Liver Metastases Of Colorectal Origin Research Articles

Abstract 6221: First-in-human study of acoustic cluster therapy consisting of PS101 combined with chemotherapy and insonation in patients with liver metastases of colorectal cancer origin

Abstract Background: Suboptimal delivery of anti-cancer agents to cancer tissue compromises the effectiveness of therapeutics. PS101 consists of microclusters of perfluorobutane microbubbles and perfluoromethylcyclopentane (PFMCP) microdroplets. Acoustic cluster therapy (ACT) consists of PS101 administered intravenously and insonated over a tumour with diagnostic ultrasound (2 MHz or above), which fuses the components of PS101 to form larger ACT bubbles that are temporarily trapped in capillaries, followed by low frequency (0.5 MHz) insonation, which induces oscillation of the ACT bubbles, stretching capillaries. Given concurrently with chemotherapy, this enhances delivery of chemotherapy to target tissues. Methods: We describe a first-in-human phase1 study to evaluate the safety and tolerability, pharmacokinetics, and preliminary anti-cancer activity of ACT treatment and the chemotherapy regimens FOLFOX or FOLFIRI in patients with liver metastases of colorectal origin (NCT04021277). The dose escalation cohorts evaluated safety of 20 µL/kg and 40 µL/kg dose levels of PS101 combined with chemotherapy. The primary assessment of anti-tumor activity consisted of within-patient comparison of radiographic responses between ACT-treated lesions (insonated) and control lesions (non-insonated). Results: We had previously treated mice bearing SW620 xenografts treated with a control arm of Irinotecan at 60 mg/kg IP or Irinotecan plus PS101 at 2ml/kg and insonation in the experimental arm and showed a difference in survival in the experimental arm 34 days Vs 54 days p <0.01 (1). In the first in human clinical trial 8 patients were enrolled into the dose escalation part of the study, of which 2 subjects were not evaluable for dose escalation decision. There were no CTCAE grade 3, or above AEs or SAEs related to PS101 or the ultrasound. 4/8 patients discontinued treatment due to AEs - all related to chemotherapy. Median plasma concentration of PFMPC 5 minutes after the injection was 117 ng/ml (n=3, range 82 to 158) in the 20 µl/kg cohort and 233 ng/ml (n=4, range 217 to 275) in the 40 µl/kg cohort. 5 out of 6 patients had greater shrinkage of the insonated lesion compared with control lesions. The median percentage difference in maximum diameter of lesions between baseline and week 8 assessments, for insonated and non-insonated lesions, was -16% (range 25 to -42) and -3% (range 12 to -19), respectively. The dose expansion part of the study is ongoing, randomizing patients receiving FOLFIRI chemotherapy up to 10 patients each between 20 µl/kg and 40 µl/kg dose levels. Conclusions: Following preclinical activity in xenograft models, the ongoing first in human study of ACT in patients with colorectal cancer has shown clinical translation of differential activity in insonated metastasis. Reference: Reference: 1.Bush N et al Front Pharmacol 2019, 10:1299 Citation Format: Udai Banerji, Wing Yau, Mark T. O'Leary, Nigel Bush, Sumita Gurung, Amir Snapir, Jeff C. Bamber, Nina Tunariu. First-in-human study of acoustic cluster therapy consisting of PS101 combined with chemotherapy and insonation in patients with liver metastases of colorectal cancer origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6221.

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.

Laparoscopic resections of the liver and the colon in patients with synchronous colorectal metastases: a case series

Aim. To evaluate the results of laparoscopic simultaneous colorectal and liver resections in patients with synchronous liver metastases.
 Materials and methods. From July 2019 to July 2021 9 patients with synchronous liver metastases of colorectal origin underwent one-stage mini-invasive surgery in the Department of Oncology №4 City Clinical Oncological Hospital №1. There were 4 totally laparoscopic procedures while 5 patients had laparoscopic colon resection and an open hepatectomy. A laparoscopic rALPPS right hepatectomy with sigmoid colon resection was performed in one case.
 Results. There were no deaths during hospitalization or within 90 days after surgery. There were no severe complications requiring repeated surgeries or long-term intensive therapy (DindoClavien IIIBIVB grade). Two patients needed an ultrasound-guided drainage of hematoma and biloma, respectively. There was one case of grade A of liver failure and one case with prolonged antibacterial therapy caused by unclear fever. The average duration of interventions was 401121 min, the average volume of blood loss was 383331 ml. Mean post-operative hospital stay was 104 days.
 Conclusion. Our initial experience in the implementation of one-stage laparoscopic surgery in the treatment of patients with synchronous liver metastases of colorectal origin is promising and requires further research and analysis of long-term results.

