Curative Resection Of Liver Metastases Research Articles

PEGylated Fluorescent Anti-carcinoembryonic Antigen Antibody Labels Colorectal Cancer Tumors in Orthotopic Mouse Models

IntroductionColorectal cancer (CRC) patients often develop liver metastasis. However, curative resection of liver metastasis is not always possible due to poor visualization of tumor margins. The present study reports the characterization of a humanized anti-carcinoembryonic antigen monoclonal antibody conjugated to a PEGylated near-infrared dye, that targets and brightly labels human CRC tumors in metastatic orthotopic mouse models. MethodsThe hT84.66-M5A (M5A) monoclonal antibody was conjugated with a polyethylene glycol (PEG) chain that incorporated a near infrared (NIR) IR800 dye to establish M5A-IR800 Sidewinder (M5A-IR800-SW). Nude mice with CRC orthotopic primary tumors and liver metastasis both developed from a human CRC cell line, were injected with M5A-IR800-SW and imaged with the Pearl Trilogy Imaging System. ResultsM5A-IR800-SW targeted and brightly labeled CRC tumors, both in primary-tumor and liver-metastasis models. M5A-IR800-SW at 75 μg exhibited highly-specific tumor labeling in a primary-tumor orthotopic model with a median tumor-to-background ratio of 9.77 and in a liver-metastasis orthotopic model with a median tumor-to-background ratio of 7.23 at 96 h. The precise labeling of the liver metastasis was due to lack of hepatic accumulation of M5A-IR800-SW in the liver. ConclusionsM5A-IR800-SW provided bright and targeted NIR images of human CRC in orthotopic primary-tumor and liver-metastasis mouse models. The results of the present study suggest the clinical potential of M5A-IR800-SW for fluorescence-guided surgery including metastasectomies for CRC. The lack of hepatic NIR signal is of critical importance to allow for precise labeling of liver tumors.

DOG1 as a novel antibody-drug conjugate target for the treatment of multiple gastrointestinal tumors and liver metastasis.

Discovered On Gastrointestinal stromal tumors protein 1 (DOG1), a major calcium-activated chloride channel, has been used as a common diagnostic marker for gastrointestinal stromal tumors. However, the therapeutic application of DOG1 was not well defined. Here, we aim to investigate its potential as a therapeutic target for an antibody-drug conjugate (ADC) in various cancers of the alimentary tract and metastasis. The DOG1 expression profile was determined among TCGA samples and tissue microarrays. High levels of DOG1 expression were ubiquitously observed in multiple cancer samples from the alimentary tract determined by TCGA samples and tissue microarrays. Circulating tumor cells isolated from metastatic colon cancer patients were also positive for DOG1 expression. The mechanisms of anti-DOG1 antibody were investigated by dual-luciferase reporter assay. The anti-DOG1 antibody could inhibit proliferation and metastasis via p53 signaling in limited cancer cell lines. The anti-DOG1 antibody was conjugated with a microtubule inhibitor DM4, to construct a new anti-DOG1-DM4-ADC to strengthen its activity. The anti-DOG1-DM4-ADC showed cytotoxicity at the nanomolar level in vitro. In the murine xenograft tumor models, treatment of anti-DOG1-DM4-ADC achieved a significant tumor growth inhibition rate. Our study indicates that anti-DOG1-DM4-ADC may be promising therapeutic molecules for DOG1-positive alimentary tract tumors and may be effective in inhibiting recurrence after curative resection of liver metastases of colorectal origin.

Perioperative Systemic Chemotherapy for Colorectal Liver Metastasis: Recent Updates.

Simple SummaryThe development of cytotoxic chemotherapy, targeted agents and immune check point inhibitors has improved survival outcomes and quality of life in patients diagnosed with metastatic colorectal cancer (CRC). Long-term survival and cure are possible in well-selected CRC patients with liver metastases (LM). The criteria for resectable LM and the eligibility of patients should be evaluated at the time of diagnosis or during the clinical course via a multidisciplinary team approach. The advantages of adjuvant chemotherapy after curative resection of LM are uncertain currently. Systemic preoperative chemotherapy may convert unresectable LM to a resectable type. However, the optimal combination of systemic drugs and treatment strategy has yet to be established. This article summarizes recent reports of perioperative systemic treatment for patients with colorectal liver metastases (CLM). This review provides an update for physicians involved in managing patients with CLM.The liver is the most common site of metastases for colorectal cancer. Complete resection in some patients with resectable liver metastases (LM) can lead to long-term survival and cure. Adjuvant systemic chemotherapy after complete resection of LM improves recurrence-free survival; however, the overall survival benefit is not clear. In selected patients, preoperative systemic treatment for metastatic colorectal cancer can convert unresectable to resectable cancer. This review will focus on patient selection, and integration of perioperative and postoperative systemic treatment to surgery in resectable and initially unresectable LM. Additionally, new drugs and biomarkers will be discussed.

