafenib. No significant difference in grade 3/4 adverse events occurred between the two arms (57% vs 55%). Lenvatinib was shown to be non-inferior to sorafenib in a randomized phase III study (13.6 months vs 12.3 months) and demonstrated a greater objective response rate (26). In the second-line setting, nivolumab plus ipilimumab has garnered accelerated approval for HCC patients with progressive disease on sorafenib. From 49 patients in the cohort from Checkmate-040 treated with the combination, 33% achieved a partial response (27). Duration of response ranged from 4.6–30.5 months with 31% lasting 24 months.

Table 2.

Comparison of Reported First-Line Studies in HCC and CCA Patients

Treatment Patient Population PFS (median) OS (median)
Atezolizumab Plus Bevacizumab vs. Sorafenib (25) Treatment Naïve Unresectable HCC Patients 6.8 months vs. 4.5 months (HR .59, 95% CI .47-.76) NR vs 13.2 months (HR .58, 95% CI .42-.79)
Lenvatinib vs. Sorafenib (26) Treatment Naïve Unresectable HCC Patients 7.4 months vs. 3.7 months (HR .66, 95% CI .57-.77) 13.6 months vs. 12.3 months (HR .92, 95% CI .79–1.06)
Sorafenib Plus SIRT vs. Sorafenib (22) Treatment Naïve Advanced HCC Patients 5.2 months vs. 3.6 months (HR .73, 95% CI .59-.91) 12.8 vs. 10.8 months (HR .91, 95% CI .691.21)
Sorafenib Plus Chemoembolization vs. Sorafenib (23) Systemic Treatment Naïve Advanced HCC Patients Not provided 12.1 months vs. 11.4 months (HR 1.01, 95% CI .81–1.25)
Gemcitabine Plus Cisplatin Plus SIRT (28) Unresectable Treatment Naïve CCA Patients 14 months (95% CI 8–17) 22 months (95% CI 1452)
Gemcitabine Plus Cisplatin Plus Nab-Paclitaxel (30) Unresectable Treatment Naïve CCA Patients 11.8 months (95% CI, 6–15.6) 19.2 months (95% CI, 13.2 -NR
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Abbreviations: HCC, hepatocellular carcinoma; CCA, cholangiocarcinoma; PFS, progression-free survival; OS, overall survival; SIRT, selective internal radiation therapy; NR, not reached; HR, hazard ratio; 95% CI, 95% confidence interval

Many of these systemic therapies have only been trialed in patients with a significant burden of hepatic disease. It is plausible to believe if utilized in lower volume settings, such as where embolization is routinely utilized, that they would be even more effective. Furthermore, in the studies where embolization was added to the previous systemic standard of care sorafenib, it did not add any survival benefit. Now, with improved systemic therapies, it does not appear to be illogical to presume that these therapies would also be superior to embolization.

Based on case reports of efficacy in intrahepatic cholangiocarcinoma (CCA), a prospective single arm phase II study of SIRT in combination with gemcitabine plus cisplatin was recently reported (28). In this trial, 46 treatment naïve patients with unresectable intrahepatic CCA were treated with SIRT (to either one or both liver lobes) plus gemcitabine plus cisplatin. The median OS of treated patients was 22 months with a one-year OS rate of 75%. Of these patients, 9% were also able to be converted to surgical candidates. Though the absolute survival benefit appears to be an improvement over gemcitabine plus cisplatin (11.7 months in the ABC-02 trial), systemic therapy efficacy has not been reported in cholangiocarcinoma patients specifically with liver-limited disease (29). It is possible the favorable disease biology of these patients was what led to the survival benefit compared to historical controls. Furthermore, novel systemic therapies in CCA may create the same degree of benefit as locoregional treatment combinations. A phase II study of gemcitabine, cisplatin and nab-paclitaxel in treatment naïve CCA (38% with intrahepatic) patients elicited median OS times of 19.2 months (30). A randomized phase III study of gemcitabine, cisplatin ± nab-paclitaxel is ongoing and if the study is positive, this will establish a new first-line standard of care in metastatic or unresectable biliary cancer patients [NCT02392637].