Stereotactic body radiation therapy in patients with liver oligometastases from colorectal cancer: a systematic review

The purpose of the systematic review is to summarize the data regarding safety and efficacy of stereotactic body radiation therapy in patients with oligometastases of colorectal cancer to the liver.Published scientific articles on the topic were identified by searching the databases mEDLInE, Pubmed, EmBASE. The review includes publications reporting on the results of treatment of patients undergoing stereotactic radiation therapy for. The systematic review includes all retrospective and prospective studies found over the past 15 years with at least 10 patients with liver metastases of colorectal origin included and standardized methodology of radiation therapy. We included into the review 20 studies comprising 919 patients. Comparative analysis was complicated because of the absence of control groups in all of the studies. moreover, 16 studies were single-center with heterogeneous groups of patients and various regimens of stereotaxic radiation therapy. Despite this, the researchers achieved 60–100 % rates of one-year local control, 56–100 % one-year overall survival with median overall survival up to 45 months and the number of clinically significant complications less than 10 %.From our point of view, the results of published studies support the safety and efficacy of stereotactic radiation therapy in patients with colorectal cancer and oligometastatic liver disease. we consider stereotactic body radiation therapy to be one of the local control options in case of careful patient selection and the use of modern radiation therapy options. further randomized controlled trials are needed.

ASO Visual Abstract: Outcomes of Combined Peritoneal and Local Treatment in Patients with Peritoneal and Limited Liver Metastases of Colorectal Origin: A Systematic Review and Metaanalysis

ASO Visual Abstract: Outcomes of Combined Peritoneal and Local Treatment in Patients with Peritoneal and Limited Liver Metastases of Colorectal Origin: A Systematic Review and Metaanalysis

Combined laparoscopic colorectal and liver resection for patients with synchronous liver metastases of colorectal origin: a retrospective, multicenter, propensity score matched study

Background: Laparoscopic simultaneous colorectal and liver resection (LSCLR) is an option with potential benefits, but there are concerns whether SCLR could increase the risk of morbidity compared with staged resections. This study aimed to identify the impact on postoperative morbidity of adding a liver resection to a colorectal resection using a laparoscopic approach. Methods: A retrospective, multicenter, propensity score matched study was performed comparing LSCLR (2009-2016; four centers) with laparoscopic colorectal resection alone. Data from the Dutch ColoRectal Audit of two participating centers were used to match control patients based on propensity scores in a 1:1 ratio. Propensity scores were calculated based on 7 pre-operative variables. Pre-, intra- and post-operative outcomes were compared using paired test. Results: A well-balanced cohort of 122 patients was analyzed (61 patients undergoing LSCLR and 61 patients undergoing laparoscopic colorectal resection alone). Liver resections consisted of minor resections only. LSCLR was associated with a small increase in operating time (206 (166-308) vs 197 (148-231) minutes, p=0.057) and increased blood loss (200 (100-700) vs 75 (5-200) ml, p=0.011). Conversion rates were 5 and 8%, p=0.687. The incidence of severe complications (Clavien-Dindo grade 3 or higher) (15% vs 21%), anastamotic leakage (8% vs 7%) and mortality (0% vs 2%) specifically did not differ between LSCLR and colorectal resection alone. Conclusion: In selected patients, LSCLR can be safely performed without increasing the risk of postoperative morbidity compared to laparoscopic colorectal resection alone.

Recurrence of liver metastases from colorectal cancer and repeat liver resection.

The purpose of this study was to assess the resectability and effectiveness of repeat hepatectomy for relapsing liver metastases of colorectal origin in terms of morbidity, mortality, overall survival, and disease-free survival. A retrospective study was performed on a prospective cohort of patients with colorectal liver metastases who underwent repeat surgery at Hospital Universitario San Cecilio, Granada (Spain), from March 2003 to June 2013. Primary outcome variables included survival and morbidity within 30 days post-surgery. A total of 147 patients with colorectal liver metastases underwent surgical excision during the study period; 61 patients had liver recurrence, and 34 of these received repeat surgery. The overall survival rate at 5 and 10 years for resected patients (n=27/34) was 48% and 48%. Mean hospital stay was 8.9 ± 3.5 days, morbidity was 9%, and mortality was 0%. Repeat liver resection for colorectal liver metastases is a safe, effective surgical procedure whose results are similar to those obtained after initial liver resection.

