Liver-dominant mCRC Research Articles

Phase I prospective trial of TAS-102 (trifluridine and tipiracil) and radioembolization with 90Y resin microspheres for chemo-refractory colorectal liver metastases

BackgroundExtrahepatic disease progression limits clinical efficacy of Yttrium-90 (90Y) radioembolization (TARE) for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). Trifluridine and tipiracil (TAS-102) has overall survival benefit for patients with refractory mCRC and may be a radiosensitizer.MethodsSequential lobar TARE using 90Y resin microspheres in combination with TAS-102 in 28-day cycles were used to treat adult patients with bilobar liver-dominant chemo-refractory mCRC according to 3 + 3 dose escalation design with a 12-patient dose expansion cohort. Study objectives were to establish safety and determine maximum tolerated dose (MTD) of TAS-102 in combination with TARE.ResultsA total of 21 patients (14 women, 7 men) with median age of 60 years were enrolled. No dose limiting toxicities were observed. Treatment related severe adverse events included cytopenias (10 patients, 48%) and radioembolization-induced liver disease (2 patients, 10%). Disease control rate in the liver lobes treated with TARE was 100%. Best observed radiographic responses were partial response for 4 patients (19%) and stable disease for 12 patients (57%).ConclusionsThe combination of TAS-102 and TARE for patients with liver-dominant mCRC is safe and consistently achieves disease control within the liver.Trial registrationClinicalTrials.gov identifier NCT02602327 (first posted 11/11/2015).

PD32 Cost-Utility Of Selective Internal Radiation Therapy Using Y-90 Resin Microspheres For Chemotherapy-Refractory Metastatic Colorectal Cancer In Brazil

IntroductionThere were an estimated 55,102 new cases of colorectal cancer (CRC) in Brazil in 2020, comprising 9.3 percent of all newly diagnosed cancers, and making it the third most common cancer in the Brazilian population. Up to half of all patients with CRC will develop liver metastases, and the prognosis for these patients is poor. The objective of the present analysis was to evaluate the cost-utility of selective internal radiation therapy (SIRT) using Y-90 resin microspheres versus best supportive care (BSC) in patients with unresectable, liver-dominant, chemotherapy-refractory metastatic CRC (mCRC).MethodsA three-state partitioned survival model was developed in Microsoft Excel to evaluate the cost-utility of SIRT using Y-90 resin microspheres versus BSC. Membership of the three model states of pre-progression, post-progression and death was governed by parametric models of Kaplan-Meier data from a retrospective, interventional study. Costs associated with SIRT using Y-90 resin microspheres, BSC, and adverse events were obtained from Brazilian sources and reported in 2021 United States dollars (USD). Future costs and effects were discounted at 5 percent. One-way and probabilistic sensitivity analyses (PSA) were performed. A willingness-to-pay threshold of USD 53,936 was used based on a 2017 review of Brazilian healthcare technology adoption.ResultsThe base case analysis showed that Y-90 resin microspheres would result in an increase of 0.76 QALYs versus BSC, increasing quality-adjusted life expectancy from 0.67 QALYs to 1.43 QALYs. The improvement in quality-adjusted life expectancy was accompanied by an increase in costs from USD 9,884 to USD 40,399 over the model time horizon, corresponding to an increase of USD 30,515, and yielding an incremental cost-utility ratio (ICUR) of USD 40,265 per QALY gained. PSA showed there was a 90.8 percent likelihood of cost-effectiveness at USD 53,936 per QALY gained.ConclusionsSIRT using Y-90 resin microspheres was cost-effective versus BSC in the treatment of unresectable, liver-dominant mCRC patients and should be considered for incorporation in the Brazilian Private Healthcare System.

Radioembolization with chemotherapy for liver-dominant colorectal cancer: Analysis of patient subgroups in the EPOCH trial.

