Hepatic metastasis from noncolorectal nonneuroendocrine tumors

Overview

Only 10% of malignant liver tumors are primary liver or bile duct cancers. The vast majority of cancerous hepatic lesions are metastatic lesions originating from extrahepatic primary tumors (see Chapters 90 and 91 ). The only potentially curative approach for most malignant liver tumors is surgical resection. This procedure can be performed safely with an acceptable risk of perioperative mortality and morbidity (see Chapters 101 and 102 ).

Recent studies provide evidence that a complex multimodality therapy has improved the clinical outcome of patients with colorectal liver metastases over the last 2 decades. In 2020, patients who underwent a partial hepatectomy for colorectal liver metastases had a median life expectancy of 6.6 years (6.0–8.3 years), and approximately two thirds of the patients are still alive after 5 years if they are treated in high-volume centers. For patients with neuroendocrine liver metastases, surgical resection is associated with 5-year survival rates of approximately 75% and a median overall survival of 125 months. ^, In contrast, the role of hepatectomy in patients with liver metastases from noncolorectal, nonneuroendocrine (NCNN) tumors is not well defined, but the number of reports on this topic are increasing.

Series summarizing multiple primary tumor types

In the past 2 decades, an increasing number of studies reporting the outcome of resection of NCNN metastases have been published. However, despite the fact that partial hepatectomy can be considered as a relatively safe surgical procedure in 2020, ^{, ,} most current reports regarding hepatectomy for metastases of NCNN tumors still combine multiple primary tumor types to obtain a sufficient number of patients to analyze. A major objection to liver resection in patients with NCNN is the argument that many NCNN liver metastases originate from extraabdominal primary tumors, which often spread simultaneously to other organs. In this case, a resection of the liver metastases would not be warranted because the extrahepatic disease burden defines the outcome in patients with a multifocal metastatic disease. For selected patients, however, partial hepatectomy for NCNN is associated with long-term survival.

To date, one of the largest cohort of patients with NCNN has been described by Sano et al. In their study, data regarding 1639 hepatectomies performed between 2001 and 2010 for 1539 patients with NCNN were collected from 124 institutions. Most frequently, patients underwent hepatectomy because of noncolorectal liver metastases originating from gastric carcinomas, gastrointestinal stromal tumors (GISTs), biliary carcinomas, ovarian cancer, and pancreatic cancer. The authors of this study report that a R0/1 hepatectomy was achieved in 90% of patients and the in-hospital mortality rate reached 1.5%. Overall survival and disease-free survival (DFS) rates of 1465 patients included in survival analysis were 41% and 21%, respectively, at 5 years, and 28% and 15%, respectively, at 10 years. Among the five most frequent tumor types, patients with a hepatic metastasized GIST ( n = 204) had the best prognosis and experienced a 5-year and 10-year survival of 72% and 40%, respectively, with a median survival of 100 months. In patients with liver metastases from breast cancer ( n = 74) the median survival was 62 months, in patients with liver metastases from ovarian cancer ( n = 107) the median survival reached 65 months. The lowest survival rate was observed in patients with liver metastases derived from pancreatic carcinoma ( n = 77) and biliary carcinoma ( n = 150), accounting for a 5-year survival of 31% and 17%, respectively.

Overall, these recent data confirm the results of previous large studies with comparable results such as the report by Adam et al. This study reports the outcome of 1452 patients who had undergone liver resection for liver metastases from noncolorectal tumors in 41 centers. With a mean follow-up of 31 months (range, 0–258 months), the 5-year and 10-year survival rates were 36% and 23%, respectively, and the median overall survival equaled 35 months. The largest subset in this series represented patients with liver metastases from breast cancer ( n = 460). These patients experienced a 5-year and 10-year survival of 41% and 22%, respectively, with a median survival of 45 months. The second largest subgroups were patients with liver metastases from different types of primary gastrointestinal (GI) cancer. In this cohort, the 5-year survival reached 31% and the median survival was 26 months. The third largest group in this study consisted of patients with liver metastases originating from urologic primary tumors. In this very heterogeneous subgroup, Adam et al. observed the most favorable outcome for patients with adrenal metastases (5-year survival, 66%), followed by testicular metastases (5-year survival, 51%) and renal metastases (5-year survival, 38%).