Extended Low Hartmann Operation with Total Mesorectal Excision - Optimal Surgical Treatment in Stage IV Mid and Upper Rectal Cancer

Background: The main surgeries that can be performed in upper and mid rectal cancer are low anterior rectal resection (LAR), lateral colostomy (LC), and extended Hartmann operation with mesorectal excision (EHO). Compared to lateral colostomy, EHO is a curative surgery; it also takes a shorter time to perform and has a lower mortality compared with LAR. Objective: The aim of this study was to analyze the postoperative surgical complications in patients who underwent LAR, LC, or EHO. Methods: The study is a prospective analysis based on a Surveillance protocol for patients with liver metastases of colorectal origin used in First Surgical Oncology Unit, Regional Institute of Oncology IaAŸi, Romania. The postoperative complications occurring within 60 days postoperatively were analyzed. Results: In the interval June 2012 – May 2014, 87 patients were diagnosed with upper and mid-rectal cancer and liver metastases; LAR was performed in 18 patients, LC in 19 patients and in 50 patients EHO with pelvic drainage abdominally exteriorized or perineally (37 and 13 patients, respectively). The postoperative complications related to surgical wound, stoma, pelvic abscess, postoperative bleeding, prolonged postoperative ileus, anastomotic leakage, reinterventions, readmissions, and mortality were analyzed. A higher rate of pelvic abscesses was found in EHO patients (24%, n=12), of which 9 patients (18%) required reinterventions for drainnage of pelvic fluid collection; all these patients had pelvic drainage exteriorized abdominally. No presacral abscesses were recorded in patients with pelvic drainage exteriorized perineally. Conclusions: Extended Hartmann Operation (EHO) remains a safe technique, that shares some indications with LAR and LC; however, it is associated with a higher percentage of pelvic abscesses and reinterventions that can be avoided by postoperative perineal drainage of the presacral space

Repeat hepatectomy for liver metastases from colorectal primary cancer: A review of the literature

After hepatectomy for metastases from colorectal cancer (CRC), approximately 50% to 70% of patients develop recurrent hepatic metastases. This recurrence is limited to the liver in about one-third of cases. The purpose of this study is to report a comprehensive review of the literature concerning the results of repeat hepatectomy for recurrent liver metastases from CRC. An electronic literature search was conducted to identify all medical articles published concerning repeat hepatectomy for liver metastases of colorectal origin during the period January 1990 to December 2010. After a second hepatectomy, the mean mortality was 1.4% and the mean morbidity rate was 21.3%. The 5-year survival ranged from 16% to 55%. After a third or fourth hepatectomy, the mean mortality rate was 0% and the mean morbidity rate was 24.5%. After a third hepatectomy, the 5-year survival ranged from 23.8% to 37.9%. After a fourth hepatectomy, the 5-year survival was 9.3% to 36%. Repeat hepatectomy seems justified, since it may result in prolonged survival with acceptable rates of morbidity and mortality, results similar to those seen after initial hepatectomy.

PMD31 Economic Evaluation of Primovist versus Extracellular Contrast in Imaging of Liver Metastases of Colorectal Origin

PMD31 Economic Evaluation of Primovist versus Extracellular Contrast in Imaging of Liver Metastases of Colorectal Origin

Adjuvant Therapy After Liver Resection for Colorectal Cancer Metastasis: What is the Evidence?

Synchronous or metachronous liver metastases of colorectal origin (colorectal liver metastases, CLM), although being the expression of systemic disease, allow a curative approach for about 25% to 35% of patients. Patients presenting with CLM should receive a multimodal management in order to increase the number of patients undergoing R0 surgery and to decrease the rate of recurrence. Current data do not allow to recommend the use of locally applied chemotherapy using hepatic artery infusion after resection of CLM. Postoperative and/or preoperative systemic chemotherapy shows a trend toward a benefit regarding progression-free and overall survival, without increasing postoperative complication rates. However, all available trials failed to show a statistical significance, so that a “formal” treatment standard is not accepted and recommendations differ between no treatment and a 5-FU/oxaliplatin combination to be considered as standard of care. Future research will help in defining treatment regimens and patients selection criteria to obtain a better approach in this setting.

Radiofrequency ablation as a treatment tool for liver metastases of colorectal origin.

