Gemcitabine with Cisplatin Versus Hepatic Arterial Infusion Pump Chemotherapy for Liver-Confined Unresectable Intrahepatic Cholangiocarcinoma.

BACKGROUND: A post-hoc analysis of ABC trials included 34 patients with liver-confined unresectable intrahepatic cholangiocarcinoma (iCCA) who received systemic chemotherapy with gemcitabine and cisplatin (gem-cis). The median overall survival (OS) was 16.7 months and the 3-year OS was 2.8%. The aim of this study was to compare patients treated with systemic gem-cis versus hepatic arterial infusion pump (HAIP) chemotherapy for liver-confined unresectable iCCA. METHODS: We retrospectively collected consecutive patients with liver-confined unresectable iCCA who received gem-cis in two centers in the Netherlands to compare with consecutive patients who received HAIP chemotherapy with or without systemic chemotherapy in Memorial Sloan Kettering Cancer Center. RESULTS: In total, 268 patients with liver-confined unresectable iCCA were included; 76 received gem-cis and 192 received HAIP chemotherapy. In the gem-cis group 42 patients (55.3%) had multifocal disease compared with 141 patients (73.4%) in the HAIP group (p = 0.023). Median OS for gem-cis was 11.8 months versus 27.7 months for HAIP chemotherapy (p < 0.001). OS at 3 years was 3.5% (95% confidence interval [CI] 0.0-13.6%) in the gem-cis group versus 34.3% (95% CI 28.1-41.8%) in the HAIP chemotherapy group. After adjusting for male gender, performance status, baseline hepatobiliary disease, and multifocal disease, the hazard ratio (HR) for HAIP chemotherapy was 0.27 (95% CI 0.19-0.39). CONCLUSIONS: This study confirmed the results from the ABC trials that survival beyond 3 years is rare for patients with liver-confined unresectable iCCA treated with palliative gem-cis alone. With HAIP chemotherapy, one in three patients was alive at 3 years.

Hepatic arterial infusion pump chemotherapy combined with systemic chemotherapy for borderline resectable and unresectable colorectal liver metastases: phase II feasibility study.

BACKGROUND: Hepatic arterial infusion pump chemotherapy combined with systemic chemotherapy (HAIP-SYS) for liver-only colorectal liver metastases (CRLMs) has shown promising results but has not been adopted worldwide. This study evaluated the feasibility of HAIP-SYS in the Netherlands. METHODS: This was a single-arm phase II study of patients with CRLMs who received HAIP-SYS consisting of floxuridine with concomitant systemic FOLFOX or FOLFIRI. Main inclusion and exclusion criteria were borderline resectable or unresectable liver-only metastases, suitable arterial anatomy and no previous local treatment. Patients underwent laparotomy for pump implantation and primary tumour resection if in situ. Primary end point was feasibility, defined as ≥70% of patients completing two cycles of HAIP-SYS. Sample size calculations led to 31 patients. Secondary outcomes included safety and tumour response. RESULTS: Thirty-one patients with median 13 CRLMs (i.q.r. 6-23) were included. Twenty-eight patients (90%) received two HAIP-SYS cycles. Three patients did not get two cycles due to extrahepatic disease at pump placement, definitive pathology of a recto-sigmoidal squamous cell carcinoma, and progressive disease. Five patients experienced grade 3 surgical or pump device-related complications (16%) and 11 patients experienced grade ≥3 chemotherapy toxicity (38%). At first radiological evaluation, disease control rate was 83% (24/29 patients) and hepatic disease control rate 93% (27/29 patients). At 6 months, 19 patients (66%) had experienced grade ≥3 chemotherapy toxicity and the disease control rate was 79%. CONCLUSION: HAIP-SYS for borderline resectable and unresectable CRLMs was feasible and safe in the Netherlands. This has led to a successive multicentre phase III randomized trial investigating oncological benefit (EUDRA-CT 2023-506194-35-00). Current trial registration number: clinicaltrials.gov (NCT04552093).

Current Practices in Hepatic Artery Infusion (HAI) Chemotherapy: An International Survey of the HAI Consortium Research Network.

BACKGROUND: An increasing number of hepatic artery infusion (HAI) programs have been established worldwide. Practice patterns for this complex therapy across these programs have not been reported. This survey aimed to identify current practice patterns in HAI therapy with the long-term goal of defining best practices and performing prospective studies. METHODS: Using SurveyMonkeyTM, a 28-question survey assessing current practices in HAI was developed by 12 HAI Consortium Research Network (HCRN) surgical oncologists. Content analysis was used to code textual responses, and the frequency of categories was calculated. Scores for rank-order questions were generated by calculating average ranking for each answer choice. RESULTS: Thirty-six (72%) HCRN members responded to the survey. The most common intended initial indications for HAI at new programs were unresectable colorectal liver metastases (uCRLM; 100%) and unresectable intrahepatic cholangiocarcinoma (uIHC; 56%). Practice patterns evolved such that uCRLM (94%) and adjuvant therapy for CRLM (adjCRLM; 72%) have become the most common current indications for HAI at established centers. Referral patterns for pump placement differed between uCRLM and uIHC, with most patients referred while receiving second- and first-line therapy, respectively, with physicians preferring to evaluate patients for HAI while receiving first-line therapy for CRLM. Concern for extrahepatic disease was ranked as the most important factor when considering a patient for HAI. CONCLUSIONS: Indication and patient selection factors for HAI therapy are relatively uniform across most HCRN centers. The increasing use of adjuvant HAI therapy and overall consistency of practice patterns among HCRN centers provides a robust environment for prospective data collection and randomized clinical trials.

