Curative Resection Of Hepatic Metastases Research Articles

LICC: L-BLP25 in patients with colorectal carcinoma after curative resection of hepatic metastases--a randomized, placebo-controlled, multicenter, multinational, double-blinded phase II trial

Background15-20% of all patients initially diagnosed with colorectal cancer develop metastatic disease and surgical resection remains the only potentially curative treatment available. Current 5-year survival following R0-resection of liver metastases is 28-39%, but recurrence eventually occurs in up to 70%. To date, adjuvant chemotherapy has not improved clinical outcomes significantly. The primary objective of the ongoing LICC trial (L-BLP25 In Colorectal Cancer) is to determine whether L-BLP25, an active cancer immunotherapy, extends recurrence-free survival (RFS) time over placebo in colorectal cancer patients following R0/R1 resection of hepatic metastases. L-BLP25 targets MUC1 glycoprotein, which is highly expressed in hepatic metastases from colorectal cancer. In a phase IIB trial, L-BLP25 has shown acceptable tolerability and a trend towards longer survival in patients with stage IIIB locoregional NSCLC.Methods/DesignThis is a multinational, phase II, multicenter, randomized, double-blind, placebo-controlled trial with a sample size of 159 patients from 20 centers in 3 countries. Patients with stage IV colorectal adenocarcinoma limited to liver metastases are included. Following curative-intent complete resection of the primary tumor and of all synchronous/metachronous metastases, eligible patients are randomized 2:1 to receive either L-BLP25 or placebo. Those allocated to L-BLP25 receive a single dose of 300 mg/m2 cyclophosphamide (CP) 3 days before first L-BLP25 dose, then primary treatment with s.c. L-BLP25 930 μg once weekly for 8 weeks, followed by s.c. L-BLP25 930 μg maintenance doses at 6-week (years 1&2) and 12-week (year 3) intervals unless recurrence occurs. In the control arm, CP is replaced by saline solution and L-BLP25 by placebo. Primary endpoint is the comparison of recurrence-free survival (RFS) time between groups. Secondary endpoints are overall survival (OS) time, safety, tolerability, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. The primary endpoint will be assessed in Q3 2016. Follow-up will end Q3 2017. Interim analyses are not planned.DiscussionThe design and implementation of such a vaccination study in colorectal cancer is feasible. The study will provide recurrence-free and overall survival rates of groups in an unbiased fashion.Trial RegistrationEudraCT Number 2011-000218-20

LICC: L-BLP25 in patients with colorectal carcinoma after curative resection of hepatic metastases—A randomized, double-blind, placebo-controlled, multicenter, multinational, phase II trial.

TPS166 Background: Distant metastases limited to the liver occur in 15-20% of all patients initially diagnosed with colorectal cancer. Complete surgical resection represents the only curative option. The 5-year survival after R0-resection of liver metastases ranges between 28 and 39%. Unfortunately, recurrence rates peak up to 70% in long-term follow-up. Adjuvant chemotherapeutic protocols did not reveal significant improvement of the situation. The primary objective of the LICC trial is to determine whether the therapeutic cancer vaccine L-BLP25 extends recurrence-free survival (RFS) time over placebo in colorectal cancer patients after resection of hepatic metastases. L-BLP25 targets the MUC1 glycoprotein, which is highly expressed in hepatic metastases of colorectal cancer. In a phase IIB trial, L-BLP25 showed acceptable tolerability and a trend toward longer survival in patients (pts) with stage IIIB locoregional NSCLC. Methods: This is a planned multinational, phase II, multicenter, randomized, double-blind trial. Planned sample size is 159 pts from 20 centers in 3 countries; accrual is planned to start in Q3 2011. Pts with colorectal adenocarcinoma after complete resection of the primary tumor and having experienced a curative-intent resection of all hepatic metastases (R0/R1, metachronous/synchronous, <6 weeks) are eligible. Pts will be randomized 2:1 to receive either L-BLP25 or placebo. Those in the L-BLP25 arm receive a single dose of cyclophosphamide (CP) (300 mg/m2) 3 days before first L-BLP25 dose, then primary treatment with sc L-BLP25 930 μg once weekly for 8 weeks, followed by sc L-BLP25 930 μg maintenance doses at 6-week (years 1&2) and 12-week (year 3) intervals until recurrence. In the control arm, CP is replaced by NaCl solution and L-BLP25 by placebo. Stratified: R0 vs. R1. Primary endpoint: RFS time between treatment groups. Secondary endpoints: overall survival (OS) time, safety, tolerability, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. Evaluation of primary endpoint is planned for Q3 2016.