Broad molecular profiling efforts in CCA have revealed a significant proportion of actionable mutations, particularly in patients with intrahepatic CCA (31). IDH1 mutations and FGFR2 fusions have been found in 30% and 15% of tumors, respectively, and targeted therapies directed towards both have demonstrated tremendous promise in refractory settings. In the randomized phase III study CLARIDHY, which enabled crossover, IDH1 mutant CCA patients who received the IDH1 inhibitor ivosidenib had a HR of .37 (p < .001) for PFS (32). In a phase I/II study, the FGFR2 inhibitor derazantinib elicited a PFS of 5.7 months and response rate of 20.7% in treatment refractory CCA patients with FGFR2 fusions (33). In another phase II study, the pan-FGFR inhibitor pemigatinib elicited a PFS of 6.9 months and response rate of 35.5% in unresectable CCA patients with FGFR2 fusions or rearrangements (34). Both approaches suggest meaningful disease progression can be achieved in CCA patients (with targetable mutations) with progression on first-line chemotherapy. In the unresectable setting for CCA patients, it appears that improvements in systemic therapy already trump the potential of locoregional treatment. Furthermore, currently available agents targeting IDH1 and FGFR2 are first generation drugs and the spectrum of resistance mechanisms are still being identified. Gatekeeper mutations which create acquired resistance to FGFR inhibitors have already begun to be identified. In a patient who progressed on pemigatinib, rapid autopsy revealed the presence of a FGFR2 N549H tumor mutation (35). It is conceivable within the next decade that newer generation FGFR2 inhibitors will be able to overcome such gatekeeper mutations akin to osimertinib in EGFR mutant non-small cell lung adenocarcinoma.

CRC

Apart from resection of oligometastatic disease to the liver, which offers CRC patients an opportunity for prolonged survival and cure, several other liver-directed approaches such as radioembolization, chemoembolization, hepatic arterial infusions (HAI) and stereotactic ablative radiation therapy (SABR) have been utilized, with varying degrees of evidence. A small 21 patient study which compared 90Y-radioembolization plus systemic fluorouracil versus systemic fluorouracil in metastatic CRC patients (86% who possessed liver-limited disease) found that patients treated with the combination experienced both time to progressive disease (18.6 months vs. 3.6 months, p < .0005) and response rate benefit (36). Other large non-randomized prospective series have suggested a greater benefit from SIRT in metastatic CRC patients who are less pretreated (37). Based on these signals, an outstanding series of phase III trials (FOXFIRE, SIRFLOX and FOXFIRI-Global) which were designed to be analyzed in aggregate, randomized treatment naïve metastatic CRC patients to FOLFOX plus SIRT (concurrent with cycle 1 or 2) or FOLFOX (38). Of the included patients, 65% had liver-limited disease. Median OS was no different between the two arms (22.6 months in the combination arm vs. 23 months in the FOLFOX arm, p = .61). This study definitively proved there was no benefit to upfront addition of radioembolization to chemotherapy in treatment naïve patients with metastatic CRC. As with HCC, there is no established role for this liver-directed therapy in CRC outside the auspices of a clinical trial.

In a large pooled analysis from Memorial Sloan Kettering Cancer Center (MSKCC), outcomes between 948 metastatic CRC patients with liver involvement treated with HAI, chemoembolization and SIRT were compared (39). The HR for HAI compared to chemoembolization was .37 and the HR for HAI compared to SIRT was .45; this was consistent across patients with both liver-limited and extrahepatic disease. Further provocative data suggests the largest benefit of HAI may be in the perioperative setting for CRC patients with resectable liver metastases. A 20-year single-center database analysis of CRC patients with resectable liver metastases from MSKCCC suggested that the median OS of patients treated with HAI was 67 months compared to 44 months in patients who were not treated with HAI (40). Most patients (74–97%) who were treated with HAI also received systemic chemotherapy. Though the OS observed in patients in this analysis was striking, a randomized phase II study of FOLFOXIRI ± panitumumab in RAS wild-type treatment naïve CRC patients produced similar outcomes (41). In the cohort of patients with resectable liver metastases, patients treated with FOLFOXIRI and the biologic agent experienced an OS of 52 months. HAI has never been compared in a randomized phase III trial against systemic chemotherapy in either patients with resectable or unresectable CRC liver metastases.