At diagnosis 10–25% of patients with colorectal liver metastases (CRLM) present as resectable disease. Liver resection is the gold standard treatment, resulting in a 5-year overall survival (OS) of 22–58%, local recurrence rates of 1.2–10.4% and a perioperative mortality of less than 5%. Multiple attempts have been made to assess the possible contribution of radiofrequency ablation (RFA) to improve OS and progression-free survival (PFS) in patients with unresectable colorectal liver metastases. The aim of this paper is to review the RFA literature in the setting of colorectal liver metastases: RFA with and without chemotherapy, RFA with and without resection, RFA for solitary unresectable CRLM, surgical and percutaneous imaging-guided RFA, RFA compared with chemotherapy. The reported OS, PFS, local recurrence rates, morbidity and mortality in these different settings are analyzed. This paper reflects on a possible role of RFA in resectable CRLM.

Radioimmunotherapy Improves Survival of Rats with Microscopic Liver Metastases of Colorectal Origin

BackgroundHalf of the patients with colorectal cancer develop liver metastases during the course of their disease. The aim of the present study was to assess the efficacy of radioimmunotherapy (RIT) with a radiolabeled monoclonal antibody (mAb) to treat experimental colorectal liver metastases.MethodsMale Wag/Rij rats underwent a minilaparotomy with intraportal injection of 1 × 106 CC531 tumor cells. The biodistribution of 111In-labeled MG1, 1 day after intravenous administration, was determined in vivo and compared with that of an isotype-matched control antibody (UPC-10). The maximal tolerated dose (MTD) of 177Lu-labeled MG1 was determined and the therapeutic efficacy of 177Lu-MG1 at MTD was compared with that of 177Lu-UPC-10 and saline only. RIT was administered either at the day of tumor inoculation or 14 days after tumor inoculation. Primary endpoint was survival.Results111In-MG1 preferentially accumulated in CC531 liver tumors (9.2 ± 3.7%ID/g), whereas 111In-UPC-10 did not (0.8 ± 0.1%ID/g). The MTD of 177Lu-MG1 was 400 MBq/kg body weight. Both the administration of 177Lu-MG1 and 177Lu-UPC-10 had no side-effects except a transient decrease in body weight. The survival curves of the group that received 177Lu-UPC-10 and the group that received saline only did not differ (P = 0.407). Administration of 177Lu-MG1 RIT immediately after surgery improved survival significantly compared with administration of 177Lu-UPC-10 (P = 0.009) whereas delayed treatment did not (P = 0.940).ConclusionThis study provides proof of principle that RIT can be an effective treatment modality for microscopic liver metastases, whereas RIT is not effective in larger tumors.

Unresectable Liver Metastases from Colorectal Cancer and Hepatic Arterial Infusion Chemotherapy: How, When and to Whom?

We have read with great interest the article by Iguchi et al. [1], reporting their experiences with hepatic arterial infusion (HAI) of 5-fluorouracil (5FU) through a port-catheter in patients with inoperable liver metastases of colorectal cancer. On the one hand, HAI has been evaluated in liver metastases of colorectal origin in three meta-analyses [2– 4]. In all of them, a superior response rate in the experimental arm, favoring HAI, was observed. On the other hand, fluoropyrimidine HAI did not improve survival compared with systemic chemotherapy regimens based exclusively on fluoropirymidines. To our knowledge, randomized studies comparing HAI (alone or plus systemic chemotherapy) and conventional standard chemotherapy such as FOLFIRI (5FU plus Irinotecan) or FOLFOX (5FU plus Oxaliplatin) have not been published. Please note that in the referenced article FOLFIRI and FOLFOX regimens were misspelled (FORFOX and FOLFILI, respectively). In patients with initially unresectable metastases solely in the liver, maximizing the response rate in an attempt to render patients resectable is the holy grail for every oncologist [5] hoping to impact patients’ survival [6]. In this sense, HAI using a port-catheter system could be an interesting approach for the treatment of patients with preoperative intent. In fact, it permits the use of active drugs like floxuridine (FUDR) [7, 8], oxaliplatin [9, 10], and 5FU. Moreover, an ambulatory treatment option is possible thanks to the use of implantable intra-arterial devices. Interestingly enough, Iguchi et al. [1] did not find severe complications during or after HAI, unlike the treatment-related toxicities shown with older HAI regimens, which included chemical hepatitis, biliary sclerosis, and peptic ulceration or pump-related complications such as hepatic artery thrombosis, catheter displacement, hematomas, infections, and liver perfusion [11, 12]. Perhaps this treatment administration system will allow us to develop more reliable randomized clinical trials and offer a new opportunity to show the impact of HAI-based protocols on survival, especially in patients with potentially resectable liver metastases from colorectal cancer.