Intraoperative sonography in patients with colorectal cancer and resectable liver metastases on preoperative FDG‐PET‐CT

Combined fluorine 18-fluorodeoxyglucose-positron emission tomography-CT imaging has been shown to be of good diagnostic value in the preoperative evaluation of patients with colorectal cancer and liver metastases. The adjunctive use of intraoperative sonography (IOUS) may have a limited impact on treatment selection in these patients. To compare the diagnostic performance of preoperative positron emission tomography (PET)-CT alone and PET-CT combined with IOUS in the evaluation of patients who are considered for curative resection of hepatic metastases from colorectal carcinoma. Patients with colorectal cancer who underwent resection of hepatic metastases and preoperative PET-CT (with or without contrast-enhanced CT) and IOUS were identified. The performance of the imaging techniques was evaluated through review of the radiologic reports, correlation with surgical and histopathologic findings, and clinical follow-up. Thirty-one patients (mean age, 63.5 years [range, 53-82 years]) were analyzed. Fifteen patients had received preoperative chemotherapy. The mean interval between PET-CT and IOUS was 22.6 days (range, 1-56 days). In 4 cases, neither PET-CT nor IOUS correctly diagnosed the liver metastases. In all 31 patients, the sensitivity of PET-CT alone and PET-CT combined with IOUS was 63% (95% CI 44-80%) and 93% (95% CI 78-98%), respectively; the positive predictive value was 81% and 89%, respectively. In patients without preoperative chemotherapy (n = 16), the sensitivity of PET-CT alone and PET-CT combined with IOUS was 77% (95% CI 49-94%) and 100% (95% CI 79-100%), respectively. In 11 cases (35%), IOUS altered the surgical strategy. In patients with colorectal carcinoma and potentially resectable liver metastases on preoperative PET-CT, IOUS can provide additional information that may alter decision making with regard to surgical technique.

Long-term survival following resection of colorectal hepatic metastases. Association Française de Chirurgie.

The aim of this study was to analyse characteristics of patients who survived more than 5 years after liver resection of colorectal metastases. A multicentre retrospective study collected 1818 patients who underwent curative resection of hepatic metastases between 1959 and 1991. Among the 747 patients operated on before 1987, 102 survived longer than 5 years, and were compared with patients who survived less than 5 years. Three risk factors proved independently significant in multivariate analysis between the two groups: serosa infiltration (P = 0.003), involvement of peritumoral lymph nodes around the primary colorectal tumour (P = 0.04), and a liver resection margin of less than 1 cm (P = 0.02). There was no significant difference for other parameters studied (location of primary tumour, location, number and size of metastases, type of resection). A trend towards a shorter survival of patients with increased carcinoembryonic antigen serum level was observed. Resection of colorectal hepatic metastases can provide long-term survival even in patients with poor prognostic factors. It seems justified to undertake resection of colorectal liver metastases whenever it may be performed safely as a curative treatment.

Current preventive treatment for recurrence after curative hepatectomy for liver metastases of colorectal carcinoma: A literature review of randomized control trials

To review the preventive approaches for recurrence after curative resection of hepatic metastases from colorectal carcinoma, we have summarized all available publications reporting randomized control trials (RCTs) covered in PubMed. The treatment approaches presented above include adjuvant intrahepatic arterial infusion chemotherapy, systemic chemotherapy, neoadjuvant chemotherapy, and immunotherapy. Although no standard treatment has been established, several approaches present promising results, which are both effective and tolerable in post-hepatectomy patients. Intrahepatic arterial infusion chemotherapy should be regarded as effective and tolerable and it increases overall survival (OS) and disease-free survival (DFS) of patients, while 5-fluorouracil-based systemic chemotherapy has not shown any significant survival benefit. Fortunately chemotherapy combined with hepatic arterial infusion and intravenous infusion has shown OS and DFS benefit in many researches. Few neoadjuvant RCT studies have been conducted to evaluate its effect on prolonging survivals although many retrospective studies and case reports are published in which unresectable colorectal liver metastases are downstaged and made resectable with neoadjuvant chemotherapy. Liver resection supplemented with immunotherapy is associated with optimal results; however, it is also questioned by others. In conclusion, several adjuvant approaches have been studied for their efficacy on recurrence after hepatectomy for liver metastases from colorectal cancer (CRC), but multi-centric RCT is still needed for further evaluation on their efficacy and systemic or local toxicities. In addition, new adjuvant treatment should be investigated to provide more effective and tolerable methods for the patients with resectable hepatic metastases from CRC.