Does primary site of colorectal cancer become a prognostic factor of patients undergoing curative resection of liver metastases?

772 Background: The comparison of prognosis between right and left-sided colon cancer (RC, LC) has recently attracted a lot of attention. We examined whether primary location of colo-rectal cancer represents a prognostic factor of patients received curative resection of liver metastasis. Methods: We reviewed all patients undergoing resection of liver metastasis of colo-rectal cancer from1992 to 2013 in the 2 YCU hospitals, and selected eligible 377 patients (59 [15.6 %] with RC, 318 [84.4 %] with LC) undergoing R0 or 1 resection of primary and metastatic lesions. Patients with transverse colon cancer were excluded. We stratified patients according to previously-reported prognostic factors of hepatic metastasis resection, and conducted univariate analysis by Log Rank test to compared overall survival (OS) in each stratum. Using those results, independent factors affecting OS were determined by multivariable Cox regression. Results: The median OS of 377 patients was 66 months, and disease free survival (DFS) was 11.6 months. Univariate analysis revealed that the number and maximum diameter of liver metastasis, existence of other metastasis apart from liver, CEA, and having pre- or post- operative chemotherapy showed significant difference of OS. Primary site did not show significant difference of OS (p = 0.547), but median OS of LC (67 months) was 24 months longer than of RC. As for DFS, there was no significant difference between RC and LC (10.75 vs. 11.6 months, p = 0.873). Multivariate Cox regression analysis was conducted using former factors showing significant difference and primary site. Then primary site was an independent prognostic factor (p = 0.047). LC showed a lower risk than RC (HR: 0.675). Conclusions: The primary site did not affect DFS, but could become a prognostic factor of OS with patients undergoing curative resection of liver metastases. It suggested that curative resection of liver metastases could contribute to prolong survival, regardless of RC or LC. And there is some possibility that the primary site affects prognosis after post-operative recurrence of colo-rectal cancer liver metastases.

The prognostic role of systemic inflammation in patients undergoing resection of colorectal liver metastases: C-reactive protein (CRP) is a strong negative prognostic biomarker.

Systemic inflammation has been associated with poor survival in several tumor types, but has been less extensively studied in resectable metastatic disease. The aim of the present study was to evaluate the prognostic role of CRP in colorectal cancer patients with liver metastases (CRLM) compared to conventional tumor- and patient-related clinicopathological features as well as other indicators of the systemic inflammatory response (SIR). A multinational retrospective study of 492 CRLM patients undergoing potentially curative resection of liver metastases between 1999 and 2009. Clinicopathological findings and the SIR markers CRP, hypoalbuminemia, and their combined Glasgow Prognostic Score (GPS) were analyzed. Multivariate analysis showed that preoperative CRP >10 mg/L was a strong predictor of compromised survival (HR = 1.72, 95%CI 1.84-2.50, P < 0.01). Patients with CRP ≤10 mg/L had a median survival of 4.27 years compared to only 47 days in patients with CRP ≥30 mg/L (P < 0.01). Similarly, increased GPS was independently predictive of poor survival (HR 1.67, 95%CI 1.22-2.27, P < 0.01), but hypoalbuminemia alone did not have significant prognostic value. CRP alone is a strong prognostic factor, following curative resection of colorectal liver metastases and should be taken into consideration when selecting treatment strategies in CRLM patients. J. Surg. Oncol. 2016;114:895-899. © 2016 2016 Wiley Periodicals, Inc.

