Lung metastases from hepatocellular carcinoma: multidisciplinary approach—narrative review

Introduction

Globally, hepatocellular carcinoma (HCC) is the sixth most commonly diagnosed cancer and the third leading cause of cancer related deaths worldwide in 2020, representing the second leading cause of cancer-related deaths in men and the sixth cause among women (1). Different approaches are considered in the treatment of HCC, such as curative hepatic surgery, liver transplantation, transcatheter hepatic arterial chemoembolization, radiotherapy including local ablation by radiofrequency or percutaneous ethanol injection, and chemotherapy also with targeted therapy, like sorafenib. The use of the aforementioned multimodality treatments has greatly improved the survival of patients affected by HCC (2).

Despite these different approaches, HCC has a high recurrence frequency rate, with Poon et al. reporting a cumulative 5-year recurrence rate of 75–100%, both in terms of local relapse and distant metastasis (3). Lungs are the most frequent site of extrahepatic metastases (47%) followed by lymph nodes (45%), bone (37%) and adrenal glands (12%) (4). Opposite to local recurrence, extrahepatic metastasis has to be considered a terminal-stage cancer, and because of the lack of effective treatments prognosis continues to be poor. Indeed, for patients with extrahepatic metastasis the median survival is 9.6 months and the overall 1-, 3-, and 5-year survival rates are 31%, 7%, and 4% respectively (5).

Furthermore, concerning patients with untreated pulmonary metastases (PM), mean survival is 3.3 months from diagnosis (6). To further improve long-term survival of HCC patients, more active treatments of extrahepatic recurrence seem to be required. The aim of this review is to evaluate the significance of surgical resection for PM from HCC and the integration of surgery with other treatment options.

We present the following article in accordance with the Narrative Review reporting checklist (available at https://asj.amegroups.com/article/view/10.21037/asj-21-54/rc).

Methods

A literature search was undertaken to identify published studies regarding treatment of PM from HCC. Candidate studies in English were sought for up to February 2021 via a computerized search of PubMed, Embase, Cochrane Central, Web of Science, and Google Scholar databases. Keywords and meSH terms entered in the search were ‘pulmonary metastasectomy’, ‘pulmonary resection’, ‘lung metastases’, ‘surgical approach’, ‘radiation therapy’, ‘chemotherapy’, ‘Sorafenib’, and ‘Hepatocellular Carcinoma’, or ‘liver transplant’.

The reference lists of all the relevant retrieved articles were evaluated manually for further relevant studies.

Studies were considered for inclusion and further analysis on the basis of the following criteria:

• Patients diagnosed with lung metastases from HCC who received surgery, chemotherapy, radiation therapy or targeted therapy either alone or in combination;
• Randomized controlled trials or observational studies (cohort and case-control studies);
• Studies providing sufficient perioperative and oncologic outcome data.

Also, studies with inextractable data, review articles, editorials, comments, letters, case reports, and animal experimentation were excluded from analysis.

The study outcomes analyzed included: number of patients, number of lesions, surgical approach, overall survival (OS) (median), and disease-free survival (DFS) (median).

Two independent analysts (GZ and LM) identified the publications based on title and abstract according to the above-mentioned eligibility criteria. Any disagreement was resolved by a third analyst (GMC). Thereafter, the full texts of potentially relevant studies were reassessed to determine their conformity with the criteria. Relevant data from included articles were extracted and entered into a standardized data table. The following data were extracted from each included study: first author, publication year, treatment of primary tumor, median disease-free interval (DFI), number of lesions, number of patients, surgical approach and median OS. Survival data were extracted directly from the text. Information used to write this paper was collected from the sources listed in Table 1.

Discussion

Pulmonary metastasectomy for HCC

Advances in surgical techniques and perioperative management has markedly improved the survival rate of patients with HCC, however it hasn’t been clarified the role of surgery for PM from HCC yet (40).

In thoracic surgery pulmonary metastasectomy is the second most frequently performed procedure after primary lung cancer surgery, and it represents a major part of thoracic surgeons profession (15–50%) (41). The original surgical indications for lung metastasectomy were proposed in 1965 by Thomford et al. (42) and summarized as follows: feasibility of a complete resection of all known disease; tolerable general and functional risk; primary tumor under control; no evidence of extrathoracic disease.

Although HCC was not included in the study of Thomford, subsequent studies reported pulmonary metastasectomy for HCC following criteria based on a modification of the principles of Thomford (12,18,21). For example, many authors agree that primary or recurrent HCC with synchronous PM shouldn’t be considered as a contraindication for pulmonary resection if hepatic nodule is thought to be controllable, in patients with adequate general physical condition and sufficient expected pulmonary function after pulmonary metastasectomy (12,25,37).

