Breast cancer is the most prevalent cancer in women with an estimated 246,000 new cases in 2016.49 The appearance of distant metastases in breast cancer disease is its most deadly aspect and represents in many cases an incurable situation. About 50% of all breast cancer patients will develop distant metastases during their disease course.50,51 Bone and lung are the most common breast cancer metastasis sites closely followed by the liver.52,53 Median overall survival in patients who develop metastatic breast cancer is 18 to 24 months, while most of patients die of their disease.54 If liver metastases are present, median survival time is even worse with 14 to 16 months while survival longer than 5 years is very rare when only medical therapy is given.55,56 Isolated liver lesions are found in 1% to 5% of the patients.54,57 Depending on the hormone status of the breast cancer lesions, hormonal therapy or systemic chemotherapy is an important cornerstone of the treatment of those patients and helps to delay progression of the disease. TACE in patients with proven liver metastasis from breast cancer is an alternative or adjunct therapeutic option to systemic treatment with an increase in survival rate by two fold.58 Two factors contribute to the efficacy of TACE: first, the high concentration of chemotherapeutic drugs at the metastatic site and second, the significantly reduced arterial flow that leads to tumor necrosis because liver metastases are mainly perfused through the liver artery.
In patients with isolated breast cancer metastases, surgical resection is an option and should be considered on an individual basis. In those select patients, a 5-year overall survival rate from 20% to 61% and median survival time from 27 to 57 months can be achieved.7,9,34,35,57,59-61 Recurrence-free survival is reported to be between 16% and 22%.57,59,60 To achieve this goal, more often major hepatectomy (64%, ≥3 segments) was performed in a study by Adam et al,62 while anatomic, nonanatomic, and combined anatomic and nonanatomic resections were performed at a similar percentage (31%, 35%, and 34%, respectively). If detection of the liver metastases was longer than 6 months before hepatic resection was performed and if adjuvant chemotherapy was performed, those patients had a better outcome.11 In this study by Reddy et al,11 the strategy of gaining time after the detection of the liver metastases and the surgical intervention was chosen in 60% of the patients. Five of the seven resected 5-year breast cancer survivors had an interval of longer than 6 months between detection and resection and all of them were treated with chemotherapy after surgical intervention. However, as very efficient chemotherapy regimens are available even for breast cancer patients with metastatic spread, most of the patients most likely underwent a significant amount of systemic therapy before and after liver surgery.11,62 As such, the impact of surgery on survival in this subgroup of breast cancer patients is difficult to evaluate, especially since studied patient cohorts who underwent partial liver resection in metastatic breast cancer disease are of about 100 patients at most while many studies do not include more than 34 patients. Additional variables that are negatively associated with survival were identified, such as failure to respond to preoperative chemotherapy, macroscopically insufficient resection status, and the absence of repeat liver resection.62 In other words, patients who have progressive disease or present on preoperative imaging or during intraoperative evaluation as not completely resectable should not undergo surgery based on their poor survival rates. In contrast, if only microscopically positive margins remain (R1), favorable 5-year survival rates of 42% are comparable with R0 resections.62
Following partial liver resection, recurrence develops in about two-thirds of the patients while the median time to recurrence varies around 10 months.62 Most often the site of recurrence is the liver followed by lung, bone, brain, abdomen, and others.11,62 Compared to most other NCNNLM primaries, breast cancer patients have a tendency to recur with brain metastases.
In sum, partial liver resection in patients with dominant breast cancer liver metastases should be considered in multimodal treatment plans. Increasing evidence shows that select patients might significantly benefit from this approach and this treatment option should not be withheld from those patients. Newer and more effective systemic cytotoxic treatments will make cytoreductive surgery even more appealing and the indication for liver resection among breast cancer patients might be even expanded.
Gastrointestinal Stromal Tumors
Gastrointestinal stromal tumors (GISTs) are rare tumors of the alimentary tract accounting for 1% to 3% of all gastrointestinal tumors and are among the most common mesenchymal tumors.63,64 If the resection criteria are met, most of the patients undergo complete excision of the primary tumor with a 40% recurrence rate within 18 to 24 months after primary resection.65 Most often, recurrence is detected in the liver or peritoneum.65-67 Prior to the era of tyrosine kinase inhibitors (TKIs), liver metastases from GISTs were resected whenever feasible achieving 5-year overall survival rates of 27% to 34%.68-70 Since the emergence of TKIs, the treatment algorithm has significantly changed.71 Although highly effective in chemotherapy-naive patients, within 2 years over 50% of the patients develop resistance to TKI and will demonstrate tumor progression and alternative treatment options would be highly warranted. Nonetheless, when evaluating the role of hepatectomy, it is critical to rely on experiences in the current era of targeted therapy.