Remission of Unresectable Lung Metastases from Rectal Cancer After Herbal Medicine Treatment: A Case Report

Lung metastasis is frequent in rectal cancer patients and has a poor prognosis, with an expected three-year survival rate of about 10%. Though western medicine has made great strides in the curative resection of liver metastases, resection of lung metastases has lagged far behind. Many preclinical studies have suggested that herbal treatments block metastasis, but few clinical studies have addressed this topic. We present the case of a 57-year-old Asian male with lung metastases from rectal cancer. He first underwent resection of the primary lesion (stage IIA, T3N0M0) and six cycles of adjuvant chemotherapy. Unfortunately, lung metastases were confirmed about one year later. Palliative chemotherapy was begun, but his disease continued to progress after three cycles and chemotherapy was halted. The patient was exclusively treated with herbal medicine-standardized allergen-removed Rhus verniciflua stokes extract combined with Dokhwaljihwang-tang (Sasang constitutional medicine in Korea). After seven weeks of herbal medicine treatment, the lung metastases were markedly improved. Regression of lung metastases has continued; also, the patient's rectal cancer has not returned. He has been receiving herbal medicine for over two years and very few side effects have been observed. We suggest that the herbal regimen used in our patient is a promising candidate for the treatment of lung metastases secondary to rectal cancer, and we hope that this case stimulates further investigation into the efficacy of herbal treatments for metastatic colorectal cancer patients.

611TiP - Adjuvant Regorafenib (Reg) in Stage Iv Colorectal Cancer (Crc) After Curative Treatment of Liver Metastases: a Phase III Randomized, Placebo (Pbo)-Controlled Trial (Coast)

ABSTRACT Background: Complete resection and pre-/peri-/post-operative chemotherapy are the standard of care for patients with stage IV CRC and resectable metastases confined to the liver. Despite this treatment approach, long-term disease-free survival of patients with resected liver metastases is poor. The oral multikinase inhibitor REG significantly improved overall survival (OS) in patients with metastatic CRC that had progressed after all standard therapies (CORRECT study; HR 0.77; one-sided p = 0.0052; Lancet 2013). COAST will evaluate the efficacy and safety of REG vs PBO in patients with CRC after curative resection of liver metastases and completion of planned chemotherapy. Trial design: This double-blind, PBO-controlled, multicenter, phase III study (ClinicalTrials.gov identifier NCT01939223) will randomize patients (n = 750 planned) 1 : 1 to treatment with oral REG 160 mg or PBO once daily in 4-week cycles of 3 weeks on, 1 week off treatment. Doses of study drug may be delayed or reduced to manage clinically significant drug-related toxicities. Treatment will continue for 2 years or until recurrence of CRC, death, intolerable toxicity, or patient/investigator decision to stop. Inclusion criteria include age ≥18 years, stage IV CRC, pathology-proven complete resection of liver metastases, and ECOG performance status 0 or 1. Patients must have completed adjuvant, neoadjuvant, or perioperative chemotherapy. Randomization will be stratified by number of preoperative liver metastases ( 6 months), and time since last surgery for any CRC lesion (≤6 months vs >6 months). The primary endpoint is disease-free survival (DFS), assessed by the investigator using computed tomography or magnetic resonance imaging. Secondary endpoints include OS, health-related quality of life, and biomarker evaluations. Analyses will be performed when approximately 317 DFS events are observed, at which time the study will have 90% power to detect a 50% improvement in median DFS. The first patient entered the study in February 2014 and the estimated primary completion date is March 2018.Previously presented at WCGI 2014 abstract number: 749 (to be presented at WCGI 2014 as a poster presentation). Disclosure: A. Grothey: has the following financial disclosures: Advisory board: Bayer Corporate sponsored research: Bayer, Genentech, Eisai, Pfizer, ImClone, Daiichi; T. Yoshino: has the following financial disclosures: Corporate sponsored research: Daiichi Sankyo, Taiho, Bayer, Eli Lilly, Pfizer, Chugai, and Yakult; J. Zalcberg: has the following financial disclosures: Advisory board: Bayer, Roche Research and travel support, expert testimony: Bayer, Roche; D.J. Sargent: has the following financial disclosures: Advisory board: Bayer, Roche Corporate sponsored research: Roche, Celgene; M. Choti: has the following financial disclosures: Research consultant: Bristol Myers Squibb; M. Rutstein: has the following financial disclosures: Employment: Bayer HealthCare; L. Cupit: has the following financial disclosures: Employment: Bayer; I. Kuss: has the following financial disclosures: Employment: Bayer Pharma AG; E. Van Cutsem: has the following financial disclosures: Corporate sponsored research: Bayer . All other authors have declared no conflicts of interest.