Indeed, many patients with HCC with PM are not considered fit for surgery due to a reduced functional status, advanced disease stage and severe liver dysfunction (37).

Nowadays, the decision to proceed with surgical resection must consider the relative risks and benefits. For this reason, a multidisciplinary group should be discussing each case with a dedicated oncologist, surgeon, radiotherapist, radiologist and pathologist.

The aim of the surgery is to completely remove lesions preserving as much lung tissue as possible, therefore taking with it a 0.5- to 1.0-cm margin of normal lung tissue in all directions (R0 resection) (43). From a technical point of view, lung metastatic lesions are resected through wedge resection for peripheral lesions, whereas anatomical resections (segmentectomy, lobectomy or bilobectomy) are preferred when metastatic lesions are located deeper in the pulmonary parenchyma (lesion involving the lobar or pulmonary hilum) or in case of larger lesions or in the presence more nodules in same segment/lobe (12,37,40).

Standard thoracotomy is the preferred access for unilateral metastasis or as staged thoracotomies for bilateral lesions (44). An open approach consents an adequate visualization and access of the organ surface and the possibility to fulfill a whole lung parenchyma palpation to identify occult nodules undetected by preoperative computed tomography (CT) scan.

Video-assisted thoracoscopic surgery (VATS) has progressively become more popular for resection of pulmonary lesions since its introduction in the 1990s. Advantages of a minimally invasive approach include limited skin incision, a decrease in postoperative pain and hospitalization time (44). The most remarkable limitation is the difficulty lung palpation in its entirety, possibly leading to incomplete metastasectomy (45,46). Despite this limitation, VATS is being utilized more and more frequently; since the majority of PM are located peripherally, nodules are the perfect candidates for this technique while the use of localization techniques (hook wires, methylene blue injection, indocyanine green injection) makes it possible to resect also deeper metastases. In addition, VATS minimizes adhesion formation and makes repeated resection more feasible, especially for patients with chronic disease such as liver cirrhosis (40). Finally, in contrast to the inaccuracy of old-generation CT scans, new high-resolution CT (HRCT) has a higher detection rate of metastatic pulmonary nodules, possibly becoming a substitute for manual palpation (40). even if other studies show that manual palpation still has a higher detection rate (47).

Many studies have been published to date comparing thoracoscopic versus open surgery approach concerning lung metastases from colorectal cancer: case-matched studies showed that survival after VATS pulmonary metastasectomy is not inferior to open thoracotomy (48), and some authors even showed better OS using thoracoscopic metastasectomy than the open approach (49). A recent study by Markowiak et al. compared video-assisted pulmonary metastasectomy to thoracotomy, experiencing that histologically complete resection (R0) was achieved in 90.5% of patients who underwent VATS and thus was comparable to the resection status after thoracotomy. Moreover, VATS metastasectomy revealed to be equally successful to thoracotomy in regard to lymph node status, recurrence-free survival and OS (50).

Furthermore, in a study by Prenafeta Claramunt et al. no significant difference was noted in ipsilateral recurrence rates between VATS and open surgery considering the treatment of colorectal cancer lung metastases, so that VATS approach in the current era is widely accepted for resection of PM from colorectal cancer (51).

On the contrary, there is still a lack of studies specifically focusing on the best surgical approach to lung metastasectomy from HCC. Recently Lee et al. investigated surgical outcomes of HCC patients who underwent pulmonary metastasectomy according to the surgical approach, showing that VATS provides results comparable to those by open metastasectomy (thoracotomy or sternotomy) in terms of OS rate, DFS rate and pulmonary-specific DFS rate (40).

Concluding, VATS metastasectomy proved to have outcomes comparable to those of open metastasectomy (40,50), but conversion to open approach should still be considered if the lesion detected by CT-scan can’t be palpated or resected by VATS approach. Further studies are still required on this topic. Regardless of the type of surgical approach used, the principal requirement for pulmonary metastasectomy remains radical resection of the lesion (40).

Lymph node dissection

According to a radiological study, HCC rarely metastasizes to mediastinal lymph nodes. Only 4.7% of extrahepatic metastasis are located in mediastinal lymph nodes and 0.6% are in subcarinal ones (52). Mechanisms for mediastinal lymph node involvement may be related to the intra-pulmonary lymphatic drainage of a lung metastasis from HCC or a direct spread from the hepatic portal region to the mediastinal lymph-nodes (53).