The randomized phase II trial SABR-COMET included 18 patients with metastatic CRC (42). In this 99-patient study, patients were randomized to systemic therapy plus SABR to each metastatic site (up to 5) or systemic therapy alone. Patients in the experimental arm achieved OS times of 41 months compared to 28 months in the standard treatment arm (HR .57, p = .09). By the prespecified statistical design, the study met statistical significance. The specific location of metastases in patients by primary tumor site was not provided in the original manuscript, thus it is unclear whether the findings are applicable to liver-predominant CRC patients.

Some of the most profound advances in systemic therapy for CRC have occurred in molecular subsets previously considered to be poorly prognostic (microsatellite instability-high (MSI-H), NTRK fusions, BRAFV600E) (Table 3) (43). Pembrolizumab and nivolumab are FDA approved for refractory MSI-H CRC patients who have progressed on prior therapy. Nivolumab elicited a response rate of 31.1%, 24-month PFS rate of just under 50% and a median duration of response which had not yet been reached in treated patients (44). Pembrolizumab produced a response rate of 33%, median OS of 31.4 months and median duration of response which had not yet been reached in treated patients (45). A recent press release from the Keynote-177 study, where pembrolizumab is being compared against FOLFOX-based chemotherapy in the first-line setting for metastatic MSI-H CRC patients, suggests the immunotherapy-treated patients achieved a statistically significant improvement in PFS compared to chemotherapy-treated patients; the final OS data is still pending (46). Beyond checkpoint inhibitor monotherapy, combining the checkpoint inhibitors nivolumab and ipilimumab has also been shown to be effective in refractory MSI-H CRC (47). Nivolumab plus ipilimumab has also been tested in treatment naïve metastatic CRC patients. In a single cohort of 45 patients who received treatment with the combination in the Checkmate-142 trial, response rate was 60%, 12-month survival was 83% and median duration of response had not yet been reached (48). Despite the striking duration of response of checkpoint inhibitors, currently, they are only available for the 5% of metastatic CRC patients with MSI-H tumors.

Table 3.

Outcomes in CRC Patients with Actionable Mutations

Study Population Treatment Sample Size Study Type Endpoint(s) (OS and PFS median unless otherwise specified)
Pretreated MSI-H CRC Patients (44) Nivolumab 74 Multi-Cohort Prospective Trial 12-month OS: 73.4%; 12- month PFS: 50.4%
Pretreated MSI-H CRC Patients (47) Nivolumab Plus Ipilimumab 119 Multi-Cohort Prospective Trial 12-month OS: 85%; 12- month PFS: 71%
MSI-H Treatment Naïve CRC Patients (48) Nivolumab Plus Ipilimumab 45 Multi-Cohort Prospective Trial 12-month OS: 83%; 12- month PFS: 77%
Pretreated Patients with NTRK Fusions (50) Larotrectinib 55 Prospective Basket Trial PFS: NR; ORR: 75%
Pretreated Patients with NTRK Fusions (51) Entrectinib 54 Prospective Basket Trial PFS: 11 months; ORR: 57%
Pretreated BRAFV600E CRC Patients (57) Encorafenib Plus Cetxumab ± Binimetinib vs. Chemotherapy 665 Randomized Trial Triplet OS: 9 months vs 5.4 months (HR .52, 95% CI .39-.7); Doublet OS: 8.4 months vs. 5.4 months (HR .6, 95% CI .45-.79)
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Abbreviations: CRC, colorectal cancer; MSI-H, microsatellite instability-high, OS, overall survival; PFS, progression-free survival; HR, hazard ratio; 95% CI, 95% confidence interval; NR, not reached; ORR, objective response rate

During the widespread adoption of genomic profiling in order to capture MSI-H CRC tumors, other colocalizing mutations such as NTRK fusions were identified. Though these fusions are found in only 1% of CRC patients, they represent a truly actionable mutation (49). In an aggregate analysis of 55 patients with mixed tumor types pooled from early phase I/II studies, the TRK inhibitor larotrectinib elicited a response rate of 75% (50). Of the 4 CRC patients included, 2 achieved a partial response and one achieved stable disease. At 1 year, 71% of responses remained ongoing and median duration of response and PFS had not yet been reached. In a subsequently reported aggregate analysis of 54 patients with mixed tumor types treated with the TRK inhibitor entrectinib, response rate was 57% and median duration of response was 10.9 months (51). Of the 4 CRC patients included, 2 achieved a partial response and one achieved stable disease. We anticipate the ongoing discovery of new biological CRC subsets defined by highly actionable targets in the next several years.