大腸癌肝転移切除後無病生存の予測ノモグラムの外的妥当性の検証

目的：全国11施設の2000～2004年の症例を対象とした再発予測因子の検討から，大腸癌肝転移切除後の無病生存を予測するノモグラムが報告された．この外的妥当性をFOLFOXなどの新規化学療法が一般化された2005年以降の症例で検証した．方法：2005年1月から2009年11月までに当院で初回肝切除を施行した大腸癌肝転移症例50例を対象とした．結果：全切除症例の3年無病生存率は48.0%，無病生存期間は中央値25.9か月であった．Concordance index（C-index）は0.54であった．再発群（n=27）と非再発群（n=23）の比較ではスコアは平均6.96対5.26（P=0.25），スコア5点以下と6点以上の比較では無病生存期間は中央値51.2か月対21.7か月（P=0.43）と有意差を認めなかった．術前にFOLFOXまたはFOLFIRIを施行した症例を，その効果により奏効群（n=10）と非奏効群（n=14）に分けて比較すると術前スコアは平均7.40対7.92（P=0.84）と有意差を認めなかったが，3年無病生存率は70.0%対28.6%（P=0.02）と有意に奏効群で良好であった．結語：本検討から周術期補助療法施行例へのノモグラムの応用は慎重にあるべきと考えられた．周術期の新規化学療法が肝切除後の無病生存に影響している可能性があり，新たなノモグラムの必要性が示唆された．

The progress in adjuvant therapy after curative resection of liver metastasis from colorectal cancer.

Colorectal cancer liver metastases (CRLM) are common and found in almost 50% of patients with colorectal cancer. Surgical resection has proved to be the most effective therapy for metastatic colorectal cancer isolated to the liver and has yielded long term survival. However, recurrence frequently occurs within the remaining liver as well as at extra-hepatic sites. The role of adjuvant therapy has been investigated in many studies but has still been controversial until now. This review examines the incorporation of adjuvant systemic chemotherapy, regional chemotherapy with hepatic arterial infusion and molecular targeted therapy following liver resection for patients with CRLM, and summarized the advantage and adverse effects for these treatments. Finally, we propose the prospective of future adjuvant treatments to further improve prognosis.

A combination of oral uracil-tegafur plus leucovorin (UFT + LV) is a safe regimen for adjuvant chemotherapy after hepatectomy in patients with colorectal cancer: Safety report of the UFT/LV study

The use of adjuvant systemic chemotherapy for resectable liver metastases from colorectal cancer (CRC) is controversial because no trial demonstrated its benefit. We conducted the phase III trial to evaluate UFT/leucovorin (LV) for colorectal liver metastases (CRLM). The primary endpoint has not been available until 2014, we first report the feasibility and safety data of UFT/LV arm. In this multicenter trial, patients who underwent curative resection of liver metastases from colorectal cancer were randomly assigned to receive surgery alone or surgery followed by adjuvant chemotherapy with UFT/LV. The primary endpoint was relapse-free survival. Secondary endpoints included overall survival and safety. A total of 180 patients were enrolled, 90 were randomly assigned to receive UFT/LV therapy. Eighty two of whom were included in safety analyses. In the UFT/LV group, the completion rate of UFT/LV was 54.9%, the relative dose intensity was 70.8% and grade 3 or higher adverse events occurred in 12.2% of the patients. Elevated bilirubin levels, decreased hemoglobin levels, elevated alanine aminotransferase levels, diarrhea, anorexia were common. Most other adverse events were grade 2 or lower and tolerable. In conclusions, UFT/LV is a safe regimen for postoperative adjuvant chemotherapy in patients who have undergone resection of liver metastases from colorectal cancer. Further studies are warranted to improve completion rate, but UFT/LV is found to be a promising treatment in this setting.

Ligadura da veia porta associada à transecção para hepatectomia em dois estágios (ALPPS): uma nova abordagem nas ressecções hepáticas

Postoperative liver failure consequent to insufficiency of remnant liver is a feared complication in patients who underwent extensive liver resections. The associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a new approach for patient which tumor is previously considered unresectable. To present ALPPS as an innovative surgical technique of two-staged hepatectomy for the treatment of patients with marginally resectable or initially nonresectable primary and metastatic liver tumors. The procedure is performed in two steps. The first consists on ligation of the right portal vein branch. Subsequently, total or nearly total parenchyma dissection along the falciform ligament is performed, including the middle hepatic vein. A plastic bag is used to cover the right extended lobe, and the abdomen is drained and closed. The second one is performed after a computer tomography, six to 12 days interval. After laparotomy, the plastic bag is removed. The right artery, right bile duct and the right hepatic vein are divided. The extended right lobe is removed. Drain is placed at the resection surface, and the abdomen is closed. The associating of liver partition and portal vein ligation can enable curative resection of liver metastasis in patients with lesions previously considered unresectable.