Combined Hepatic Arterial Infusion Pump and Systemic Chemotherapy in the Modern Era for Chemotherapy-Naive Patients with Unresectable Colorectal Liver Metastases.

PURPOSE: Chemotherapy-naive patients with unresectable colorectal liver metastases (CRLM) have been the best responders to hepatic arterial infusion (HAI) therapy. The current treatment paradigm has drifted away from HAI in the first-line setting. We aimed to analyze outcomes of combined first-line systemic therapy with HAI therapy (HAI+SYS) in the modern era. METHODS: We conducted a retrospective study of consecutive chemotherapy-naive patients with unresectable CRLM who received HAI+SYS between 2003 and 2019. Patients were selected from a prospectively maintained database. Outcomes included radiological response rate, conversion to resection (CTR) rate, and overall survival (OS). RESULTS: Fifty-eight chemotherapy-naive patients were identified out of 546 patients with unresectable CRLM managed with HAI. After induction treatment, 4 patients (7%) had a complete radiological response, including two durable responses. In total, 32 patients (55%) underwent CTR. CTR or complete response without resection was achieved after seven cycles of systemic therapy and four cycles of HAI therapy. Median OS for the whole cohort was 53.0 months (95% confidence interval 23.0-82.9). Three- and 5-year OS in patients who achieved CTR or complete response versus patients who did not was 88% and 72% versus 27% and 0% respectively. Of patients who underwent CTR, complete and major pathological response (no and <10% viable tumor cells, respectively) was observed in 7 (22%) and 12 patients (38%). CONCLUSIONS: Combined HAI+SYS in chemotherapy-naive patients resulted in durable and substantial response in a large proportion of patients. Nearly two-thirds of patients achieved a complete response or proceeded to conversion surgery, which was associated with prolonged survival.

Recurrence-free survival versus overall survival as a primary endpoint for studies of resected colorectal liver metastasis: a retrospective study and meta-analysis.

BACKGROUND: Recurrence-free survival has been used as a surrogate endpoint for overall survival in trials involving patients with resected colorectal liver metastases. We aimed to assess the correlation between recurrence-free survival and overall survival after resection of colorectal liver metastases to determine the adequacy of this surrogate endpoint. METHODS: In this retrospective study and meta-analysis, we compiled an institutional cohort of consecutive patients who had complete resection of colorectal liver metastases from the Memorial Sloan Kettering Cancer Center (New York, NY, USA) prospective database. Patients were eligible for inclusion if they were aged 18 years or older, and underwent hepatectomy, with or without operative ablation, between Jan 1, 1991, and April 30, 2019. We estimated overall survival and recurrence-free survival probabilities at various timepoints using the Kaplan-Meier method, and we assessed pairwise associations between these endpoints using Spearman's rank correlation. We also did a meta-analysis of adjuvant phase 3 clinical trials for colorectal liver metastases to assess the correlation between hazard ratios (HRs) for recurrence-free survival and overall survival. We searched MEDLINE for articles of phase 3 randomised controlled trials analysing adjuvant treatment strategies for resected colorectal metastases from database inception to Jan 1, 2022. The titles and abstracts of identified studies were screened before full-text screening and summary data were either recalculated or extracted manually from the published Kaplan-Meier curves (depending on data availability). FINDINGS: Data were available for 3299 patients in the institutional database, of whom 2983 were eligible for inclusion in our cohort. Median follow-up was 8·4 years (95% CI 7·9-9·1) , during which time there were 1995 (67%) disease recurrences and 1684 (56%) deaths. Median recurrence-free survival was 1·3 years (95% CI 1·3-1·4) and median overall survival was 5·2 years (95% CI 5·0-5·5). 1428 (85%) of 1684 deaths were preceded by recurrence, and median time from recurrence to death was 2·0 years (IQR 1·0-3·4). Pairwise correlations between recurrence-free survival and overall survival were low to moderate, with a correlation estimate ranging from 0·30 (SD 0·17) to 0·56 (0·13). In the meta-analysis of adjuvant clinical trials, the Spearman's correlation coefficient between recurrence-free survival HR and overall survival HR was r=0·20 (p=0·71). INTERPRETATION: We found a minimal correlation between recurrence-free survival and overall survival after resection of colorectal liver metastases. Recurrence-free survival is an inadequate surrogate endpoint for overall survival in this disease setting. FUNDING: US National Cancer Institute.

