A Modified Floxuridine Reduced-Dose Protocol for Patients with Unresectable Colorectal Liver Metastases Treated with Hepatic Arterial Infusion.

BACKGROUND: Most patients treated with the standard dosing protocol (SDP) of hepatic arterial infusion (HAI) floxuridine require dose holds and reductions, thereby limiting their HAI therapy. We hypothesized that a modified dosing protocol (MDP) with a reduced floxuridine starting dose would decrease dose holds, dose reductions, and have similar potential to convert patients with unresectable colorectal liver metastases (uCRLM) to resection. PATIENTS AND METHODS: We reviewed our institutional database of patients with uCRLM treated with HAI between 2016 and 2022. In 2019, we modified the floxuridine starting dose to 50% (0.06 mg/kg) of the SDP (0.12 mg/kg). We compared treatment related outcomes between the SDP and MDP cohorts. RESULTS: Of n = 33 patients, 15 (45%) were treated on the SDP and 18 (55%) with our new institutional MDP. The MDP cohort completed more cycles before a dose reduction (mean 4.2 vs. 2), received more overall cycles (median 7.5 vs. 5), and averaged 39 more days of treatment (all P < 0.05). The SDP experienced more dose reductions (1.4 vs. 0.61) and dose holds (1.2 vs. 0.2; both P < 0.01). Of the patients in each group potentially convertible to hepatic resection, three patients (23%) in the SDP and six patients (35%) in the MDP group converted to resection (P = 0.691). Overall, four patients (27%) in the SDP developed treatment ending biliary toxicity compared with one patient (6%) in the MDP. CONCLUSIONS: A 50% starting dose of HAI floxuridine provides fewer treatment disruptions, more consecutive floxuridine cycles, and a similar potential to convert patients with initially uCRLM for disease clearance.

Adjuvant imatinib in high-risk resected gastrointestinal stromal tumors: Merely delaying the inevitable?

INTRODUCTION: Patients with high-risk resected gastrointestinal stromal tumors (GIST) receiving adjuvant imatinib have improved recurrence-free survival (RFS), however whether a complete cytocidal effect exists is unknown. We investigated this using a normalized recurrence timeline measured from end of oncologic treatment (EOOT), defined as the later of resection or end of adjuvant therapy. METHODS: We reviewed patients with resected high-risk GIST at our cancer center from 2003 to 2018. RFS (measured from resection and EOOT), overall survival (OS), and time to imatinib resistance (TTIR) were analyzed using Kaplan-Meier analysis and multivariable Cox proportional hazards modeling. The performance of the Memorial Sloan Kettering (MSK) GIST nomogram was assessed. RESULTS: We identified 86 patients with high-risk GIST with a median 106 months of postsurgical follow-up. One-third (n = 29; 34%) did not receive adjuvant imatinib, while 57 (66%) did for a median of 3 years. The MSK nomogram-predicted 5-year RFS for patients receiving adjuvant imatinib was similar to those who did not (29% vs. 31%, p = 0.64). When RFS was measured from EOOT, the MSK-predicted RFS was independently associated with EOOT RFS (hazard ratio 0.22, p = 0.02), while adjuvant imatinib receipt and duration were not. Neither receipt nor duration of adjuvant imatinib were associated with TTIR or OS (all p > 0.05). CONCLUSIONS: Treatment with adjuvant imatinib delays, but does not clearly impact ultimate recurrence, TTIR, or OS, suggesting many patients with high-risk GIST may receive adjuvant imatinib unnecessarily. Additional studies are needed to establish the benefit of adjuvant therapy versus initiating therapy at first radiographic recurrence.

Safety and Effectiveness of Portal Vein Embolization after Hepatic Arterial Infusion Therapy.

Portal vein embolization (PVE) is a tool potentially useful for inducing future liver remnant (FLR) hypertrophy in patients with advanced hepatic malignancies who are at high risk of hepatic insufficiency if treated with surgical resection. However, the safety and effectiveness of PVE in the context of patients who have undergone hepatic arterial infusion (HAI) are unknown. This retrospective, single-center study identified 9 patients who underwent PVE after HAI between January 2015 and December 2022. There were no major adverse events, including biliary injury or high-grade liver failure. Analysis showed an increase in standardized FLR from 21.1% (SEM ± 2.4) to 34.8% (SEM ± 2.1) over 9.8 weeks (SEM ± 1.2), with a mean kinetic growth rate of 1.9% (interquartile range, 0.9%-2.4%). Patients who have undergone HAI therapy should not be excluded from consideration of PVE as part of their operative clearance strategy.