Regional chemotherapy is indicated after surgical resection of colorectal metastases to the liver: a debate.

Surgical resection for selected patients with hepatic metastases from colorectal cancer can cure approximately one-fourth of these patients. The addition of regional chemotherapy as an attempt to improve this statistic has been extensively investigated in clinical trials. As part of a multidisciplinary educational program, a series of debates on various topics in oncology are held at the Roswell Park Cancer Institute, Buffalo, New York, involving the medical, surgical, and radiation oncology departments. One such debate focused on the use of regional chemotherapy after potentially curative resection of hepatic metastases from colorectal cancer. The representative medical and surgical oncology fellows (N.I.K. and B.P.M.), with guidance from their respective mentors (C.G.L., J.F.G., and N.J.P.), presented concise reviews from the literature arguing for and against the use of regional chemotherapy in this setting. They appear as Parts 1 and 2 in this article. This exercise is purely educational and does not in any way reflect the opinion or the clinical practice of the authors. .

Genetic markers of survival and liver recurrence after resection of liver metastases from colorectal cancer.

A significant number of patients with liver metastases from colorectal cancer (CRC) achieve 5-year survival after liver resection. Increased expression of genetic markers in the primary tumor are known to predict outcome after colonic resection, but the predictive value of such markers after resection of hepatic metastases is unknown. The objective of this study was to evaluate whether DNA content and multiple genetic markers, separately or expressed together, can predict patient outcome (liver recurrence and survival) after resection of hepatic metastases. We studied the paraffin-embedded liver tissue of 71 consecutive patients who had undergone a potentially curative resection of hepatic metastases from CRC. Using DNA flow cytometry and immunohistochemical staining techniques we determined the DNA content and the level of co-expression of seven tumor-associated proteins: proliferating cellular nuclear antigen (PCNA), epidermal growth factor receptor (EGFr), p53, c-erbB-2, H-ras, c-myc, and nm23. Three endpoints (liver recurrence, cancer specific, overall survival) were correlated with these tumor markers. The 5-year overall survival of the group was 31.2%. There was no correlation detected between the DNA aneuploidy and overall or cancer-specific survival. Similarly, expression of the individual tumor-associated proteins did not predict survival. Patients whose tumors co-expressed multiple markers had survivals similar to those whose tumors expressed fewer markers. However, a significant difference in hepatic recurrence was found between the p53-positive and p53-negative patients (p = 0.007), with marker-negative tumors having decreased recurrence. In conclusion, this study demonstrates that the DNA content and genetic markers c-myc, c-erbB-2, EGFr, H-ras, p53, PCNA, and nm23 do not predict survival after potentially curative resection of hepatic metastases from CRC. However, the immunoreactivity of p53 may be an important marker of local recurrence in the liver, which may be useful if re-resection of metastatic liver tumors is considered a viable management option in this disease.

A Pilot Study of Cryochemotherapy for Hepatic Metastases from Colorectal Cancer

Cryosurgery of hepatic metastases from colorectal carcinoma is a form of local therapy for unresectable disease. After curative resection, failures occur in the liver, and at extrahepatic sites. This pilot study evaluated the toxicity and tolerance to cryotherapy and intraoperative chemotherapy for unresectable hepatic metastases from colorectal cancer. If after exploratory celiotomy for potential curative resection of hepatic metastases the patient was deemed unresectable because of location and/or number of lesions, cryosurgery and intraoperative chemotherapy with systemic 5-fluorouracil 600 mg/m2and leucovorin 500 mg/m2was performed. Four patients were treated with cryochemotherapy. All patients developed toxicity. Two patients developed grade III leukopenia on Postoperative Days 2 and 12, and grades II and III diarrhea on Postoperative Days 5 and 7, respectively. Grade III hyperbilirubinemia and thrombocytopenia occurred in one patient on Postoperative Days 3 and 7. Acute respiratory distress syndrome, postoperative ileus, and grade II mucositis occurred in one patient each. All patients had delays and dose reductions on their subsequent chemotherapy treatments secondary to toxicity. Two patients had disease progression, one had stable disease, and one is “disease free.” Combining the tumoricidal effects of chemotherapy and cryosurgery is in theory a good concept. However, the toxicity of 5-FU and leucovorin is enhanced by this approach.