To date, there is no agreement concerning the need for dissection of the mediastinal lymph nodes during surgery for PMs from HCC.

Kawamura et al. described only 4 cases (9%) of lymphatic metastases proven histologically in patients undergoing metastasectomy for HCC, but did not analyze the impact of positive lymph nodes on prognosis (19).

A study by Han et al. reported mediastinal lymph node dissection in 75% of cases of pulmonary metastasectomy in a series of 41 patients, and found 19.4% of patients presenting metastatic mediastinal lymph nodes. Hence it was concluded that dissection of mediastinal lymph nodes is required and should be carried out as a routine procedure in pulmonary metastasectomy for HCC (22). Despite this, mediastinal lymph nodes were not routinely dissected in most cases reported in literature, unless preoperative examination particularly through fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT scans identifies enlarged lymph-nodes (14,21,23,36,40,54), but no study focused on the impact that positive lymph nodes have on prognosis. Thus, it is advisable that more studies should be produced on this topic.

Prognostic factors after pulmonary metastasectomy

Over the last few years many authors aimed to evaluate the prognostic factors related to PM from HCC.

According to a recent work by Nakamura et al. three risk factors influence the prognosis in patients with lung metastasis from HCC: number of pulmonary nodules, viral hepatitis and presence of other site recurrence before pulmonary metastasectomy (37).

Regarding the number of lesions and based on the consideration that in most cases PM from HCC were multiple and, even when a metastasis seemed solitary, it was commonly supposed that occult metastases were present, PM from HCC were not considered amenable of surgical resection (55). Lam et al. were among the first who demonstrated that a prolonged survival is possible in selected patients after surgical resection of isolated PM from HCC reporting a median survival after lung resection of 42 months (7).

However subsequent studies showed conflicting results. Nakagawa et al. for instance, found that the number of lesions (single or multiple) and their location (unilateral or bilateral) showed no correlation to cancer-specific survival in a significant way (13).

On the contrary, in a study by Kuo et al., bilateral distribution and multiple PM were described as adverse factors for DFS at univariable analysis, and only the number of PM was seen to be an independent prognostic factor at multivariable analysis (14). The same results were obtained by Kawamura et al., in particular a stepwise regression analysis identified three or less PM to be an independent factor of better prognosis, with no other factors influencing the outcomes (19). Lee et al. showed that pulmonary metastasectomy in HCC patients might be beneficial if primary tumor was controlled by surgery and with less than three pulmonary nodules (21). Yoon et al. found that long DFI, lung as first site of recurrence and solitary PM were associated with better OS by univariate analysis (23).

More recently, in a retrospective study considering 103 patients who underwent surgical resection for PM from HCC, a correlation was highlighted between patients with a single lesion, tumor size <2 cm, tumor located on one side or one lobe, and a significantly better OS (38).

Secondly, with regard to viral hepatitis and hepatic status in general, absence of hepatitis B virus (HBV) infection was described as a favorable predictive factor for survival in a study by Kwon et al. (18). Indeed, median survival is longer for patients with a Child-Pugh score A at the moment of surgery (21), and the maintenance of normal liver function after pulmonary metastasectomy tends to be associated with favorable OS (38), whereas history of liver cirrhosis has been described as an independent negative prognostic factor (40).

Thirdly, it is widely accepted that the presence of extrahepatic/extrapulmonary recurrence is an unfavorable factor for survival. An analysis of recurrence by Han et al. revealed poorer survival rate in patients with recurrence in organs besides, liver or lung, which suggests that a scrupulous search for distant metastasis is necessary for patient selection before pulmonary metastasectomy (22). The proportion of patient with inoperable disease has increased in parallel with the development of PET, allowing for a better selection of surgical candidates (56).

Liver recurrence at the time of pulmonary metastasectomy is also significantly associated with unfavorable OS after surgery (38) and in a recent study by Lee et al. local recurrence or progression of HCC and high preoperative level of alpha-fetoprotein (AFP) were described to be independent negative prognostic factors (40).

Regarding the correlation between preoperative levels of AFP and OS after pulmonary metastasectomy, a study by Nakagawa et al. showed a mean survival of 15.9 months for patients with levels of AFP of 500 ng/mL or more, and 39.2 months for those with AFP less than 500 ng/mL (P=0.015) (13).

Similar results were obtained by Ohba et al., who pointed out that significantly poorer OS and cancer specific survival rates were acquired in patients with preoperative AFP ≥500 ng/mL in comparison to those with AFP <500 ng/mL (P<0.05) (27).

Furthermore, an AFP level after metastasectomy <100 ng/mL has been described as a favorable prognostic factor (14,24).