Prognostic value of concomitant resection of extrahepatic disease in patients with liver metastases of colorectal origin

Operative resection is the treatment of choice for colorectal liver metastasis. In the present study, we investigated the prognostic factors after hepatic resection, focusing on the concomitant resection of extrahepatic metastases. A retrospective cohort study was performed in 187 consecutive patients who had undergone initial hepatic resections for colorectal metastases using the Cox proportional hazards model. The overall survival rates at 3, 5, and 10 years were 49%, 30%, and 22%, respectively. Hilar lymph node involvement (HLN), localized peritoneal seeding (P), and distant organ metastasis (M) were resected in addition to the liver metastases in 9, 13, and 21 patients, respectively. The P and M factors were related univariately to an unfavorable patient prognosis, but the HLN factor was not. In a multivariate regression analysis, the hazard ratios of these three factors of interest were 1.58 (HLN; 95% confidence interval 0.64-2.52, median survival 48 months), 2.12 (P; 1.38-2.85, 18 months), and 3.07 (M; 2.45-3.68, 19 months), respectively. Aggressive operative resection for colorectal liver metastases yielded an acceptable long-term outcome. The presence of distant organ metastasis seems to be a contraindication for operative intervention and/or resection; although the number of patients enrolled in the present study was small, resection of localized peritoneal seeding or hilar lymph node involvement, in addition to the resection of the liver metastases, may benefit patient survival.

Ultrasound-Guided Radiofrequency Ablation (RFA) for Inoperable Gastrointestinal Liver Metastases

Surgery is the most effective treatment for liver metastases. Some patients, however, cannot tolerate this procedure due to co-morbidity, advanced age, site of the lesion or previous liver surgery. In our institution we have now increasing experience with radiofrequency ablation (RFA), a thermo-ablative modality. We compare our outcome and survival results to standard treatments for liver metastases. From April 2000 to June 2005, 30 consecutive patients with liver metastases from gastrointestinal primaries were treated with ultrasound guided RFA for their liver metastases (patients mean age 63.5 years, range 37-80. Size of lesions, range 0.4-6 cm). Main indications were non-operable lesions due to site of the lesion or co-morbidity. RFA was also applied as an additive to liver surgery and as a repetitive palliative treatment. 15 patients underwent one RFA-intervention, 8 patients two, 3 patients three, 1 patient four, 2 patients five and 1 patient six. RFA-interventions (n = 60) were performed either percutaneously (71.5%), in an open approach without liver surgery (22%) or in addition to liver surgery (6.5%). Mean observation time after first RFA was 23.5 months (range 3-63). Median survival in our patient cohort is 34 months, which compares favourably with results obtained by hepatic resection, the standard of care for liver metastases. Complication rate, attributed to the RFA procedure, was small in our series (5.5%) with one pleural effusion and one abscess formation in the ablated lesion due to underlying bacteraemia. RFA is an effective and low risk treatment modality in patients with liver metastases. The procedure is safe (complication rate < 6%) with low morbidity. RFA can be performed repeatedly on an outpatient basis with good palliative effects. Of note, surgery remains the treatment of choice in resectable liver metastases of colorectal origin.

Multicenter Randomized Trial of Adjuvant Fluorouracil and Folinic Acid Compared With Surgery Alone After Resection of Colorectal Liver Metastases: FFCD ACHBTH AURC 9002 Trial

Complete resection of liver metastases of colorectal origin is the only potentially curative treatment. In order to decrease recurrences, the use of adjuvant systemic chemotherapy after liver resection is controversial because no randomized study demonstrated its benefit. In a multicenter trial, we randomly assigned 173 patients with completely resected (R0) hepatic metastases from colorectal cancer to surgery alone and observation (87 patients) or to surgery followed by 6 months of systemic adjuvant chemotherapy with a fluorouracil and folinic acid monthly regimen (86 patients). The main outcome criterion was disease-free survival. Secondary outcome measures were overall survival and treatment-related toxicity. The intention-to-treat analysis was based on 171 patients, after a median follow-up of 87 months (SE = 5.8). The 5-year disease-free survival rate, after adjustment for major prognostic factors, was 33.5% for patients in the chemotherapy group and 26.7% for patients in the control group (Cox multivariate analysis: odds ratio for recurrence or death = 0.66; 95% CI, 0.46 to 0.96; P = .028). With regard to secondary outcome measures, a trend towards increased overall survival was observed but did not reach statistical significance (5-year overall survival: chemotherapy group, 51.1% v control group, 41.1%; odds ratio for death, 0.73; 95% CI, 0.48 to 1.10; P = .13). Despite a suboptimal regimen, which was the standard at the beginning of the study, adjuvant intravenous systemic chemotherapy provided a significant disease-free survival benefit for patients with resected liver metastases from colorectal cancer.