115 Background: The EPOCH trial evaluated potential benefit of second-line transarterial radioembolization (TARE) plus chemotherapy compared to chemotherapy alone in patients with liver-dominant metastatic colorectal disease (mCRC). Presented here are additional results from EPOCH of depth and duration of response (DoR), and progression-free survival (PFS) and hepatic progression-free survival (hPFS) subgroup analyses. Methods: EPOCH was a 1:1 randomized, open-label, global, multicenter phase 3 trial of second-line chemotherapy for liver-dominant mCRC comparing outcomes from chemotherapy with or without unilobar or same-day bilobar TARE treatment using glass microspheres. Primary study endpoints were PFS and hPFS. Pre-specified subgroup analyses of PFS and hPFS were performed. PFS, hPFS, DoR for patients with objective response, and depth of response (percent change from baseline to nadir in sum of longest diameters of target lesions) were based on blinded, independent central review using RECIST 1.1. The use of TheraSphere in the trial in the USA was under Investigational Device Exemption from FDA. Results: Both primary endpoints of PFS (HR = 0.69, 95% CI: 0.54, 0.88; 1-sided p=0.0013) and hPFS (HR = 0.59, 95% CI: 0.46, 0.77; 1-sided p<0.0001) were met in the EPOCH study. Median DoR in the 73 responders of the TARE arm was numerically longer, with 7.2 months by Kaplan-Meier analysis; in the 45 responders of the chemotherapy only arm, 6.6 months (HR = 0.79, 95% CI: 0.48, 1.30; 1-sided p = 0.178). Mean depth of response across all patients in the TARE arm with data available (N=196) was -25.6%, compared to -13.0% in the chemotherapy only arm (N=182; mean difference -12.6 percentage points; 95% CI: -18.9, -6.3; 1-sided p = 0.0001). Key subgroups of interest which showed improved PFS and/or hPFS in the TARE arm (ie, 95% CI for the HR entirely below 1) are as follows: Conclusions: These data suggest that liver-dominant mCRC patients in this trial benefitted in second-line treatment from a combination of TARE plus chemotherapy based upon improved PFS and hPFS over the full set of patients and in a number of subgroups. The addition of TARE to chemotherapy improves depth of response compared to chemotherapy alone. Clinical trial information: NCT01483027. [Table: see text]

Radioembolization with chemotherapy for liver-dominant colorectal cancer: Time to subsequent treatment and quality of life in the EPOCH trial.

114 Background: The primary objective of the EPOCH trial evaluated potential benefit of adding second-line transarterial radioembolization (TARE) with yttrium-90 glass microspheres to chemotherapy compared to chemotherapy alone in patients with liver-dominant metastatic colorectal disease (mCRC). Secondary endpoints included time to deterioration of quality of life (TTDQoL). Methods: EPOCH was a 1:1 randomized, open-label, global, multicenter phase 3 trial. TTDQoL was assessed using the Functional Assessment of Cancer Therapy-colorectal (FACT-c) questionnaire and defined as the time from randomization to the change from baseline in FACT-c total score ≤ -7 points or date of death and was estimated using Kaplan-Meier analysis. Time to subsequent therapy was defined as the time from randomization to the start of subsequent therapy and was estimated using Kaplan-Meier analysis. Restricted mean survival time (RMST) analysis was used to estimate the area under Kaplan-Meier curves (AUC) for progression-free survival (PFS), hepatic PFS (hPFS), and TTDQoL, and the difference in AUC estimates between the two arms were assessed. The use of TheraSphere in the USA in the trial was under Investigational Device Exemption from FDA. Results: The EPOCH trial included 428 patients. Both primary endpoints of PFS (HR = 0.69, 95% CI: 0.54, 0.88; 1-sided p=0.0013) and hPFS (HR = 0.59, 95% CI: 0.46, 0.77; 1-sided p<0.0001) were met in the EPOCH study. Median time to subsequent therapy in the TARE plus chemotherapy arm was 21.0 months, compared to 10.1 months in the chemotherapy only arm (HR = 0.49, 95% CI: 0.37, 0.67). TTDQoL before subsequent therapy was reported in 53.5% (115/215) patients in the TARE plus chemotherapy arm, compared to 43.7% of patients in the chemotherapy only arm (93/213). Median TTDQoL was 3.8 months in both the TARE plus chemotherapy arm and the chemotherapy alone arm (1-sided p=0.1513; HR = 0.86, 95% CI: 0.65, 1.14). AUC for PFS until 22.1 months was 9.4 months (95% CI: 8.4, 10.4) for the TARE plus chemotherapy arm, compared to 7.4 months (95% CI: 6.6, 8.1) for the chemotherapy only arm (1-sided p=0.0008). AUC for hPFS until 22.1 months was 10.3 months (95% CI: 9.2, 11.3) for the TARE plus chemotherapy arm, compared to 7.4 months (95% CI: 6.7, 8.2) for the chemotherapy only arm (1-sided p<0.0001). AUC for TTDQoL until 18.5 months was 6.6 (95% CI: 5.6, 7.6) for the TARE plus chemotherapy arm, compared to 5.5 (95% CI: 4.4, 6.5) for the chemotherapy only arm (1-sided p=0.0663). Conclusions: These results suggest that the addition of TARE to second-line chemotherapy in patients with liver-dominant mCRC extended PFS, hPFS, and time to subsequent treatment without compromising quality of life. Clinical trial information: NCT01483027.