Hepatic Artery Infusion Pumps: A Surgical Toolkit for Intraoperative Decision-Making and Management of Hepatic Artery Infusion-Specific Complications.

BACKGROUND: Hepatic artery infusion (HAI) is a liver-directed therapy that delivers high-dose chemotherapy to the liver through the hepatic arterial system for colorectal liver metastases and intrahepatic cholangiocarcinoma. Utilization of HAI is rapidly expanding worldwide. OBJECTIVE AND METHODS: This review describes the conduct of HAI pump implantation, with focus on common technical pitfalls and their associated solutions. Perioperative identification and management of common postoperative complications is also described. RESULTS: HAI therapy is most commonly performed with the surgical implantation of a subcutaneous pump, and placement of its catheter into the hepatic arterial system for inline flow of pump chemotherapy directly to the liver. Intraoperative challenges and abnormal hepatic perfusion can arise due to aberrant anatomy, vascular disease, technical or patient factors. However, solutions to prevent or overcome technical pitfalls are present for the majority of cases. Postoperative HAI-specific complications arise in 22% to 28% of patients in the form of pump pocket (8%-18%), catheter (10%-26%), vascular (5%-10%), or biliary (2%-8%) complications. The majority of patients can be rescued from these complications with early identification and aggressive intervention to continue to deliver safe and effective HAI therapy. CONCLUSIONS: This HAI toolkit provides the HAI team a reference to manage commonly encountered HAI-specific perioperative obstacles and complications. Overcoming these challenges is critical to ensure safe and effective pump implantation and delivery of HAI therapy, and key to successful implementation of new programs and expansion of HAI to patients who may benefit from such a highly specialized treatment strategy.

Distinct Genomic Profiles are Associated With Conversion to Resection and Survival in Patients With Initially Unresectable Colorectal Liver Metastases Treated With Systemic and Hepatic Artery Chemotherapy.

OBJECTIVE: To examine genomic correlates of conversion to resection (CTR and overall survival (OS) in patients with initially unresectable colorectal liver metastasis (IU-CRLM) treated with combination systemic and hepatic artery infusion (HAI) chemotherapy. BACKGROUND: In patients presenting with IU-CRLM, combination systemic and HAI chemotherapy enables CTR with associated long-term OS in a subset of patients. Genomic correlates of CTR and OS in IU-CRLM have not been previously explored. METHODS: Specimens from IU-CRLM patients receiving systemic/HAI chemotherapy (2003-2017) were submitted for next-generation sequencing. Fisher Exact test assessed associations with CTR, and Kaplan-Meier/Cox methods assessed associations with OS from HAI initiation. RESULTS: Of 128 IU-CRLM patients, 51 (40%) underwent CTR at median 6 months (range: 3-35) from HAI initiation. CTR and persistently unresectable cohorts differed significantly in preoperative systemic chemotherapy exposure, node-positive primary status, and size of largest liver metastasis. Median and 5-year OS was 66 months and 51%. CTR was associated with prolonged survival (time-dependent HR 0.23,95% CI: 0.12-0.46, P < 0.001). The most frequently altered genes were APC (81%), TP53 (77%), and KRAS (37%). Oncogenic mutations in SOX9 and BRAF were associated with CTR. BRAF mutations, any RAS pathway alterations, and co-altered RAS/RAF-TP53 mutations wereassociated with worse survival. Classification and regression tree analysis defined prognostically relevant clusters of genomic risk to reveal co-altered RAS/RAF-TP53 as the highest risk subgroup. Co-altered RAS/RAF-TP53 remained independently associated with worse survival (HR 2.52, 95% CI: 1.37-4.64, P = 0.003) after controlling for CTR, number of liver metastases, and preoperative extrahepatic disease. CONCLUSIONS: Distinct genomic profiles are associated with CTR and survival in patients with IU-CRLM treated with HAI/systemic chemotherapy. Presence of SOX9, BRAF , and co-altered RAS/RAF- TP53 mutations are promising biomarkers that, when validated in larger datasets, may impact treatment of IU-CRLM patients.

Genomic Stratification of Resectable Colorectal Liver Metastasis Patients and Implications for Adjuvant Therapy and Survival.