A multi-institutional study of 39 patients reported by Turley et al72 assessed the role of liver resection in the era of TKI therapy. They demonstrated a 3-year overall survival rate of 67.4% with a median survival longer than 5 years.72 The combined approach of treating metastatic GIST with TKI and liver resection may be superior to other experiences that reported median survival times of 48 months for TKI alone and 36 to 47 months for liver resection only.68–70,73 While the combined approach of TKI and resection has emerged as acceptable when feasible, the appropriate sequencing of those two therapeutic components is not clear. Haller et al74 recommended that liver resection should not be performed before TKI resistance develops. Stagnation of tumor shrinkage on cross-sectional pictures is considered an early sign of tumor resistance. The second treatment approach was suggested by DeMatteo et al75 from the Memorial Sloan Kettering Cancer Center (MSKCC). He and his collaborators recommend that recurrent metastatic disease in GIST patients should be treated with first-line TKI followed by liver resection within 6 months.75,76 This strategy does anticipate the fact that many patients will develop TKI resistance and that TKI therapy effectiveness does often reach a plateau after 6 months of therapy. This approach is furthered by the finding in a prospective trial comparing preoperative and postoperative TKI in conjunction with resection with TKI alone.77 The study by Turley et al72 does also support the approach by DeMatteo et al75 as in their cohort: patients who had a long TKI exposure (median 18 months) before surgery had shorter disease-free and overall survivals compared to patients who received only postoperative TKI therapy. It is hypothesized that debulking of the tumor load in the liver does increase and prolong the effectiveness of TKI by decreasing the risk of a secondary mutation by the GIST tumor cells leading to resistance to this highly active drug.
Epithelial Gastrointestinal Tumors
Partial liver resection for isolated liver metastases with a primary carcinoma in the gastrointestinal tract outside of colorectal or neuroendocrine tumors is very rare. In a series reported by Reddy et al,11 only 3 of 82 patients undergoing liver surgery for NCNNLMs had primary gastrointestinal adenocarcinomas, while in other series the percentage of gastrointestinal metastases was higher reaching up to 18%.12,14 Overall, the poor long-term outcomes in those patients is unlikely to be significantly impacted by liver surgery and is therefore not considered in most of the patients. In a study presented by Cordera et al,10 the hazard ratio for overall survival comparing patients with gastrointestinal primaries to other NCNNLMs was 2.4 (95% confidence interval: 1.2 to 4.8, p = 0.01) after adjusting for multiple covariates, favoring the nongastrointestinal primaries. This finding is supported by others who reported a substantially worse prognosis for patients with gastrointestinal tumors compared to breast, genitourinary, and soft tissue cancer.9,35
Despite these generally unfavorable outcomes, multiple reports exist in the literature reporting long-term survivors in patients with isolated liver metastases. In a recent retrospective analysis from South Korea, 1508 patients after curative gastric resections for primary gastric cancers were analyzed.78 Of those patients, 12 presented with resectable liver metastases while 3 of them underwent synchronous and 9 metachronous resections. An overall survival rate after 1 year and 5 years of 65% and 39% was achieved with a median overall survival of 31 months. Two of the patients even lived longer than 5 years. Others presented similar 5-year survival rates of 34% to 37%.79,80 However, recurrences are seen in most of the patients. Even though liver resection can be feasible, the studied patients represent a highly selected group that does not yet allow broader generalizability and should only be considered after extensive evaluation.
Among patients with primary tumors from the pancreaticobiliary system and liver metastases, even less data in the literature exist. Adam et al8 reported data from 41 centers including 1452 patients who underwent liver resection for NCNNLMs. Of those, 84 patients presented with a primary of the pancreatic (41 patients) or biliary (23 patients with gallbladder cancer, 15 with ampullary cancer, 5 with others) system.8 Overall, 5-year survival was 27%, while those with an ampullary primary tumor had a more favorable 5-year survival rate of 46%. Focusing on patients with liver metastases from pancreatic adenocarcinomas, 5-year survival was 20%. Given that 5-year survival after resection of pancreatic adenocarcinoma without liver metastases does not exceed 25%, this experience cuts against commonly held perceptions and is met with great skepticism. Takada et al81 reported their early aggressive experience of simultaneous resection of the pancreas head and liver resection for metastasized pancreas head cancer. This simultaneous surgery did not lead to any beneficial outcome compared to palliative bypass surgery with median survival of 6 months versus 4 months, respectively. Of the resected patients, all died within a year from recurrent metastatic disease. A more recent analysis from Johns Hopkins University on 1563 patients with periampullary or pancreatic adenocarcinoma compared patients who underwent primary tumor resection with concomitant hepatic resection versus those with palliative surgery alone.82 No difference was found between the two approaches, with median survival times of 5.9 months for patients undergoing resection versus 5.6 months for the palliative approach. The higher the rate of postoperative complications, the longer the median surgical time and the length of hospital stay does not justify this aggressive approach at present.
At present, hepatic resection in patients with gastrointestinal adenocarcinomas other than colorectal cancers should only be performed under controlled conditions based on ongoing trials.