Phase I prospective trial of TAS-102 (trifluride and tipiracil) and radioembolization with 90Y resin microspheres for chemo-refractory colorectal liver metastases.

110 Background: Clinical efficacy of Yttrium-90 (90Y) radioembolization (TARE) for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC) is limited by extrahepatic disease progression. TAS-102 (trifluride and tipiracil) has overall survival benefit for patients with refractory mCRC and may be a radiosensitizer. We aimed to evaluate the safety of the combination of TAS-102 and 90Y resin TARE in a Phase I dose-escalation trial. Methods: Adult patients with bilobar liver-dominant chemo-refractory mCRC were treated with sequential Y90 resin TARE (body surface area dosimetry) in combination with TAS-102 (20mg/m2, 27mg/m2, and 35mg/m2) in 28-day cycles according to 3+3 dose-escalation design. Beginning with cycle 3, TAS-102 was administered as monotherapy until disease progression or development of intolerable toxicity. Primary objectives were to determine maximum tolerated dose (MTD) of TAS-102, to assess toxicity, and to establish safety of TAS-102 in combination with 90Y TARE. Results: A total of 14 patients (10 women, 4 men) have been treated to date. Among 9 patients enrolled in the dose-escalation phase, no dose limiting toxicities were observed. The MTD of TAS-102 in combination with Y90 was 35mg/m2, which was selected for the dose expansion phase. Severe adverse events (AEs) included: neutropenia (46%); anemia (23%); and thrombocytopenia (8%), which were attributed to TAS-102. All other AEs were mild and transient. At least one follow-up imaging study has been obtained for 13 patients, and 10 patients have completed trial participation. Disease control rate in the liver was 100%. Conclusions: The combination of TAS-102 and 90Y TARE for patients with liver-dominant mCRC is safe and consistently achieved disease control within the liver. Severity and incidence of AEs is within the expected range of TAS-102 and 90Y TARE monotherapy. A dose-expansion phase with planned enrollment of 12 patients is ongoing. Clinical trial information: NCT02602327.

Overall survival analysis of the FOXFIRE prospective randomized studies of first-line selective internal radiotherapy (SIRT) in patients with liver metastases from colorectal cancer.