OBJECTIVE: To determine whether genomic risk groups identified by somatic mutation testing of colorectal liver metastasis (CRLM) can be used for "molecularly-guided" selection for adjuvant systemic chemotherapy and hepatic artery infusion of FUDR (SYS+HAI-FUDR). BACKGROUND: Several genomic biomarkers have been associated with clinical phenotype and survival for patients with resectable CRLM. It is unknown whether prognostication afforded by genomic stratification translates into enhanced patient selection for adjuvant hepatic artery infusion therapy. METHODS: Consecutive patients with resected CRLM and available mutational characterization via Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets were reviewed from a prospective institutional database. Patients were stratified into three genomic risk groups based on previously defined alterations in SMAD4, EGFR and the RAS/RAF pathway. The association between SYS+HAI-FUDR and overall survival, relative to adjuvant chemotherapy alone (SYS), was evaluated in each genomic risk group by Cox proportional hazard regression and propensity score matched analyses. RESULTS: A total of 334 patients (SYS+HAI-FUDR 204; SYS 130) were identified; the rates of RAS/RAF alterations and SMAD4 inactivation were 47.4% and 11.7%, respectively. After a median follow-up of 58 months, adjuvant SYS+HAI-FUDR was independently associated with a reduced risk of death (HR 0.50, 95%CI 0.26-0.98, P = 0.045) in the low-risk genomic group, but not in the moderate-risk (HR 1.07, 95%CI 0.5-2.07, P = 0.749) or high-risk (HR 1.62, 95%CI 0.29-9.12, P = 0.537) cohorts. Following propensity score matching, adjuvant SYS+HAI-FUDR remained associated with significant improvements in long-term survival selectively in the low-risk genomic cohort (5-year actuarial survival: 89% vs. 68%, P = 0.019). CONCLUSIONS: Genomic alterations in RAS/RAF, SMAD4, and EGFR may be useful to guide treatment selection in resectable CRLM patients and warrant external validation and integration in future clinical trial design.

Genetic Determinants of Outcome in Intrahepatic Cholangiocarcinoma.

BACKGROUND AND AIM: Genetic alterations in intrahepatic cholangiocarcinoma (iCCA) are increasingly well characterized, but their impact on outcome and prognosis remains unknown. APPROACH AND RESULTS: This bi-institutional study of patients with confirmed iCCA (n = 412) used targeted next-generation sequencing of primary tumors to define associations among genetic alterations, clinicopathological variables, and outcome. The most common oncogenic alterations were isocitrate dehydrogenase 1 (IDH1; 20%), AT-rich interactive domain-containing protein 1A (20%), tumor protein P53 (TP53; 17%), cyclin-dependent kinase inhibitor 2A (CDKN2A; 15%), breast cancer 1-associated protein 1 (15%), FGFR2 (15%), polybromo 1 (12%), and KRAS (10%). IDH1/2 mutations (mut) were mutually exclusive with FGFR2 fusions, but neither was associated with outcome. For all patients, TP53 (P < 0.0001), KRAS (P = 0.0001), and CDKN2A (P < 0.0001) alterations predicted worse overall survival (OS). These high-risk alterations were enriched in advanced disease but adversely impacted survival across all stages, even when controlling for known correlates of outcome (multifocal disease, lymph node involvement, bile duct type, periductal infiltration). In resected patients (n = 209), TP53mut (HR, 1.82; 95% CI, 1.08-3.06; P = 0.03) and CDKN2A deletions (del; HR, 3.40; 95% CI, 1.95-5.94; P < 0.001) independently predicted shorter OS, as did high-risk clinical variables (multifocal liver disease [P < 0.001]; regional lymph node metastases [P < 0.001]), whereas KRASmut (HR, 1.69; 95% CI, 0.97-2.93; P = 0.06) trended toward statistical significance. The presence of both or neither high-risk clinical or genetic factors represented outcome extremes (median OS, 18.3 vs. 74.2 months; P < 0.001), with high-risk genetic alterations alone (median OS, 38.6 months; 95% CI, 28.8-73.5) or high-risk clinical variables alone (median OS, 37.0 months; 95% CI, 27.6-not available) associated with intermediate outcome. TP53mut, KRASmut, and CDKN2Adel similarly predicted worse outcome in patients with unresectable iCCA. CDKN2Adel tumors with high-risk clinical features were notable for limited survival and no benefit of resection over chemotherapy. CONCLUSIONS: TP53, KRAS, and CDKN2A alterations were independent prognostic factors in iCCA when controlling for clinical and pathologic variables, disease stage, and treatment. Because genetic profiling can be integrated into pretreatment therapeutic decision-making, combining clinical variables with targeted tumor sequencing may identify patient subgroups with poor outcome irrespective of treatment strategy.

Timing of Primary Tumor Resection in Synchronous Metastatic Colon Cancer Patients Undergoing Hepatic Arterial Infusion Pump Placement.

INTRODUCTION: Hepatic arterial infusion (HAI) chemotherapy is associated with improved survival in stage IV colon cancer with liver metastases. Whether simultaneous colon resection and HAI pump (HAIP) placement is associated with increased morbidity has not been specifically studied. The purpose of this study was to compare perioperative outcomes of simultaneous colon resection and HAIP placement versus HAIP placement alone. METHODS: This was a retrospective study of consecutive patients with colon cancer and synchronous liver metastases who underwent HAIP placement between 2007 and 2018. Clinicopathologic characteristics, operative data, complications, and time to first cycle of HAIP chemotherapy were compared between patients who underwent colon resection simultaneously with HAIP placement and those who underwent HAIP placement alone. RESULTS: A total of 258 patients underwent simultaneous colectomy and HAIP placement, and 116 patients underwent HAIP placement alone. Grade 1-2 complications were more common in patients who underwent simultaneous colectomy and HAIP placement (36.8% vs. 19.0%, P < 0.001), but grade 3-4 complications were not observed more frequently (14.3% vs. 12.9%, P = 0.872). The median interval between HAIP placement and start of HAIP chemotherapy did not differ between groups (simultaneous colectomy, 27 days [interquartile range (IQR) 17-34]; HAIP placement alone, 30 days [IQR 21-34]; P = 0.924). Infection of the pump causing either delay of initiation of chemotherapy or explantation of the pump occurred in five patients with simultaneous colectomy and in one patient with HAIP placement alone (P = 0.671). CONCLUSIONS: Simultaneous HAIP implantation and colectomy is safe in patients with liver metastases of colon carcinoma.