Phase II Trial of Adjuvant Chemotherapy with S-1 for Colorectal Liver Metastasis

This phase II trial was designed to evaluate the safety and efficacy of adjuvant chemotherapy with S-1 in patients with curatively resected liver metastasis from colorectal cancer. Results of an interim analysis of safety and short-term outcomes are reported. Patients who underwent curative resection of liver metastasis from colorectal cancer received S-1 monotherapy (on days 1-28, followed by 14 days' rest, 8 cycles) as adjuvant chemotherapy. Among 62 patients enrolled between October 2008 and August 2010, a total of 60 patients were eligible for analysis. The most frequent grade 3 or higher hematologic toxicity involved neutropenia in three patients (5.0 %). Nonhematologic toxicities of grade 3 or higher were fatigue in 6.7 % of patients. Grade 4 enteritis occurred in one patient, but resolved promptly after withdrawal of S-1 therapy. The completion rate of the eight scheduled cycles of chemotherapy was 58.3 %. The most common reasons for withdrawal of treatment was the detection of early relapse in 16 patients (64 %). When the 16 patients who had recurrence during adjuvant treatment were excluded from analysis, 79.5 % of the remaining 44 patients completed the scheduled treatment. Early recurrence within 1 year after curative liver resection occurred in 21 patients (35 %). The most common site was the remnant liver in 14 patients. Orally administered S-1 after curative liver resection has an acceptable toxicity profile and a high rate of completion of the therapy. S-1 can be safely used and might be a viable treatment option in an adjuvant setting.

PCN70 Cost-Effectiveness of Cetuximab and Bevacizumab in the First-Line Treatment of Metastatic Colorectal Cancer (mCRC) for Patients with Kras Wild-Type Tumours in the United Kingdom

Combinations of chemotherapy and monoclonal antibodies (MAbs) against the vascular endothelial growth factor (bevacizumab) and the epidermal growth factor receptor (cetuximab) have been shown to improve the clinical outcome of patients with mCRC. Little is known about the economic implications of their use. The aim of this analysis was to evaluate the cost, clinical- and cost-effectiveness of adding the MAbs cetuximab or bevacizumab to chemotherapy in the first-line treatment of mCRC patients with KRAS wild-type tumours, from the UK (UK) NHS perspective. A semi-Markov model was developed to simulate patient outcomes and costs for first and subsequent lines of treatment including long-term survival after a curative resection of liver metastases. Data for progression-free survival, resection rates and other model parameters were mainly derived from the CRYSTAL and NO16966 phase 3 studies. The long-term benefits of surgery were estimated from a consecutive series of 1439 patients. Resource use included drugs, physician visits, scans, hospitalizations and treatment of adverse events. Extensive sensitivity analyses were undertaken to explore the robustness of the results. In the base case, the estimated mean life expectancy for cetuximab- and bevacizumab-containing regimens was 3.22 and 2.31 years (all undiscounted) respectively. The incremental cost-effectiveness ratio (ICER) for FOLFIRI+cetuximab compared with FOLFIRI alone was £30,665 per quality-adjusted life year (QALY) and £17,626 per QALY compared with FOLFOX+bevacizumab. The ICER is mainly driven by the number of patients becoming resectable and the acquisition cost for each antibody. This analysis suggests that cetuximab in combination with FOLFIRI is the most effective treatment regimen compared with FOLFOX+bevacizumab or chemotherapy alone for patients with KRAS wild-type tumours. The incremental cost-effectiveness ratios of cetuximab in combination with chemotherapy compared with chemotherapy alone, and bevacizumab-containing regimens are within the commonly accepted threshold for cost-effectiveness in the UK.