3507 Background: The FOXFIRE, SIRFLOX and FOXFIRE-Global (FF-SF-FFG) randomized studies evaluated the efficacy of combining first-line chemotherapy for metastatic colorectal cancer (mCRC) with selective internal radiotherapy (SIRT) using yttrium-90 resin microspheres in patients with liver metastases. The studies were designed for prospective, combined analysis of overall survival (OS). Methods: FF-SF-FFG randomized (1:1) chemotherapy-naïve mCRC patients (performance status 0/1) with liver metastases not suitable for curative resection/ablation. Arm A was oxaliplatin-based chemotherapy (mFOLFOX6/ OxMdG) ± investigator-chosen biologically targeted agent. Arm B was the same systemic therapy (oxaliplatin dose modification) + single treatment SIRT with cycle 1/2 of chemotherapy. Primary tumor in situ and/or limited extra-hepatic metastases were permitted. Minimum sample size was 1075 patients (HR 0.8, 80% power, two-sided 5% significance). Secondary outcomes included PFS, liver-specific PFS and response rate. Apart from safety, outcomes were analysed on intention-to-treat population using meta-analytic methods of pooled individual patient data. Results: Between 2006 and 2014, 1103 patients were randomized in 14 countries. Median age was 63 years (range 23-89); median follow-up 43.3 months. There were 844 deaths. There was no difference in OS (HR 1.04; 95% CI 0.90-1.19, p= 0.609) or PFS (HR 0.90, CI 0.79-1.02, p= 0.108) between Arms. Objective response rate ( p= 0.001) and liver-specific progression (HR 0.51, CI 0.43-0.62, p< 0.001) were significantly more favorable in Arm B. Patients in Arm B had higher risk of non-liver progression as first event (HR 1.98, CI 1.53-2.58, p< 0.001). Grade 3-5 adverse events were more common in Arm B (74.0%) than A (66.5%), p= 0.009. In health status questionnaires, EQ-5D utility scores were not significantly different between Arms at 6, 12 or 24 months. Conclusion: Despite higher response rates and improved liver-specific PFS, the addition of SIRT to first-line oxaliplatin-fluorouracil chemotherapy for patients with liver-only and liver-dominant mCRC did not improve OS or PFS. Clinical trial information: 83867919.

Mapping EORTC-QLQ-C30 to EQ-5D-3L in patients with colorectal cancer

Aims: The primary aim of this study was to perform a mapping of the EORTC-QLQ-C30 scores to EQ-5D-3L for the SIRFLOX study; a large dataset of patients with previously untreated liver-only or liver-dominant metastatic colorectal cancer (mCRC). A secondary aim was to compare the predictive validity of existing mappings from EORTC-QLQ-C30 to EQ-5D-3L conducted in other cancers.Methods and materials: Questionnaires (completed within 529 patients) were used in a linear mixed regression to model EQ-5D-3L utility values (scored using the UK tariff) as a function of the five function scores, nine symptom scores, and the global score from the EORTC-QLQ-C30 questionnaire. A Tobit regression was also performed. The mean EQ-5D-3L values for the SIRFLOX trial were calculated and compared with predicted EQ-5D-3L values derived using published mapping algorithms.Results: The linear mixed regression model provided a satisfactory mapping between the EORTC-QLQ-C30 and the EQ-5D-3L, whilst the Tobit model did not perform as well. When utilities from the SIRFLOX data were calculated with previously published mapping studies, three out of five studies performed well (< 10% mean difference).Limitations: The main limitation of the study was the lack of meaningful observations post-progression (67 paired observations). For this reason, this study was unable to test whether the mapping holds by disease stage. Additionally, although the study adds to the literature of mappings to the EQ-5D-3L, it is not known how results would differ using the EQ-5D-5L.Conclusion: This study is the first of its kind in liver-only or liver-dominant mCRC, and mCRC in general. The mapping constructed showed a good fit to the data and provides practitioners with an additional mapping between EORTC-QLQ-C30 to EQ-5D-3L using a large dataset (529 patients, 707 paired observations). The study also confirmed the generalizability of mappings published by Proskorovsky, Kontodimopoulos, and Longworth to liver-only or liver-dominant mCRC.

Y90 Radioembolization in chemo-refractory metastastic, liver dominant colorectal cancer patients: outcome assessment applying a predictive scoring system.