Genomic Predictors of Recurrence Patterns After Complete Resection of Colorectal Liver Metastases and Adjuvant Hepatic Artery Infusion Chemotherapy.

BACKGROUND: Despite curative hepatectomy, most colorectal liver metastasis (CRLM) patients relapse locally within 2 years. Genomic predictors for hepatic recurrence are poorly understood. This study was designed to identify genomic signatures for recurrence in resected CRLM patients treated with adjuvant hepatic artery infusion (HAI) and/or systemic (SYS) chemotherapy. METHODS: Patients undergoing curative hepatectomy and adjuvant HAI+SYS or SYS between January 2000 and October 2017 with next-generation sequencing data were catalogued. Gene and signaling-level alterations were checked for association with time to any (AR), liver (LR), and extrahepatic recurrence (ER) by using Kaplan-Meier analysis. RESULTS: Of 172 receiving HAI+SYS, 100 patients recurred, with 69 LR and 83 ER. Five- and ten-year LR-free rates were 57% (95% confidence interval [CI] 48-65%) and 51% (95% CI 41-60%), respectively. Five- and 10-year ER-free, rates were 51% (95% CI 43-58%) and 45% (95% CI 36-54%), respectively. More ER was observed with tumors harboring altered KRAS (38% [95% CI 25-50%] vs. 63% [95% CI 53-71%], p-adj = 0.003) and RAS/RAF (36% [95% CI 25-48%] vs. 66% [95% CI 56-74%], p-adj < 0.001) than wild-type. Co-altered RAS/RAF-TP53 was associated with worse AR (26% [95% CI 14-40%] vs. 48% [95% CI 39-57%], p-unadj < 0.001), ER (30% [95% CI 17-45%] vs. 62% [95% CI 53-70%], p-unadj < 0.001), and LR rate (40% [95% CI 24-57%] vs. 70% [95% CI 60-77%], p-unadj = 0.002). On multivariable analysis, controlling for clinical risk score, ablation, margin status, and primary T-stage, co-altered RAS/RAF-TP53 was associated with increased risk for AR (HR = 2.14, 95% CI 1.38-3.31, p-unadj < 0.001), LR (HR = 1.79, 95% CI 1.06-3.02, p-unadj = 0.029), and ER (HR = 2.81, 95% CI 1.78-4.44, p-unadj < 0.001). CONCLUSIONS: Altered KRAS, RAS/RAF, and RAS/RAF-TP53 associated with earlier local and distant recurrence in resected CRLM patients receiving adjuvant HAI+SYS. Co-altered RAS/RAF-TP53 was a novel predictor of LR warranting investigation of whether genomic cooperativity is associated with this relapsing phenotype. Systemic therapies tailored to high-risk tumor biology are needed to reduce distant relapse after hepatectomy.

Percutaneous liver venous deprivation: outcomes in heavily pretreated metastatic colorectal cancer patients.

BACKGROUND: To evaluate liver venous deprivation (LVD) outcomes in patients with colorectal liver metastasis (CRLM) heavily pretreated with systemic and hepatic arterial infusion pump (HAIP) chemotherapies that had an anticipated insufficient future liver remnant (FLR) hypertrophy after portal vein embolization (PVE). METHODS: PVE was performed with liquid embolics using a transsplenic or ipsilateral transhepatic approach. Simultaneously and via a trans-jugular approach, the right hepatic vein was embolized with vascular plugs. Liver volumetry was assessed on computed tomography before and 3-6 weeks after LVD. RESULTS: Twelve consecutive CRLM patients that underwent LVD before right hepatectomy or trisectionectomy were included, all previously treated with systemic chemotherapy for a mean of 11.9 months. Six patients had additional HAIP. After embolization, FLR ratio increased from 28.7% ± 5.9 to 42.2% ± 9.0 (P < 0.01). Mean kinetic growth rate (KGR) was 3.56%/week ± 2.3, with a degree of hypertrophy (DH) of 13.8% ± 7.1. In the HAIP subgroup, mean KGR and DH were respectively 3.58%/week ± 2.8 and 14.3% ± 8.7. No severe complications occurred. Ten patients reached surgery after 39 days ± 7.5. CONCLUSION: In heavily pretreated patients, LVD safely stimulated a rapid and effective FLR hypertrophy, with a resultant high rate of resection.

Considerations and barriers to starting a new HAI pump program: an international survey of the HAI Consortium Research Network.

