Unresectable Liver Disease Research Articles

Diagnosis and Treatment of Metastatic Disease to the Liver

A number of cancers present with synchronous or metachronous hepatic metastases. Historically, many of these patients were considered unresectable and were treated with either systemic chemotherapy or supportive care. Today, a variety of options exist for the management of hepatic metastases. Newer agents for systemic therapy continue to be introduced and are providing improved progression-free and overall survival and increased resectability of liver metastases. However, complete surgical resection of isolated hepatic metastases remains the optimal management for these patients. Surgical interventions can be offered to patients with hepatic-only metastases. Hepatic artery chemotherapy represents an adjunct for those patients undergoing resection and can improve survival. This benefit may be even more pronounced when combined with systemic chemotherapy. Newer generation biologic agents can improve results. New therapeutic modalities to treat lesions that are unresectable include ablative techniques such as radiofrequency ablation (RFA) and cryoablation. This article will examine modalities of diagnosis of hepatic metastases and highlight the data regarding hepatic resection for metastases of several types of primary cancers, the rationale for, and efficacy of, hepatic arterial chemotherapy, in both the postoperative adjuvant setting and in unresectable liver disease, and review the current literature for ablative techniques in the treatment of liver metastases.

Repeat hepatic resections for colorectal metastases

Abstract We identified 106 patients who had undergone complete resection of isolated colorectal hepatic metastases. Nine of these patients subsequently underwent repeat liver resections for isolated hepatic recurrences. The median follow-up for these patients was 21 months. One postoperative death was related to the second hepatectomy. At the time of last follow-up, five patients were alive and free of recurrent disease at 9, 19, 31, 50, and 67 months after their second hepatic resection. The remaining three patients were alive, but disease had recurred 11 months after resection in the first patient, 12 months after resection in the second, and 18 months after resection in the third. Among these three patients, two had solitary pulmonary nodules, which were resected, and one had unresectable liver disease. Our experience and a review of the literature suggest that repeat hepatic resection for isolated colorectal metastases can result in long-term survival in selected patients.

Longterm Results and Prognostic Indicators after Cryotherapy and Hepatic Arterial Chemotherapy With or Without Resection for Colorectal Liver Metastases in 224 Patients: Longterm Survival Can Be Achieved in Patients With Multiple Bilateral Liver Metastases

Only a minority of patients are suitable for liver resection for colorectal liver metastases. Cryotherapy was the first widely used ablative technique, achieving a median survival of more than 2 years. Patient selection is important, but the prognostic criteria have been controversial. The combined treatment modality of cryotherapy, resection, and hepatic arterial chemotherapy has been used in treating unresectable liver disease. Many centers would not surgically treat patients with multiple (five or more lesions) bilateral liver metastases. This series reports on longterm results after cryotherapy and hepatic arterial chemotherapy with or without liver resection in 224 patients with colorectal liver metastases, especially in patients with multiple bilateral liver disease, and identifies important prognostic determinants for survival. A longterm retrospective analysis was performed of prospectively collected clinical data of 224 patients with colorectal liver metastases who received cryotherapy and hepatic arterial chemotherapy with or without resection. Morbidity, mortality, recurrence, and survival rates were reported and Kaplan-Meier and Cox regression analysis were used to identify prognostic indicators. Median length of followup was 26 months (range 1 to 130 months). Perioperative mortality rate was 0.4% and morbidity rate was 21%. Cryosite, remaining liver, and extrahepatic recurrence rates were 39%, 62%, and 67%, respectively. Median survival was 31 months (range 1 to 130 months) with 1-, 3-, and 5-year survival rates of 87%, 43%, and 23%, respectively. Ninety-one patients had five or more bilateral lesions. Median and 5-year survival was 31 months (2 to 88 months) and 26%, respectively. Four factors were independently associated with favorable survival outcomes: cryotherapy with resection, complete tumor eradication, low pre- and postoperative CEA levels. Cryotherapy and hepatic arterial chemotherapy with or without resection can achieve long survival advantage in patients with unresectable colorectal liver metastases.

Kinase substrate protein microarray analysis of human colon cancer and hepatic metastasis

Background Liver metastases represent the major determinant of survival in patients with colorectal cancer (CRC). In cases with unresectable liver disease, more effective agents are needed, since chemotherapy achieves median survival of only 15 months. Protein kinases coordinate complex functions that are often disregulated in cancer and are therefore considered important targets for molecular therapeutics. In this study, we investigated the phosphoproteomic status of different protein kinases in primary CRC and in liver metastases. Methods The status of 29 key endpoints was evaluated using reverse phase protein array on laser capture microdissected neoplastic cells from five primary CRCs without metastases, three patient-matched primary CRCs and synchronous liver metastases and five CRC metachronous liver metastases. Results Unsupervised hierarchical two-way clustering analysis showed an entirely different phosphoproteomic profile in primary CRCs compared to liver metastases. This difference was observed also in primary and metastatic patient-matched lesions. Conclusions Our findings of different signaling pathways between primary and metastatic CRC suggest a possible microenvironment effect, and emphasize the need to perform molecular network analysis of metastatic tissue when molecular targeting is considered.

Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients

BackgroundThe aim of this study was to observe the effects of neoadjuvant therapy with irinotecan and5-fluorouracil (5-FU)/folinic acid (FA) on the resection rate and survival of colorectal cancer patients with initially unresectable hepatic metastases. Patients and methodsForty patients received neoadjuvant chemotherapy comprising irinotecan 180 mg/m2 administered intravenously (i.v.) on day 1, FA 200 mg/m2 i.v. on days 1 and 2, 5-FU 400 mg/m2 i.v. bolus on days 1 and 2, and 5-FU 1200 mg/m2 as a continuous 48-h i.v. infusion on day 1. The treatment was repeated every 2 weeks and response was assessed every 12 weeks (six cycles). ResultsThe objective response rate to chemotherapy was 47.5% (n = 19), with two complete responses and disease stabilization in 11 (27.5.%) patients. Responses were unconfirmed for 11 patients undergoing surgery within 2 weeks. Treatment was well tolerated and adverse events were typical of the chemotherapy agents used. Twenty-seven (67.5%) patients reported hematological toxicity (35.0% grade 3/4) and 14 (35.0%) reported gastrointestinal toxicity (12.5% grade 3/4). Thirteen patients (32.5%) underwent potentially curative liver resection following chemotherapy. Chemotherapy was particularly effective in patients with large metastases on entry to the study. The median time to progression is 14.3 months and, at a median follow-up of 19 months, all patients are alive. ConclusionsNeoadjuvant therapy with irinotecan combined with 5-FU/FA enabled a significant proportion of patients with initially unresectable liver metastases to undergo surgical resection. The effects of treatment on survival have yet to be determined.

Neoadjuvant Chemotherapy in the Management of Colorectal Metastases: A Review of the Literature

Introduction: Five-year survival rates of between 20% and 45% are achievable in patients following hepatectomy for liver metastases from colorectal cancer. Sadly, a great majority of patients present with unresectable liver disease with virtually no long-term survival. This paper reviews the development and role of preoperative chemotherapy in trying to downstage unresectable liver disease. Methods: The author retrieved most of the citations by performing a PubMed search for studies related to preoperative chemotherapy followed by surgical resection of liver metastases. Results: Larger series have reported resectability rates ranging from 10% to 40% for unresectable colorectal liver metastases after treatment with preoperative chemotherapy. Chemotherapy generally consisted of oxaliplatin added to 5-fluorouracil/leucovorin administered in a chronomodulated fashion. A median of about 5 to 10 months of treatment was necessary for adequate tumour reduction. The 5-year survival rates, after surgery, in completely resected patients were between 30% and 60%. The majority of these patients will relapse, of which half of these will remain confined to the liver. Patients who are able to undergo a repeat hepatectomy may achieve long-term survival rates similar to the initial resection. Preliminary data from a recent study suggest that initial treatment with an oxaliplatin-containing regimen may lead to a higher resectability rate compared to an irinotecan-containing combination (18% versus 7%). Selective intra-arterial infusion has not demonstrated a clear advantage over systemic infusion and, if administered preoperatively, it may even compromise the safety of surgery. Conclusions: Palliative chemotherapy remains the standard of care for unresectable colorectal liver metastases. However, in carefully selected patients, neoadjuvant chemotherapy may be able to downstage the disease adequately for curative resection.

Surgery after downstaging of unresectable hepatic tumors with intra-arterial chemotherapy.

This retrospective study was performed to assess the outcome among patients who underwent hepatic resection or tumor ablation after hepatic artery infusion (HAI) therapy down-staged previously unresectable hepatocellular carcinoma (HCC) or liver metastases from colorectal cancer (CRC). Between 1983 and 1998, 25 patients with HCC and 383 patients with hepatic CRC metastases were treated with HAI therapy for unresectable liver disease. We retrospectively reviewed the records of 26 (6%) of these patients who underwent subsequent surgical exploration for tumor resection or ablation. At a median of 9 months (range 7-12 months) after HAI treatment, four patients (16%) with HCC underwent exploratory surgery; two underwent resection with negative margins, and the other two were given radiofrequency ablation (RFA) because of underlying cirrhosis. At a median postoperative follow-up of 16 months (range 6-48 months), all four patients were alive with no evidence of disease. At a median of 14.5 months (range 8-24 months) after HAI therapy, 22 patients with hepatic CRC metastases underwent exploratory surgery; 10 underwent resection, 6 underwent resection and RFA or cryotherapy, and 2 underwent RFA only. At a median follow-up of 17 months, 15 (83%) of the 18 patients with CRC who had received surgical treatment had developed recurrent disease; the other 3 died of other causes (1 of postoperative complications) within 7 months of the surgery. One patient in whom disease recurred underwent a second resection and was disease-free at 1 year follow-up. Hepatic resection or ablation after tumor downstaging with HAI therapy is a viable option for patients with unresectable HCC. However, given the high rate of recurrence of metastases from CRC, hepatic resection or ablation after downstaging with HAI should be used with caution.