BackgroundIn treatment-refractory liver dominant metastatic colorectal cancer, the role of liver directed therapies still is unclear. We sought to determine a prognostic score for Y90 radioembolization in these patients.MethodsWe analyzed 106 patients with refractory liver dominant mCRC who had undergone a total of 178 Y90 radioembolizations with resin microspheres was collected. Potential factors influencing survival were analyzed using a Cox regression. The Log rank test served to establish prognostic factors and to form a clinical score for outcome prediction after Y90 radioembolization.ResultsMedian survival of all patients was 6.7 months. Neither age nor prior surgical or systemic therapy nor metastatic spread had an effect on survival. In contrast, hepatic tumor load, Karnofsky index as well as CEA and CA19-9 serums level had a significant influence (p < 0.001, p = 0.037, p = 0.023 and p < 0.001, respectively). These three factors formed a score with 1 point each for tumor load >20 %, CEA >130 ng/ml or CA19-9 > 200U/ml and Karnofsky index <80 %. Patients with a score of 0 and 1 displayed a median OS of 10.4 months. Patients with a score of 2 and 3 demonstrated a median OS of 5.1 months only (p < 0.001).ConclusionOveraggressive patient selection for Y90 radioembolization of liver dominant chemorefractory mCRC is of questionable benefit. A scoring system comprising hepatic tumor load, CEA and CA19-9 serum levels and Karnofsky index (TuCK-score) may support an improved patient selection. In our cohort of liver only versus liver dominant disease, extrahepatic lung or lymphatic metastases did not significantly alter the prognosis.

SIRFLOX: Differences in site of first progression between mFOLFOX6 ± bevacizumab (bev) versus mFOLFOX6 ± bev + selective internal radiation therapy (SIRT) in first-line patients (pts) with metastatic colorectal cancer (mCRC).

637 Background: SIRFLOX, an international multi-centre open-label RCT in first-line pts with non-resectable, liver-only or liver-dominant mCRC, showed that compared to FOLFOX (± bev) chemotherapy alone [arm A] FOLFOX (± bev) plus SIRT using Y-90 resin microspheres [arm B] did not improve overall PFS (median 10.2 v 10.7 months arm A v B, HR: 0.93; 95% CI 0.77–1.12; p = 0.429). However, liver PFS by competing risk analysis was improved with the addition of SIRT (median 12.6 v 20.5 months in arm A v B, HR: 0.69; 95% CI 0.55–0.90; p = 0.002). The current analysis examines patterns of disease progression and potential impact on the primary study endpoint. Methods: Site and pattern (intra/extra-hepatic) of first progression, and whether progression was due to growth of existing lesions or the appearance of new lesions, was judged by an independent reader blinded to study arm. Results: From Oct 2006 to Apr 2013, 530 pts were randomised (arm A, n = 263; arm B, n = 267); 212 (40%) had extra-hepatic metastases at study entry; 292 (55%) were stratified to receive bev. As of 31 Jan 2015, the total number of patients with disease progression in arm A v B were 178 and 166, respectively. The site of first progression was more frequently in the liver (± other sites) in arm A v B (92.1% v 72.3%; p &lt; 0.001). Conversely, site of first progression was less frequent in the lung (± other sites) in arm A v B (19.1% v 42.8%; p &lt; 0.001). A higher proportion of first progression occurred in the liver alone in arm A v B (77.0% v 52.4%; p &lt; 0.001). Conversely, a lower proportion of first progression occurred only in non-liver sites, primarily lung, in arm A v B (7.9% v 47.7%; p &lt; 0.001). Of patients with first progression in the liver, a higher proportion occurred in existing liver lesions (± extrahepatic sites) in arm A v B (72.5% v48.2%; p &lt; 0.001). Conclusions: The addition of SIRT to FOLFOX chemotherapy alone (± bev) reduced the frequency at which first disease progression occurred in the liver. Where first progression did occur in the liver, the addition of SIRT led to this more frequently being due to the appearance of lesions not evident on baseline imaging. Clinical trial information: NCT00724503.