Almost of the studies are based on a small study population, prognostic factors should be seen with caution.

Pulmonary metastasectomy from HCC after liver transplantation

HCC is the only solid cancer that can be cured by transplantation, and this evidence completely changed the strategy of treatment for this tumor. Nonetheless, HCC recurrence post-transplant persists as the primary cause of death in these patients, associated with a high incidence of extrahepatic metastasis.

In one large, single center study, HCC-recurrences after liver transplantation has been detected in 18% of patients and in patients who experienced recurrence the 5-year survival was significantly worse (from 64% to 22%) but, despite shortened survival, significant benefit was described in patients who underwent surgical resection for recurrence (57).

Bates et al. retrospectively studied a cohort of five patients who underwent orthotopic liver transplantation for HCC and subsequent resection of the pulmonary recurrences, concluding that survival times of patients who underwent LT for HCC with PM treated by surgery are similar to those of patients who underwent hepatectomy for HCC with PM (16).

In a further assessment, Hwang et al. evaluate the effect of resection of PM from HCC after liver transplantation comparing outcomes in patients who underwent pulmonary metastasectomy after liver transplantation, and patients who did not due to multiple lung nodules (>5), comorbidity or residual extrapulmonary metastases (26). The OS rate was significantly improved in patients who underwent surgery, hence the conclusion that pulmonary metastasectomy should be performed for resectable PM-HCC, even following LT, as it may provide an improved chance of long-term survival.

More recently, an Italian multicenter experience considering 25 patient who developed PM after liver transplantation for HCC, showed that the 1-, 3-, and 5-year OS from pulmonary recurrence is about 100%, 66% and 43% respectively, with a median OS of 51 months after surgery (39). They concluded that in selected patients with solitary PM from HCC after LT and showing conserved hepatic function, surgical approach may be effective and that repeated pulmonary metastasectomies are not a risk factor for long-term survival in these patients (Table 1).

Non-surgical local ablative therapies

Radiation therapy is considered a palliative therapy that purposes to improve local control and reduce symptoms (58).

External beam radiotherapy (EBRT) is known as one of the most effective options for local control of lung cancer in patients unsuitable for surgical resection, but it has rarely been employed in lung metastatic cases from HCC, and published data on this topic is scarce. Some authors reported that PM from HCC is sensible to EBRT when administered at 50–60 Gy in conventional fractions, with an objective response observed by CT in 76.9% of subjects, leading to median progression-free survival for all patients of 13.4 months, and 2-year survival rate from PMs of 70.7%. Hence EBRT can be considered an effective palliative therapy with a reasonable safety in patients with multiple PMs that were not considered fit for surgery (58).

An additional study by Li et al. reported a series of 29 unresectable cases with PM from HCC that were treated using percutaneous CT-guided radiofrequency ablation sessions, and revealed that 1-, 3-, and 5-year OS rates were 71.6%, 27.9% and 9.3% respectively, with a median survival of 26.3 (range, 3–66) months (59).

Other studies showed that ¹²⁵I brachytherapy combined with sorafenib treatment in patients with multiple lung metastases guarantees an overall 1-, 2-, and 3-year survival rates of 100%, 50% and 12.5%, respectively, with a median survival time of 21 months (60). However, more recent studies, suggested that the combined therapy of sorafenib and radiotherapy lead to an overall incidence of adverse events in 93.3% of patients, and an incidence of severe adverse events in 20% of patients (61). To date there is a lack of information in literature regarding stereotactic radiotherapy in the treatment of HCC lung metastases (62). Li et al. performed a meta-analysis comparing pulmonary metastasectomy and stereotactic body radiotherapy (SBRT) in patients with PM from solid tumors, and no significant difference was observed between the two cohorts of patients in terms of OS and DFS rate (62). Moreover, SBRT was described as a good option for patients with PMs from colorectal cancer who refuse to undergo surgery or considered medically inoperable (63). However, the small sample size, heterogeneity of SBRT protocols and incomparable follow-up periods between the two treatment groups together with the selection bias made the conclusions particularly weak.

Therefore, stereotactic ablative radiotherapy is an arising competitive treatment modality for the management of lung metastases but there is still no evidence of its specific efficacy in PM from HCC (63).

Chemotherapy

Despite extensive efforts, systemic therapy for recurrent HCC has proven ineffective (64,65), and metastatic HCC is generally considered a chemo-refractory tumor (66). Many drugs tested both as single agents or in combination have provided unsatisfactory results, never achieving solid evidence of efficacy.