Chromosome allele loss in colorectal liver metastases and its association with clinical features.

Molecular genetic changes are better characterized in colorectal carcinoma than in other common adult tumours. Consistent allele losses, or loss of heterozygosity (LOH), on chromosomes 5q, 17p and 18q have been well established. These changes are associated with the prognosis of the disease. Little is known of such changes in liver metastases of colorectal origin. The extent of allelic loss and its association with clinical features were investigated in 19 patients with colorectal liver metastases by using 24 probes to detect restriction fragment length polymorphism. A high frequency of LOH on chromosomes 5q, 17p and 18q was found in these secondary tumours. No consistent loss has so far been shown in any other chromosome. The frequency of allele loss correlated significantly with prognostic features such as the number and size of liver secondaries (P < 0.005), metastasis to the lymph nodes (P < 0.01) and curative or palliative operation (P < 0.02).

A phase I study of hepatic arterial infusion (HAI) of irinotecan in patients with inoperable liver metastases of colorectal cancer

3714 Background: Hepatic intraarterial (IA) chemotherapy with agents such as FUDR has been shown to reduce local recurrence rates in patients with liver metastases of colorectal origin. Irinotecan is active in metastatic colorectal cancer. This phase I study was conducted to determine the maximum tolerated dose (MTD) of IA irinotecan in patients with inoperable liver metastases. Methods: Patients were required to have histologically confirmed disease, adequate hematologic, liver and renal function, no symptomatic CNS metastasis, a Karnofsky performance status of at least 70% and a life expectancy of at least 12 weeks. Patients received HAI irinotecan on days 1, 15, 29 and 43. Starting from an initial dose of 140 mg/m2, irinotecan was escalated in 20-mg/m2 steps up to a maximum dose of 200 mg/m2. Three patients were treated per dose level. Dose-limiting toxicity (DLT) was defined as WHO grade >= 3 myelosuppression or grade >= 3 non-hematologic toxicity. The MTD was reached when 2 of 3 patients experienced DLT during the first cycle. Tumor response was assessed after each cycle by CT and MRI. Clinical response benefit was evaluated using a standardized questionnaire (EORTC QLQ-C30). Results: So far, 9 patients have been enrolled (5 male, 4 female, median age 65.8 yrs). All patients tolerated the treatment well, and no DLT was observed. Overall, 3 patients (33%) achieved a partial response (PR), 3 patients (33%) stable disease, and 3 (33%) had progressive disease. Patients with PR subsequently received laser-induced thermotherapy (LITT). Conclusions: Preliminary results from this ongoing study indicate that HAI irinotecan is well tolerated and can produce encouraging response rates in patients with liver metastases of colorectal origin. No significant financial relationships to disclose.

A phase I study of hepatic arterial infusion (HAI) of irinotecan in patients with inoperable liver metastases of colorectal cancer

3714 Background: Hepatic intraarterial (IA) chemotherapy with agents such as FUDR has been shown to reduce local recurrence rates in patients with liver metastases of colorectal origin. Irinotecan is active in metastatic colorectal cancer. This phase I study was conducted to determine the maximum tolerated dose (MTD) of IA irinotecan in patients with inoperable liver metastases. Methods: Patients were required to have histologically confirmed disease, adequate hematologic, liver and renal function, no symptomatic CNS metastasis, a Karnofsky performance status of at least 70% and a life expectancy of at least 12 weeks. Patients received HAI irinotecan on days 1, 15, 29 and 43. Starting from an initial dose of 140 mg/m2, irinotecan was escalated in 20-mg/m2 steps up to a maximum dose of 200 mg/m2. Three patients were treated per dose level. Dose-limiting toxicity (DLT) was defined as WHO grade >= 3 myelosuppression or grade >= 3 non-hematologic toxicity. The MTD was reached when 2 of 3 patients experienced ...