BACKGROUND: Widespread implementation of HAI pump chemotherapy has been limited by logistic and feasibility concerns. Recent studies demonstrating excellent outcomes have fueled renewed enthusiasm and multiple new programs have emerged. This survey aims to identify barriers critical to establish a successful HAI program. METHODS: Using SurveyMonkey™, a 17-question survey assessing factors required for establishing a successful program was developed by 12 HAI Consortium Research Network (HCRN) surgical oncologists. Content analysis was used to code textual responses. Frequency of categories and average rank scores for each choice were calculated. RESULTS: Twenty-eight HCRN members responded to the survey. Implementation time varied, with 15 institutions requiring less than a year. Most programs (n = 17) became active in the past 5 years. Medical and surgical oncology were ranked most important for building a program (average ranking scores: 7.96 and 6.59/8). Administrative or regulatory approval was required at half of the institutions. The top 3 challenges faced when building a program were related to regulatory approval (6.65/9), device/equipment access (6.33/9), and drug (FUDR) access (6.25/9). CONCLUSION: Development of successful programs outside of historically established centers is feasible and requires a multidisciplinary team. Future collaborative efforts are critical for sustainability of safe/effective new programs.

A Randomized Phase II Trial of Adjuvant Hepatic Arterial Infusion and Systemic Therapy With or Without Panitumumab After Hepatic Resection of KRAS Wild-type Colorectal Cancer.

OBJECTIVE/BACKGROUND: The purpose was to determine whether adding Pmab versus no Pmab to an adjuvant regimen of hepatic arterial infusion (HAI) of floxuridine (FUDR) plus systemic (SYS) leucovorin, fluorouracil, and irinotecan (FOLFIRI) improves 15-month recurrence-free survival for patients with RAS wild-type colorectal cancer. Secondary endpoints included overall survival, toxicity, and influence of predictive biomarkers. METHODS: This phase II trial randomized patients with KRAS wild-type resected colorectal liver metastases to adjuvant HAI FUDR + SYS FOLFIRI +/- Pmab (NCT01312857). Patients were stratified by clinical risk score and previous chemotherapy. Based on an exact binomial design, if one arm had ≥24 patients alive and disease-free at 15 months that regimen was considered promising for further investigation. RESULTS: Seventy-five patients were randomized. Patient characteristics and toxicity were not different in the 2 arms, except for rash in +Pmab arm. Grade 3/4 elevation in bilirubin or alkaline phosphatase did not differ in the 2 arms. Twenty-five (69%; 95% CI, 53-82) patients in the Pmab arm versus 18 (47%; 95% CI, 32-63) patients in the arm without Pmab were alive and recurrence-free at 15 months. Only the Pmab arm met the decision rule, while the other arm did not. After median follow-up of 56.6 months, 3-year recurrence-free survival was 57% (95% CI, 43-76) and 42% (95% CI, 29-61), and 3-year overall survival was 97% (95% CI, 90-99) and 91% (95% CI, 83-99), +/- Pmab, respectively. CONCLUSIONS: The addition of Pmab to HAI FUDR + SYS FOLFIRI showed promising activity without increased biliary toxicity and should be further investigated in a larger trial.

Bronchial or Pulmonary Artery Chemoembolization for Unresectable and Unablatable Lung Metastases: A Phase I Clinical Trial.

Background Lung chemoembolization is an emerging treatment option for lung tumors, but the optimal embolic, drug, and technique are unknown. Purpose To determine the technical success rate and safety of bronchial or pulmonary artery chemoembolization of lung metastases using ethiodized oil, mitomycin, and microspheres. Materials and Methods Patients with unresectable and unablatable lung, endobronchial, or mediastinal metastases, who failed systemic chemotherapy, were enrolled in this prospective, single-center, single-arm, phase I clinical trial (December 2019-September 2020). Pulmonary and bronchial angiography was performed to determine the blood supply to the lung metastases. Based on the angiographic findings, bronchial or pulmonary artery chemoembolization was performed using an ethiodized oil and mitomycin emulsion, followed by microspheres. The primary objectives were technical success rate and safety, according to the National Cancer Institute Common Terminology Criteria for Adverse Events. CIs of proportions were estimated with the equal-tailed Jeffreys prior interval, and correlations were evaluated with the Spearman test. Results Ten participants (median age, 60 years; interquartile range, 52-70 years; six women) were evaluated. Nine of the 10 participants (90%) had lung metastases supplied by the bronchial artery, and one of the 10 participants (10%) had lung metastases supplied by the pulmonary artery. The technical success rate of intratumoral drug delivery was 10 of 10 (100%) (95% CI: 78, 100). There were no severe adverse events (95% CI: 0, 22). The response rate of treated tumors was one of 10 (10%) according to the Response Evaluation Criteria in Solid Tumors and four of 10 (40%) according to the PET Response Criteria in Solid Tumors. Ethiodized oil retention at 4-6 weeks was correlated with reduced tumor size (ρ = -0.83, P = .003) and metabolic activity (ρ = -0.71, P = .03). Pharmacokinetics showed that 45% of the mitomycin dose underwent burst release in 2 minutes, and 55% of the dose was retained intratumorally with a half-life of more than 5 hours. The initial tumor-to-plasma ratio of mitomycin concentration was 380. Conclusion Lung chemoembolization was technically successful for the treatment of lung, mediastinal, and endobronchial metastases, with no severe adverse events. Clinical trial registration no. NCT04200417 © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Georgiades et al in this issue.