In fact, for the patients with PM that underwent chemotherapy treatment median survival is 4.6–14 months and 1-year survival rate is only 20–42%, compared to a reported 24–41.4% and 5-year survival rate for patients that underwent metastasectomy (40).

These data can be explained by the difficulty to manage patients with PM from HCC as they commonly show advanced liver disease, so that systemic chemotherapy can rarely be successfully tolerated, and it must be considered that patients not qualifying for surgery generally present a more advanced disease and poorer performance status (67,68). Only in a retrospective study by Chok et al. (30) patients with resectable lung metastases from primary HCC were compared to patients deemed unresectable and treated with systemic therapy. Predictably, patients undergoing surgery showed a better OS than those with unresectable PM (31). However, it shouldn’t be forgotten that the study was influenced by many biases, as previously mentioned (31).

Therefore, local treatments, when feasible, are always preferred to chemotherapy. Additionally, no data are available regarding the role of chemotherapic treatments before or after local therapies.

A novel treatment for PM from HCC is represented by targeted chemotherapy with sorafenib, a multikinase inhibitor approved for the treatment of advanced HCC only in 2008. Anyhow, published results are not homogeneous, and further research is needed.

Some authors validated the use of sorafenib in eradicating multiple lung metastasis, providing a new perspective for patients with recurrent HCCs (69).

In this case, a series of 602 patients with advanced HCCs receiving either sorafenib or placebo have been evaluated in the international phase III placebo-controlled sorafenib HCC assessment randomized protocol trial. Within the sorafenib group, the median OS was 10.7 months, and 7.9 months in the placebo group, and median time to progression was significantly less in patients receiving sorafenib than in those treated with placebo (70).

Despite this, systemic therapy with sorafenib revealed ample variability in terms of prolonged survival, even though not many patients truly profit from this therapy.

It is interesting to point out that, in the study by Chok et al. (30), among unresectable patients, no differences were noted in terms of survival in patients treated with first line sorafenib and patients with standard chemotherapy. Notably, in the former group the improvement in survival was very modest, and the percentage of response to sorafenib in the treatment of advanced HCC was low, 2–3% only (33).

Recently, multimodal therapies merging sorafenib and other treatments, like transarterial chemoembolization or everolimus have been evaluated (67,68). Apparent profits seem promising, but it is auspicable that the future advent of new effective systemic therapy will further improve the survival of the patients (71,72).

Another study by Xiong et al. investigated the effect of saracatinib (a tyrosine kinase inhibitor selective for Src) on PM from HCC, and results indicated that Src inhibition reduces lung metastases effectively (73).

Sheng et al. described in a case report the eradication of multiple bilateral lung metastases from HCC after ablation of primary tumor by transarterial infusion with recombinant adenovirus p53 gene (74).

Moreover, a study by Lu et al. investigated the effect and the underlying mechanisms of ZLDI-8, an inhibitor of ADAM-17 (a key cleavage enzyme of Notch pathway), that seems to inhibit the metastasis of HCC both in vitro and in vivo (75).

Other studies are trying to find new pathways to prevent and cure PM from HCC, and it is fundamental to increase research and trials in this area.

Conclusions

Despite the absence of randomized controlled trials, the results acquired from retrospective case-series suggest that surgical approach to PM from HCC is a valid treatment option.

Collectively, these studies indicate that resection of lung nodules from HCC in well-selected patients (tolerable risk; feasibility of a complete resection; sufficient expected pulmonary reserve after surgery; primary tumor under control) has the potential of leading to long-term survival.

Furthermore, the longer OS after pulmonary metastasectomy from HCC might be achieved in patients with a long DFI, reduced number of lung metastases (≤5 nodules), no presence of liver dysfunction or viral hepatitis at the time of surgery, and no presence of other sites of recurrence before metastasectomy. To date, there is no evidence in literature that open versus VATS approach or routine mediastinal lymph node dissection could present a real advantage in terms of survival, but more studies need to be done in this regard.

Assumed the relative shortage of effective systemic and target therapies, on the basis of available retrospective data, it seems legitimate to perform pulmonary metastasectomy for resectable lung nodules from HCC as it is the only treatment that may provide an improvement of long-term survival, in the hope that more effective therapies will be discovered in the near future.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Davide Tosi, Alessandro Palleschi and Paolo Mendogni) for the series “Management and Treatment of Lung Metastases” published in AME Surgical Journal. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://asj.amegroups.com/article/view/10.21037/asj-21-54/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://asj.amegroups.com/article/view/10.21037/asj-21-54/coif). The series “Management and Treatment of Lung Metastases” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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