Massive ongoing research efforts are exploring methods to sensitize microsatellite stable (MSS) CRC to checkpoint inhibitors. One promising strategy involves combining nivolumab with the anti-angiogenic regorafenib; the latter is thought to reduce feedback expression of immune suppressive markers programmed death ligand-1 (PD-L1) and indoleamine 2,3-dioxygenase (IDO) on tumor cells in response to checkpoint inhibitors (52). In the phase I study of the combination in 25 metastatic MSS CRC patients, 29% of patients achieved an objective response (53). In the past, nivolumab or other checkpoint inhibitor monotherapy elicited response rates of 0% in this patient group (54). A single arm phase II study of nivolumab plus regorafenib in MSS CRC patients is ongoing [NCT04126733]. Beyond regorafenib, a staggering array of molecules are being tested in combination with checkpoint inhibitors in MSS CRC to try to unlock the efficacy of the agents. Some of these include other immune modulators, chemotherapeutics and biological agents (55). We believe within the next decade the puzzle of unlocking the immunosuppressive tumor microenvironment of MSS CRC will be achieved. Once immunotherapy becomes a cornerstone therapy in most CRC patients, given the likelihood of durable response in patients deriving benefit from the treatments, there will be much less need for locoregional therapies, including resection, in CRC patients with hepatic metastases. BRAFV600E mutations are found in 5–15% of CRC patients and carry an extremely poor prognosis (56). The median OS of metastatic CRC patients with the mutation is close to 1 year whereas the median OS for patients with metastatic CRC is greater than 30 months. A recent phase III study which compared non-chemotherapy triplet (cetuximab, encorafenib and binimetinib) and doublet combinations (cetuximab, encorafenib) to standard second-line chemotherapy demonstrated significant improvements in both experimental arms compared to the chemotherapy arm (57). This trial will establish cetuximab plus encorafenib as the second-line treatment standard for BRAFV600E patients and backbone upon which future experimental agents may be added. Outcomes in patients with BRAFV600E have in large part not been reported from studies of patients undergoing liver-directed therapies. It is likely these patients were excluded from such studies by not being candidates due to fulminant disease. We anticipate, with subsequent additions to the encorafenib plus cetuximab backbone over the next 10 years, that OS in BRAFV600E CRC patients will approach the OS in other CRC patients.

RAS mutant CRC tumors remain a subgroup in need of further drug development. RAS mutations are found in 40–45% of metastatic CRC and, beyond predicting a lack of benefit from frontline therapy with anti-EGFR agents, tend to predict a more aggressive disease course (58). Many agents have been developed for this target however have failed in clinical testing; initial treatment approaches targeted post-translational RAS modifications including MEK and farnesyltransferase inhibitors (59). Preclinical work suggests the promise of novel agents such as the engineered pan-RAS monoclonal antibody inRAS37 as monotherapy or in combination with inhibitors of downstream effectors (60). We anticipate in the coming decade that a successful RAS inhibitor will be developed for CRC patients. Whether the agent is added to first-line chemotherapy or perhaps used in the maintenance setting post-response to initial chemotherapy, it will add to the armamentarium of active therapies available for CRC patients.

Other Gastrointestinal Malignancies

We have discussed the data for locoregional therapy for hepatic metastases in gastrointestinal cancers where the practice is routinely utilized. In several others, such as pancreatic adenocarcinoma and gastroesophageal adenocarcinoma, liver directed therapy, including complete resection of synchronous metastases, is not often attempted due to the lack of prospective data about the practice changing disease outcomes for patients (61,62). Systemic treatments for patients with pancreatic cancer and gastroesophageal adenocarcinoma have improved steadily over the last decade with the development of therapeutics targeting DNA damage repair, HER2 amplifications and PD-L1 overexpression. Recent data in pancreatic adenocarcinoma patients suggests patients with actionable mutations who are matched to appropriate targeted therapies demonstrate significant survival benefit over patients who receive standardized therapies (63). Given the emergence of novel targets and ongoing preclinical drug development efforts, we anticipate breakthroughs as the landscape of systemic therapy continues to evolve in these diseases.