Impact of Primary Tumor Laterality on Adjuvant Hepatic Artery Infusion Pump Chemotherapy in Resected Colon Cancer Liver Metastases: Analysis of 487 Patients.

BACKGROUND: Hepatic artery infusion (HAI) chemotherapy is associated with overall survival (OS) in patients with resected colon cancer liver metastases (CLM). The prognostic impact of primary tumor location in CLM following hepatic resection in patients receiving regional HAI is unknown. This study seeks to investigate the prognostic impact of HAI in relation to laterality in this patient population. METHODS: Consecutive patients with resected CLM, with known primary tumor site treated with and without HAI, were reviewed from a prospective institutional database. Correlations between HAI, laterality, other clinicopathological factors, and survival were analyzed, and Cox proportional hazard regression was used to determine whether laterality was an independent prognostic factor. RESULTS: From 1993 to 2012, 487 patients [182 with right colon cancer (RCC), 305 with left colon cancer (LCC)] were evaluated with a median follow-up of 6.5 years. Fifty-seven percent (n = 275) received adjuvant HAI. Patients with RCC had inferior 5-year OS compared with LCC (56% vs. 67%, P = 0.01). HAI was associated with improved 5-year OS in both RCC (68% vs. 45%; P < 0.01) and LCC (73% vs. 55%; P < 0.01). On multivariable analysis, HAI remained associated with improved OS (HR 0.52; 95% CI 0.39-0.70; P < 0.01) but primary tumor site did not (HR 0.83; 95% CI 0.63-1.11; P = 0.21). Additional significant prognostic factors on multivariable analysis included age, number of tumors, node-positive primary, positive margins, RAS mutation, two-stage hepatectomy, and extrahepatic disease. Cox proportional hazard regression determined no significant interaction between HAI and laterality on OS [parameter estimate (SEM), 0.12 (0.28); P = 0.67]. CONCLUSIONS: Our data show an association of adjuvant HAI and increased OS in patients who underwent curative hepatectomy, irrespective of primary tumor location. Laterality should therefore not impact decision-making when offering adjuvant HAI.

Recurrence After Liver Resection of Colorectal Liver Metastases: Repeat Resection or Ablation Followed by Hepatic Arterial Infusion Pump Chemotherapy.

BACKGROUND: The aim of this study was to investigate the effectiveness of adjuvant hepatic arterial infusion pump (HAIP) chemotherapy after complete resection or ablation of recurrent colorectal liver metastases (CRLM). METHODS: A retrospective cohort study was conducted of patients from two centers who were treated with resection and/or ablation of recurrent CRLM only between 1992 and 2018. Overall survival (OS) and hepatic disease-free survival (hDFS) were estimated using the Kaplan-Meier method. The Cox regression method was used to calculate hazard ratios (HRs) with corresponding 95% confidence intervals (CI). RESULTS: Of 374 eligible patients, 81 (22%) were treated with adjuvant HAIP chemotherapy. The median follow-up for survivors was 65 months (IQR 32-118 months). Patients receiving adjuvant HAIP were more likely to have multifocal disease and receive perioperative systemic chemotherapy at time of resection for recurrence. A median hDFS of 46 months (95% CI 29-81 months) was found in patients treated with adjuvant HAIP compared with 18 months (95% CI 15-26 months) in patients treated with resection and/or ablation alone (p = 0.001). The median OS and 5-year OS were 89 months (95% CI 52-126 months) and 66%, respectively, in patients treated with adjuvant HAIP compared with 57 months (95% CI 47-67 months) and 47%, respectively, in patients treated with resection and/or ablation only (p = 0.002). Adjuvant HAIP was associated with superior hDFS (adjusted HR 0.599, 95% CI 0.38-0.93, p = 0.02) and OS (adjusted HR 0.59, 95% CI 0.38-0.92, p = 0.02) in multivariable analysis. CONCLUSION: Adjuvant HAIP chemotherapy after resection and/or ablation of recurrent CRLM is associated with superior hDFS and OS.

Early liver metastases after "failure" of adjuvant chemotherapy for stage III colorectal cancer: is there a role for additional adjuvant therapy?