Safety and Efficacy of Radioembolization in Elderly (≥ 70 Years) and Younger Patients With Unresectable Liver-Dominant Colorectal Cancer

BackgroundThe effects of advancing age on clinical outcomes after radioembolization (RE) in patients with unresectable liver-dominant metastatic colorectal cancer (mCRC) are largely unknown. Patients and MethodsThis study was a retrospective analysis of 160 elderly (≥ 70 years) and 446 younger (< 70 years) consecutive patients from 11 US centers who received RE using ytrrium-90 (90Y) resin microspheres (90Y radioembolization [90Y-RE]) between July 2002 and December 2011. A further analysis was conducted in 98 very elderly patients (≥ 75 years). Statistical analyses of safety, tolerability, and overall survival were conducted. ResultsMean ages (± standard deviation) in the younger (< 70 years), elderly (≥ 70 years), and very elderly (≥ 75 years) cohorts were 55.9 ± 9.4 years, 77.2 ± 4.8 years, and 80.2 ± 3.8 years, respectively. Overall survival was similar between elderly and younger patients: 9.3 months (95% confidence interval [CI], 8.0-12.1) and 9.7 months (95% CI, 9.0-11.4) (P = .335). There were no differences between cohorts for any grade adverse events (P = .433) or grade 3+ events (P = .482). Analysis of patients ≥ 75 years and < 75 years confirmed similar overall survival (median, 9.3 months vs. 9.6 months, respectively; P = .987) and grade 3+ events (P = .398) or any adverse event (P = .158) within 90 days of RE. ConclusionFor patients with unresectable liver-dominant mCRC who meet eligibility criteria for RE, 90Y-RE microspheres appear to be effective and well-tolerated, regardless of age. Criteria for selecting patients for RE should not include age for exclusion from this potentially beneficial intervention.

P-230 Cost effectiveness of Selective Internal Radiation Therapy (SIRT) using yttrium-90 resin microspheres for the treatment of patients with inoperable colorectal liver metastases in France

Introduction: Treatment options for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC) are limited. Selective internal radiation therapy (SIRT) using yttrium-90 (90Y)-labelled resin microspheres (SIR-Spheres; Sirtex, Sydney, Australia) has been shown to be a well-tolerated and effective treatment in patients with inoperable liver-dominant chemotherapy-refractory mCRC. The aim of this analysis was to assess the cost-effectiveness of SIRT with SIR-Spheres 90Y resin microspheres compared to best supportive care (BSC) from the perspective of the national health service in France. Methods: Survival data from a comparative retrospective cohort study of 90Y-resin microspheres vs. BSC in chemotherapy-refractory mCRC was analysed and used in a state-transition cost-effectiveness model, using Quality Adjusted Life Years (QALYs) gained as the measure of effectiveness. The model included costs for treatment acquisition, pre-treatment work-up and delivery of microspheres, and chemotherapy. Additionally, costs of managing adverse events and a cost of death were included. Utility data were taken from a recent NICE economic evaluation in mCRC. A wide range of sensitivity analyses were performed on utility, overall survival and costs. The one-way sensitivity analysis varied each parameter between its lower and upper bound and investigated the effect on the cost per QALY. The probabilistic analysis simultaneously sampled each parameter from its appropriate distribution (beta for utilities, normal for costs and multivariate normal for survival curve parameters) for 1,000 simulations and investigated the uncertainty around the cost per QALY. The scenario analysis explored alternative parametric curves for overall survival, alternative sources for utility values and alternative assumptions for the proportion of time spent in the pre- and post-progression health states. Results: The results show an increase in overall survival for patients receiving 90Y-resin microspheres compared to BSC by a mean of 1.15 life years (2.12 vs. 0.98 years), with a corresponding increase in quality adjusted life years (1.50 vs. 0.70). The associated costs for SIRT and BSC are €48,552 vs. €23,300, respectively. The additional costs are due to the SIRT treatment and the cost associated with extension to life. The cost per QALY is €30,610. Sensitivity analyses show that the model is robust to changes in parameters. Scenario analysis results demonstrate that the cost per QALY is not sensitive to alternative assumptions for survival curves, utilities or progression, varying only between €28,363 and €31,940. The one-way sensitivity analysis found that the parameters that had the biggest effect are those relating to the curve used to model overall survival. The probabilistic sensitivity analysis found that the probability of 90Y-resin microspheres being cost effective at a willingness-to-pay threshold of €33,506/QALY (1xGDP) is 69%. Conclusion: This analysis demonstrated that the use of 90Y-resin microspheres is a cost-effective option in the treatment of patients with chemotherapy-refractory liver-dominant mCRC in France. The results are robust to a wide range of sensitivity analyses, which ensures the predictability of the results.