Pilot study of hepatic arterial infusion chemotherapy with gemcitabine and 5-fluorouracil for patients with postoperative liver metastases from pancreatic cancer

Hepatic metastasis is a common cause of treatment failure after curative resection of pancreatic cancer. We report a pilot study of hepatic arterial infusion (HAI) chemotherapy with gemcitabine and 5-fluorouracil (5-FU) for postoperative liver metastases from pancreatic cancer. Five patients who had undergone curative resection of liver metastases from pancreatic cancer received HAI of gemcitabine and 5-FU between October 2008 and September 2010 at Kanazawa University Hospital. Gemcitabine at a dose of 800 mg was infused over 30 min via a bedside pump. After gemcitabine administration, 250 mg of 5-FU was infused continuously over 24 h on days 1-5, comprising one cycle of therapy. These treatment cycles were continued biweekly. In the evaluation according to RECIST criteria, a partial response was obtained in 2 of the 5 cases, with stable disease being achieved in the remaining 3 cases (response rate, 100%). In 4 of the 5 cases, a decrease in serum tumor marker CA19-9 was observed after 10 HAI treatment cycles. The median time to treatment failure was 10 months (range 3-17). As to adverse events, leukocytopenia was grade 3 in 1 of 4 affected cases and all 5 were anemic, although 4 of the 5 cases had anemia prior to HAI therapy. Grade 2 thrombocytopenia was observed in 2 cases. No nonhematologic events, such as nausea, diarrhea, liver injury and neuropathy, occurred. There were no life-threatening toxicities, but 4 cases (80%) developed catheter complications, and the HAI catheter and subcutaneous implantable port system had to be removed. HAI delivers high doses of chemotherapeutic agents directly into tumor vessels, producing increased regional levels with greater efficacy and a lower incidence/severity of systemic side effects. In conclusion, HAI chemotherapy is useful and safe for the treatment of malignancies confined to the liver.

Chemotherapy-Associated Hepatotoxicity: Do We Need to Be Concerned?

Curative resection of liver metastases from colorectal cancer is associated with improved overall survival rates, making complete resection the goal of therapy for many patients. The addition of newer, more active chemotherapeutic regimens has prolonged patient survival in those with advanced disease and increased the number of patients eligible for surgical therapy. However, concerns regarding chemotherapy-associated liver injury may have a negative impact on the ability to offer potentially curative therapy and may increase morbidity in some patients. Specific forms of liver injury have been associated with various chemotherapeutic regimens, including steatosis and steatohepatitis with prolonged fluorouracil and irinotecan therapy, and sinusoidal injury with oxaliplatin-based regimens. While the histologic association appears likely, the contribution of chemotherapy-associated hepatotoxicity to postoperative morbidity remains ill defined.

Perioperative or Adjuvant Therapy for Resectable Colorectal Hepatic Metastases

Perioperative or Adjuvant Therapy for Resectable Colorectal Hepatic Metastases

Neoadjuvant or adjuvant therapy for patients with resectable liver metastases

Curative resection of liver metastases from colorectal cancer is associated with high 5-year overall survival rates, making complete resection the goal of therapy for many patients. Improved outcomes in recent years have resulted in the application of increasingly aggressive multidisciplinary approaches for patients with metastatic disease. The addition of newer, more active chemotherapeutic regimens has prolonged patient survival in those with advanced disease and increased the number of patients eligible for surgical therapy. Furthermore, integration of chemotherapy with hepatectomy in patients with initially resectable disease offers the potential for improving survival beyond that seen with resection alone. Recent randomized studies have demonstrated a benefit of both adjuvant and neoadjuvant chemotherapy. However, questions regarding the optimal indications, regimen, and sequence of therapy remain. The use of neoadjuvant chemotherapy has potential advantages over postoperative adjuvant therapy, including improved patient selection, determining response to therapy, and achieving earlier delivery of systemic therapy. The disadvantages sometimes seen with neoadjuvant therapy include chemotherapy-associated hepatotoxicity and inability to identify resectable lesions. Ultimately, a therapeutic strategy that includes all aspects of multidisciplinary and multimodality care is required to select and treat this complex group of patients.

Systemic or hepatic arterial chemotherapy after curative resection of liver metastases from colorectal cancer. A meta-analysis of randomized controlled trials

4077 Background: Curative treatment of liver metastases from colorectal cancer (CRC) relies upon R0 surgery whenever feasible (5-year survival: 40 %). Whether or not addition of adjuvant systemic o...