Conclusion

Though liver metastases are an important cause of morbidity and mortality in cancer patients, we demonstrate, using a backdrop of gastrointestinal cancer, that current evidence for locoregional therapy, outside of curative resection, is not superior to the current evidence for systemic therapies in patients. In fact, few studies have shown survival benefit for any liver-directed therapy in cancer aside from potentially curative resection, and the continued use of liver-directed therapies is usually based on retrospective data or single arm phase II studies with highly selected patient cohorts. The use of many of these unproven therapies off clinical trials impedes the advancement of novel therapies in patients who may not be receiving benefit and are getting toxicities. Further, we contend that pending developments in the field, such as the widespread adoption of immunotherapy, identification of new targetable biologic disease subsets through comprehensive genomic profiling and development of increasingly potent therapeutics will produce more durable responses and render liver-directed therapies obsolete over time. The last decade has seen an unparalleled series of advances in most cancers. In fact, many diseases such as lung cancer, breast cancer and melanoma have seen more advances than the gastrointestinal cancers we opted to discuss in this article. The promise of immunotherapy, targeted therapy and other agents such as antibody-drug conjugates is encouraging and at some point will hopefully reduce the need for surgical resection as well. Though this may seem controversial, we believe the preceding paragraphs fortify our position.

Key points.

  1. Outside of curative resection of hepatic metastases, locoregional therapy for liver metastases has not demonstrated benefit over systemic therapy in neuroendocrine tumor, hepatobiliary or colorectal cancer patients.

  2. Though studies reporting on neuroendocrine tumor patients treated with hepatic debulking (even incomplete resections) present impressive survival data, these analyses do not include patients treated with newer systemic standards such as peptide receptor radionuclide therapy.

  3. In diseases such as hepatocellular carcinoma or colorectal cancer, embolization therapy has not added any survival benefit for patients when combined with standard of care systemic therapies. In other diseases such as cholangiocarcinoma, the survival benefit of embolization therapy in combination with systemic therapy, is approximated by novel systemic therapy combinations.

  4. Advances in systemic therapy for gastrointestinal, and indeed all cancer patients have been driven by the identification of targetable biologic subgroups, the development of more potent therapeutics and the widespread adoption of immunotherapy.

Synopsis.

Hepatic metastases are a major cause of morbidity and mortality for cancer patients. Apart from curative resection, which offers patients the potential for long term survival, an array of locoregional therapies, with limited evidence of improving survival, are employed to treat them. We utilize examples from the realm of gastrointestinal cancer, largely focusing on the experience of neuroendocrine tumor, hepatobiliary cancer and colorectal cancer patients, to suggest that current systemic therapies offer, at minimum, similar survival outcomes for patients compared to these locoregional approaches. Further, we posit that advances in systemic therapy, driven by improved molecular understanding of disease and identification of targetable subgroups, will deepen responses for patients and make locoregional therapies for those with hepatic metastases obsolete within the next decade.

Footnotes

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Disclosure statement:

Satya Das receives Speakers’ Bureau fees from Ipsen and has received honoraria in the past from Targeted Oncology and Medsphere; Jordan Berlin participates in a consulting or advisory role for Abbvie, Arno Therapeutics, AstraZeneca, Bayer Health, BeiGene, Celgene, Cornerstone Pharmaceuticals, Eisai, EMD Serono, Erytech Pharma, Exelixis, Five Prime Therapeutics, Genentech/Roche, Gritstone Oncology, Karyopharm Therapeutics, LSK Biopharma and Seattle Genetics. He has received honoraria in the past from Nestle Health Science.

Contributor Information

Satya Das, Department of Medicine, Division of Hematology Oncology, Vanderbilt University Medical Center, 777 Preston Research Building, 2220 Pierce Avenue, Nashville, TN 37232,.

Jordan Berlin, Department of Medicine, Division of Hematology Oncology, Vanderbilt University Medical Center, 777 Preston Research Building, 2220 Pierce Avenue, Nashville, TN 37232.

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