Liver-Directed Therapies: Does It Make Sense in the Current Therapeutic Strategy for Patients With Confined Liver Colorectal Metastases?

Nearly half of patients with colorectal cancer will have metastases in the course of their disease and the liver appears to be the most common location for metastases. For patients with confined hepatic colorectal metastases, complete surgical resection is the only chance for cure, with a 5-year postoperative survival rate between 35% and 50%. Over the past 5 years, combinations of chemotherapy with targeted therapies have succeeded in inducing tumoral response and have made curative surgery of initially unresectable liver metastases possible. However despite optimal preoperative treatment, disease in the majority of patients remains unresectable. For patients with liver-limited or liver-dominant metastatic colorectal cancer (mCRC), the current challenges are to explore different locoregional treatments to improve local control, overall survival (OS), and curative resection. In this way, liver-directed therapy, which is defined by injection, infusion, or embolization of chemotherapy or loaded radionuclide (with radioactive yttrium-90) microspheres into the arterial liver vasculature, has been an appealing investigational method for patients with liver-confined mCRC, in whom it has yielded reproducibly higher response rates (RRs) than conventional intravenous therapy. In this article, we propose to review, compare, and discuss the clinical benefit, the current indications, and the optimal use of liver-directed therapies for patients with liver-dominant mCRC.

Phase I/II Study of Oncolytic Herpes Simplex Virus NV1020 in Patients with Extensively Pretreated Refractory Colorectal Cancer Metastatic to the Liver

This multicenter phase I/II study evaluated the safety, pharmacokinetics, and antitumor effects of repeated doses of NV1020, a genetically engineered oncolytic herpes simplex virus, in patients with advanced metastatic colorectal cancer (mCRC). Patients with liver-dominant mCRC received four fixed NV1020 doses via weekly hepatic artery infusion, followed by two or more cycles of conventional chemotherapy. Phase I included cohorts receiving 3 × 10(6), 1 × 10(7), 3 × 10(7), and 1 × 10(8) plaque-forming units (PFU)/dose to determine the optimal biological dose (OBD) for phase II. Blind independent computed tomography scan review was based on RECIST (response evaluation criteria in solid tumors) to assess hepatic tumor response. Phase I and II enrolled 13 and 19 patients, respectively. Patients experienced transient mild-moderate febrile reactions after each NV1020 infusion. Grade 3/4 virus-related toxicity was limited to transient lymphopenia in two patients. NV1020 shedding was not detected. Simultaneous cytokine and grade 1 coagulation perturbations were dose-limiting at 1 × 10(8) PFU/dose, considered the OBD. All 22 OBD patients had previously received 5-fluorouracil; most had received oxaliplatin or irinotecan (50% had both), many with at least one targeted agent. After NV1020 administration, 50% showed stable disease. The best overall tumor control rate after chemotherapy was 68% (1 partial response, 14 stable disease); this did not correlate with baseline variables or chemotherapy. Median time to progression was 6.4 months (95% confidence interval: 2, 8.9); median overall survival was 11.8 months (95% confidence interval: 8.3, 20.7). One-year survival was 47.2%. We conclude that NV1020 stabilizes liver metastases with minimal toxicity in mCRC. It may resensitize metastases to salvage chemotherapy and extend overall survival. A randomized phase II/III trial now appears justified.