Genitourinary tumors include several primary cancer sites including kidney, adrenal, testicular, bladder, prostate, cervix, uterus, and ovaries. In the large series of Adam et al8 including 1452 patients with NCNNLMs, 332 patients had primary tumors arising from the genitourinary system. The 5-year survival rates differed from primary to primary and were reported as 66% for adrenal, 51% for testicular, 38% for renal, 50% for ovarian, and 35% for uterine metastases. Groeschl et al7 recently reported survival outcomes of 92 patients who underwent liver resection of genitourinary liver metastases. Given a median follow-up of 23 months, median overall survival was 46 months with a 5-year overall survival rate of 32% and a median disease-free survival time of 28 months. Recurrence of the disease was found in 61% of the patients, while 34% had local or regional and 53% distant recurrence. The primary sites of recurrence were liver (34%) and abdomen (35%), followed by lung (17%) and bone (8%).
Hepatic metastases arising from testicular cancer deserve special mention among this heterogenous group of diseases. The overall survival rate of these patients, given the presence of effective chemotherapy regimens, is favorable with 95% to 97% (5 years) in early-stage disease but even 67% in patients with visceral metastases. Goulet et al83 reported on 57 patients who underwent liver resection for metastatic testicular cancer. Despite the highly active chemotherapy regimens, only 9 patients showed complete pathologic response while 29 patients had residual teratoma, and 19 patients had viable malignant tumor cells in the resected specimen. While some advocate for close follow-up and resection only if detected liver metastases increase in size after chemotherapy,84 others recommend “salvage” hepatic resection for the following reasons: (1) complete response in liver metastases can only be assessed after its removal, (2) teratomas can transform to malignant disease, (3) liver resection is associated with acceptable morbidity and mortality, and (4) retroperitoneal resection of residual lymph nodes can be performed together with the liver resection and is associated with favorable outcome.85
Melanoma is increasing in incidence and already ranks fifth among the most common malignancies in men and seventh in women in the United States, accounting for about 76,690 new cases in 2013.49 Liver metastases from melanoma primaries are among the most frequent NCNNLMs ranking on place 3 to 4. Patients with ocular melanoma frequently present (40%) with liver metastasis and 95% of the patients develop liver metastases in the long run; even 15 years after initial diagnosis, they less often appear in patients with cutaneous melanoma but still at a rate of 15% to 20%.86-88 In general, patients with hepatic melanoma metastasis have a dismal prognosis with a median survival ranging from 2 to 7 months.86,89-91 Systemic therapy even in the current era is associated with limited efficacy with treatment response rates no greater than 30%.92-95 Partial hepatectomy has been met with significant skepticism, given the relatively low likelihood of cure following surgery. A number of contemporary reports highlight improved morbidity with resection and the fact that while small, there is a cohort of patients who can experience long-term survival.39,96-103 However, the evidence for this approach is still ill-defined and the treatment has to be tailored to individual patients.
Patients with liver metastases arising from cutaneous melanoma more often present with metachronous development of the metastases (93.5%) than NCNNLMs originating from other malignancies (72.4%). 7 A multi-institutional review of patients with liver melanoma metastasis showed that the median survival after resection was 28.2 months (range 4.6 to 93.7 months) with a 5-year survival rate of 10.9%.104 While this represents the largest cohort of patients to date, smaller reports showed mixed results with median survival times ranging from 14 to 39 months.7,105 In a series by Rivoire et al,106 patients who underwent complete tumor resection (R0) did show beneficial outcomes with a median overall survival of 24 months compared to 16 months in patients with R2 resections or 11 months without surgical resection. This large diversity in overall survival rates mainly represents the dilemma that indications for partial liver resection and the presentation of those patients differ substantially across centers. Patients with liver metastases originating from ocular melanoma tend to have favorable outcomes compared to their cutaneous counterparts.104 Five-year survival rates in patients with uveal melanoma primary was 20% compared to 0% in patients with cutaneous melanoma. If liver resection was not curative and metastases from melanoma recur, liver (31%) and lung (34%) are the primary tumor locations followed by abdomen (24%), bone (7%), and others.7 Metastases from cutaneous melanoma, however, tend to be more disseminated than from uveal melanoma primaries.104
The management of NCNNLMs remains a challenge in the current era. The improving morbidity profile of hepatic resection in conjunction with a relative lack of other curative options and the experiences of patients with colorectal and neuroendocrine metastases has led many centers to offer this modality to selected patients with NCNNLMs. In most instances it is highly unlikely that randomized trials will be conducted. NCNNLM represents a diverse spectrum of diseases, some of which have systemic treatment options on top of which partial hepatectomy can be used in conjunction. Patients with genitourinary primaries are associated with the best outcomes, while those with gastrointestinal epithelial and cutaneous histologies have much more difficult prognoses. Nonetheless, even patients with these diseases can experience long-term survival if properly selected. Multidisciplinary coordination is essential in directing patients toward their optimal treatment strategies.