Andreou et al. performed hepatic resection in 51 patients with liver metastases from a noncolorectal primary. This cohort consisted of 26 patients with a primary tumor from the adrenal gland, 11 patients with thyroid cancer as primary site, 9 patients with a primary testicular germ cell tumor, and 5 patients with a primary ovarian granulosa cell cancer. Ninety-day postoperative morbidity and mortality were 27% and 2%, respectively. After a median follow-up of 20 months, the 5-year overall and recurrence-free survival rates were 58% and 37%, respectively. Noteworthy in this small cohort, they identified only the presence of more than one site of extrahepatic tumor disease as an independent prognostic marker in their multivariate analyses ( P = .016). In contrast, survival was not affected by the primary tumor type. Based on these observations, the authors concluded that mostly the extrahepatic burden defines the prognosis for patients with NCNN.

The Memorial Sloan Kettering Cancer Center (MSKCC) experience regarding hepatic resection for metastases from NCNN carcinoma was analyzed by Weitz et al. The objectives of this study were to define perioperative and long-term outcome and to define prognostic factors for survival in 141 patients who underwent resection for liver metastases from NCNN carcinoma during the period April 1981 through April 2002. Table 92.1 depicts the primary tumor types. The median operative time was 238 minutes (interquartile range [IQR], 180–321 minutes), and the median blood loss was 600 mL (IQR, 250–1420 mL). The median length of hospital stay was 9 days (IQR, 7–12 days). Of 141 patients, 46 (33%) experienced postoperative complications, but the 30-day mortality rate was 0%. The median follow-up was 26 months, with a median follow-up of 35 months. The 3-year relapse-free survival rate was 30% (median, 17 months), and the 3-year cancer-specific survival rate was 57% (median, 42 months). Primary tumor type and length of disease-free interval from the primary tumor were significant independent prognostic factors for relapse-free and cancer-specific survival ( Figs. 92.1–92.3 ; Table 92.2 ).

Margin status was significant for cancer-specific survival and showed a strong trend in relapse-free survival. Patients with a primary reproductive tract tumor who underwent R0 resection had the best outcome, with a 3-year cancer-specific survival of 78%. In the group of patients with primary non–reproductive tract tumors, survival after R0 resection was influenced largely by the length of the disease-free interval. Patients with a disease-free interval of 24 months or less achieved a 3-year survival of 36%, but only 5% were free of relapse after 3 years. Patients with a non–reproductive tract primary and a disease-free interval of more than 24 months had a 3-year cancer-specific survival of 72% and a 3-year relapse-free survival of 30%, with 14 5-year survivors in this group.

Martel et al. performed a hepatectomy in 52 patients with liver metastases from a noncolorectal, noncarcinoid, and nonsarcoma primary tumor. Ninety-day mortality was 0%. The overall 5-year survival rate was 58%, with the following results for various primary tumors: adrenal carcinoma 100% ( n = 3), breast cancer 85% ( n = 11), ocular melanoma 66% ( n = 5), other melanomas 83% ( n = 6), gastroesophageal cancer 50% ( n = 7), and renal cell cancer 0% ( n = 4). The authors pointed out that the overall survival in this highly selected group of patients was similar to results they obtained in 185 patients who underwent liver resection for metastases of colorectal cancer (CRC) during the same period.

In a systematic review, Fitzgerald et al. summarized the benefits of liver resection for NCNN liver metastases. This report includes 3596 patients from 73 studies that were published after 1990. The largest subset of patients had undergone liver resection because of breast cancer metastases ( n = 1013). The next two largest populations were patients with liver metastases originating from melanoma ( n = 643) and from gastric cancer ( n = 481). In this systematic review, Fitzgerald et al. showed that the longest expected survival is observed for patients with liver metastases derived from genitourinary primaries (median, 63 months; range, 5.4–142 months), followed by patients with breast cancer (median, 44.4 months; range, 8–74 months), patients with GI cancer (median, 22.3 months; range, 5–58 months), and 23.7 months for other tumor types (range, 10–72 months). From their point of view, there is a benefit to resection for patients with NCNN liver metastases. However, the degree of survival advantage is predicated by primary tumor site.