BACKGROUND: The utility of adjuvant chemotherapy after resection of colorectal liver metastasis (CLM) in patients with rapid recurrence after adjuvant chemotherapy for their primary tumor is unclear. The aim of this study was to evaluate the oncologic benefit of adjuvant hepatic arterial plus systemic chemotherapy (HAIC + Sys) in patients with early CLM. METHODS: A retrospective analysis of patients with early CLM (≤12 months of adjuvant chemotherapy for primary tumor) who received either HAIC + Sys, adjuvant systemic chemotherapy alone (Sys), or active surveillance (Surgery alone) following resection of CLM was performed. Recurrence and survival were compared between treatment groups using Kaplan-Meier methods and Cox proportional hazards models. RESULTS: Of 239 patients undergoing resection of early CLM, 79 (33.1%) received HAIC + Sys, 77 (32.2%) received Sys, and 83 (34.7%) had Surgery alone. HAIC + Sys was independently associated with reduced risk of RFS events (adjusted hazard ratio [HRadj]: 0.64, 95%CI:0.44-0.94, p = 0.022) and all-cause mortality (HRadj: 0.54, 95%CI:0.36-0.81, p = 0.003) compared to Surgery alone patients. Largest tumor >5 cm (HRadj: 2.03, 95%CI: 1.41-2.93, p < 0.001) and right-sided colon tumors (HRadj: 1.93, 95%CI: 1.29-2.89, p = 0.002) were independently associated with worse OS. CONCLUSION: Adjuvant HAIC + Sys after resection of early CLM that occur after chemotherapy for node-positive primary is associated with improved outcomes.

Adjuvant Hepatic Artery Infusion Chemotherapy is Associated With Improved Survival Regardless of KRAS Mutation Status in Patients With Resected Colorectal Liver Metastases: A Retrospective Analysis of 674 Patients.

OBJECTIVE: To investigate the impact of adjuvant hepatic artery infusion (HAI) in relation to KRAS mutational status in patients with resected colorectal cancer liver metastases (CRLM). BACKGROUND: Patients with KRAS-mutated CRLM have worse outcomes after resection. Adjuvant HAI chemotherapy improves overall survival after liver resection. METHODS: Patients with resected CRLM treated at MSKCC with and without adjuvant HAI who had available KRAS status (wild-type, WT; mutated, MUT) were reviewed from a prospectively maintained institutional database. Correlations between KRAS status, adjuvant HAI, clinical factors, and outcomes were analyzed. Cox proportional hazard model was used to adjust for confounders. RESULTS: Between 1993 and 2012, 674 patients (418 KRAS-WT, 256 MUT) with a median follow up of 6.5 years after resection were evaluated. Fifty-four percent received adjuvant HAI. Tumor characteristics (synchronous disease, number of lesions, clinical-risk score, 2-stage hepatectomy) were significantly worse in the HAI group; however, there were more patients with resected extrahepatic metastases in the no-HAI group. In KRAS-WT tumors, 5-year survival was 78% for patients treated with HAI versus 57% for patients without HAI [hazard ratio (HR) 0.51, P < 0.001]. In KRAS-MUT tumors, 5-year survival was 59% for patients treated with HAI versus 40% for patients without HAI (HR 0.56, P < 0.001). On multivariate analysis, HAI remained associated with improved OS (HR 0.53, P < 0.002) independent of KRAS status and other clinicopathologic factors. CONCLUSION: Adjuvant HAI after resection of CRLM is independently associated with improved outcomes regardless of KRAS mutational status. Adjuvant HAI may mitigate the worse outcomes seen in patients with resectable KRAS-MUT CRLM.

Is Hepatectomy Justified for BRAF Mutant Colorectal Liver Metastases?: A Multi-institutional Analysis of 1497 Patients.

OBJECTIVE: To analyze clinical outcomes and prognostic variables of patients undergoing hepatic resection for BRAF mutant (BRAF-mut) colorectal liver metastases (CRLM). BACKGROUND: Outcomes following hepatectomy for BRAF-mut CRLM have not been well studied. METHODS: All patients who underwent hepatectomy for CRLM with complete resection and known BRAF status during 2001 to 2016 at 3 high-volume centers were analyzed. RESULTS: Of 4124 patients who underwent hepatectomy for CRLM, 1497 had complete resection and known BRAF status. Thirty-five (2%) patients were BRAF-mut, with 71% of V600E mutation. Compared with BRAF wild-type (BRAF-wt), BRAF-mut patients were older, more commonly presented with higher ASA scores, synchronous, multiple and smaller CRLM, underwent more major hepatectomies, but had less extrahepatic disease. Median overall survival (OS) was 81 months for BRAF-wt and 40 months for BRAF-mut patients (P < 0.001). Median recurrence-free survival (RFS) was 22 and 10 months for BRAF-wt and BRAF-mut patients (P < 0.001). For BRAF-mut, factors associated with worse OS were node-positive primary tumor, carcinoembryonic antigen (CEA) >200 µg/L, and clinical risk score (CRS) ≥4. Factors associated with worse RFS were node-positive primary tumor, ≥4 CRLM, and positive hepatic margin. V600E mutations were not associated with worse OS or RFS. A case-control matching analysis on prognostic clinicopathologic factors confirmed shorter OS (P < 0.001) and RFS (P < 0.001) in BRAF-mut. CONCLUSIONS: Patients with resectable BRAF-mut CRLM are rare among patients selected for surgery and more commonly present with multiple synchronous tumors. BRAF mutation is associated with worse prognosis; however, long-term survival is possible and associated with node-negative primary tumors, CEA ≤ 200 µg/L and CRS < 4.