Neoadjuvant treatment with weekly high-dose 5-fluorouracil as a 24h-infusion, folinic acid (AIO regimen) and oxaliplatin in patients with primary resectable liver metastases of colorectal cancer: Long-term results of a phase II trial

15083 Background: Only 15–20% of all patients (pts.) with colorectal liver metastases are suitable for primary surgical resection. Liver resection offers the only chance of cure for these pts. In 2003 Wein et al. (Oncology) published the first data of neoadjuvant therapy following curative resection of liver metastases after a short median follow up (23 months) within a phase II trial. Here we report on the long-term results (median follow up: 45,5 months). Methods: Prospective phase II trial; pts.: n=20; start: 1/1998; end of recruitment: 2/2000; neoadjuvant chemotherapy: oxaliplatin (Eloxatin, 85 mg/m2 i.v. as a 2h-infusion (inf.); d 1, 15, 29 qd 57) and FA (Rescuvolin, 500 mg/m2 i.v. as a 1h- to 2h-inf.; d 1, 8, 15, 22, 29, 36 qd 57) followed by 5-FU (2600 mg/m2 i.v. as a 24h-inf.; d 1, 8, 15, 22, 29, 36 qd 57). Results: Last date of evaluation: 31/5/2007; localisation of the primary tumor: colon: n=40%, rectum: n=60%; histology: adenocarcinoma: n=20; G1/G2/G3/G4: 0/17/3/0; median age: 62,5 years; men/women: 75%/25%; ECOG 0/1: 10/10; higher grade toxicity: diarrhea CTC toxicity grade 3: 30%, vomiting grade 3+4: 15%; response of the neoadjuvant chemotherapy: CR: 10%, PR: 90%; metastatic resection: R0: 80%, R2: 20%. Median survival of all pts. (n=20): 3,0 years; 5-year overall survival (n=20): 40%. Median survival of the pts. (n=16) with R0 resection: 4,8 years; 5-year overall survival of the R0 resected pts.: 50%; 5-year disease-free survival rate: 25%. Median disease-free time period: 20,9 months. Conclusions: The neoadjuvant treatment with weekly high-dose 5-FU in the form of a 24h-inf. combined with FA and Oxaliplatin has proved to be highly effective and well tolerated. Disease-free survival rates and median overall survival rates are promising. Additionally, the data of a phase III trial published by Nordlinger et al. (ASCO 2007) indicate that a perioperative chemotherapy treatment combined with a curative resection of metastases may improve the prognosis in pts. with primarily resectable liver metastases. No significant financial relationships to disclose.

Evaluation of the correlation of complete metabolic response with 18-FDG PET scan and complete pathologic response induced by neoadjuvant chemotherapy for colorectal liver metastases

4070 Background: In the setting of neoadjuvant chemotherapy before colorectal liver metastases resection, treatment efficacy can be evaluated by 18-FDG-PET scan. So far, it remains unclear how much this so-called metabolic response is indicative of the tumor destruction and correlates to pathologic response. Methods: Patients with liver metastases from CRC receiving neoadjuvant chemotherapy and undergoing hepatectomy in two academic hospitals were reviewed. Inclusion criteria were: (1) a metabolic (by FDG-PET scan) and radiologic (by CT scan) evaluation of the hepatic metastases before the initiation and at the end of chemotherapy just preceding surgery; (2) histopathologic examination of hepatic lesions. The metabolic (by visual assessment and SUV) and radiologic (RECIST criteria) response were classified as complete, partial, no change and progression and compared to the histological findings on surgical specimens. Results: A total of seventy patients were evaluated. Fifteen patients fit the inclusion criteria. A total number of 39 hepatic metastases (both synchronous and metachronous) were recorded and analyzed. Chemotherapy consisted in folfox or folfiri ± biologicals (median number of cycles: 6; range 3–15). Complete metabolic response was observed in 20 metastases (51%) (associated with a complete radiological response in 10);five of which (5/20=25%) disclosed the persistence of viable tumoral cells at histopathologic examination. Partial metabolic response was observed in 10 metastases, all corresponding to radiological partial response, but five of which (50%) showing complete pathological response.In the other hand, complete pathologic response was observed in 20 metastases, 5 of which showing persistence of metabolic activity at preoperative PET scan.Overall, there was a concordance between metabolic and histologic responses in 19 / 39 metastases (48.7%). Conclusion: FDG-PET evaluation can be useful to evaluate early response to therapy but cannot be used to predict complete pathologic response after neoadjuvant chemotherapy. Consequently, curative resection of liver metastases in these selected patients should not be deferred on the basis of FDG-PET results. No significant financial relationships to disclose.