In conclusion, those studies show that the safety of hepatectomy for patients with NCNN metastases has increased substantially for the past 2 decades. More importantly, however, there is an increasing number of patients who show very good results for long-term survival after resection of liver metastases from NCNN origin. Crucial for this successful surgical treatment of NCNN metastases is the preoperative evaluation and selection of patients based on clinical factors and tumor biology.

Therefore laparoscopy might be a reasonable staging tool for patients with NCNN liver metastases (see Chapter 24 ). D’Angelica and coworkers examined 30 patients with potentially resectable NCNN tumors based on preoperative imaging. Of these patients, 9 had unresectable disease, 6 of whom were identified by laparoscopy. If possible, laparoscopic liver resection also should be the method of choice for curative resection of NCNN metastases. Triantafyllidis et al. evaluated the perioperative and long’ëterm outcomes of laparoscopic liver resections for noncolorectal liver metastases in 56 patients. Major postoperative morbidity was reported to reach 3.6%, and the perioperative mortality was zero. Overall survival rates at 3 and 5 years were 71.4% and 52.9%, respectively, and 8 of 56 (14.3%) patients with NCNN metastases underwent repeat laparoscopic liver resection for recurrent metastatic tumors.

However, the retrospective nature of these studies and the consequent bias related to patient selection represent major limitations. Nevertheless, the general theme is one of potential benefit of hepatic resection in selected patients with limited disease, specific primary tumor types, and a longer disease-free interval.

Series focused on one primary tumor type

Sarcoma

One of the first surgical series of patients with sarcoma metastatic to the liver was composed of 56 patients who underwent liver resection. These patients were selected from 331 patients with liver metastases from sarcomas who had been admitted to MSKCC during the years 1982 through 2000. GISTs ( Fig. 92.4 ) and leiomyosarcomas were the most common histologic findings; no perioperative deaths were reported in patients undergoing complete resection of the tumor, and the 5-year overall survival rate was 30%, with a median of 39 months in completely resected patients. Patients who did not undergo complete resection had a 5-year survival of only 4% ( Fig. 92.5 ). A disease-free interval of less than 24 months was a significant adverse prognostic parameter for survival on univariate and multivariate analysis ( Fig. 92.6 ).

In a report from Pawlik et al., 66 patients undergoing liver resection and/or ablation were included; the 5-year disease-free and overall survival rates were 16.4% and 27.1%, respectively. Patients in whom radiofrequency ablation (RFA) was part of the treatment and patients who did not receive chemotherapy, mostly imatinib mesylate for metastatic GISTs, showed a significantly reduced survival.

The treatment strategy for patients with liver metastases from GISTs has changed since the development of the targeted agent imatinib mesylate, which achieves dramatic tumor response rates ^, such that imatinib is now the first-line treatment. Resection is considered for patients when they reach the maximal response to imatinib if all gross tumors can be removed and for those who have immediate or limited acquired resistance to the drug. In a randomized trial, Xia et al. demonstrated that surgical resection of liver metastases in combination with imatinib results in a significantly longer survival rate than treatment with imatinib alone. However, although patients responding to a preoperative tyrosine kinase inhibitor therapy benefit from surgical resection, there seems to be no advantage from a surgical intervention for nonresponders. For patients with non-GIST sarcoma liver metastases, innovative advances in perioperative therapy have significantly improved the prognosis for long-term survival. Goumard et al. reported a 5-year overall survival rate of 49%, independent of histologic subtype and primary tumor location in a cohort of 126 patients undergoing resection of non-GIST sarcoma liver metastases. ([6]). Among the 65 patients (52%) who received preoperative chemotherapy, radiologic response according to the Choi criteria specifically was associated with improved overall survival ([6]). Based on their data, the authors suggested that in particular the radiologic response to preoperative chemotherapy can be a significant indicator and decision aid for the selection of patients with non-GIST sarcoma liver metastases that are scheduled for hepatectomy ([6]).