Outcomes of Late-Line Systemic Treatment in GIST: Does Sequence Matter?

Ripretinib and avapritinib have demonstrated activity in the late-line treatment of gastrointestinal stomal tumors (GISTs). We investigated whether patients previously treated with ripretinib benefit from avapritinib, and vice versa. Patients diagnosed with metastatic/unresectable GIST and treated with both drugs at two institutions in 2000-2021 were included. Patients were grouped by drug sequence: ripretinib-avapritinib (RA) or avapritinib-ripretinib (AR). Radiographic response was evaluated using RECIST 1.1. Kaplan-Meier and log-rank tests were used to compare time-to-progression (TTP) and overall survival (OS). Thirty-four patients (17 per group) were identified, with a median age of 48 years. The most common primary site was the small bowel (17/34, 50%), followed by the stomach (10/34, 29.4%). Baseline characteristics and tumor mutations were not significantly different between groups. Response rates (RRs) for ripretinib were 18% for RA and 12% for AR; RRs for avapritinib were 12% for AR and 18% for RA. Median TTPs for ripretinib were 3.65 months (95%CI 2-5.95) for RA and 4.73 months (1.87-15.84) for AR. Median TTPs for avapritinib were 5.39 months (2.86-18.99) for AR and 4.11 months (1.91-11.4) for RA. Median OS rates following RA or AR initiation were 29.63 (95%CI 13.8-50.53) and 33.7 (20.03-50.57) months, respectively. Both ripretinib and avapritinib were efficacious in the late-line treatment of GIST, with no evidence that efficacy depended on sequencing.

Clinician overconfidence in visual estimation of the posthepatectomy liver remnant volume: A proximal source of liver failure after major hepatic resection?

BACKGROUND: Post-hepatectomy liver failure is a source of morbidity and mortality after major hepatectomy and is related to the volume of the future liver remnant. The accuracy of a clinician's ability to visually estimate the future liver remnant without formal computed tomography liver volumetry is unknown. METHODS: Twenty physicians in diagnostic radiology, interventional radiology, and hepatopancreatobiliary surgery reviewed 20 computed tomography scans of patients without underlying liver pathology who were not scheduled for liver resection. We evaluated clinician accuracy to estimate the future liver remnant for 3 hypothetical major hepatic resections: left hepatectomy, right hepatectomy, and right trisectionectomy. The percent-difference between the mean and actual computed tomography liver volumetry (mean percent difference) was tested along with specialty differences using mixed-effects regression analysis. RESULTS: The actual future liver remnant (computed tomography liver volumetry) remaining after a hypothetical left hepatectomy ranged from 59% to 75% (physician estimated range: 50%-85%), 23% to 40% right hepatectomy (15%-50%), and 13% to 29% right trisectionectomy (8%-39%). For right hepatectomy, the mean future liver remnant was overestimated by 95% of clinicians with a mean percent difference of 22% (6%-45%; P < .001). For right trisectionectomy, 90% overestimated the future liver remnant by a mean percent difference of 25% (6%-50%; P < .001). Hepatopancreatobiliary surgeons overestimated the future liver remnant for proposed right hepatectomy and right trisectionectomy by a mean percent difference of 25% and 34%, respectively. Based on years of experience, providers with <10 years of experience had a greater mean percent difference than providers with 10+ years of experience for hypothetical major hepatic resections, but was only significantly higher for left hepatectomy (9% vs 6%, P = .002). CONCLUSION: A clinician's ability to visually estimate the future liver remnant volume is inaccurate when compared to computed tomography liver volumetry. Clinicians tend to overestimate the future liver remnant volume, especially in patients with a small future liver remnant where the risk of posthepatectomy liver failure is greatest.

Imaging of the hepatic arterial infusion pump: Primer for radiologists.

Hepatic arterial infusion (HAI) pumps are used to deliver liver-directed therapy by allowing the administration of selective chemotherapy to the liver via a catheter implanted most commonly into the gastroduodenal artery connected to a subcutaneous pump. This selective administration helps maximize the chemotherapeutic effect within the hepatic tumors while minimizing systemic toxicity. While HAI therapy has primarily been used to treat liver-only metastatic colorectal cancer, the indications have expanded to other malignancies, including intrahepatic cholangiocarcinoma. Radiologists play an important role in pre-operative planning, assessment of treatment response, and evaluation for potential complications using various imaging studies, including computed tomography angiography, magnetic resonance imaging, and perfusion scintigraphy. This article describes the radiologist's role as part of a multi-disciplinary oncology team to help maximize the success of HAI therapy and also helps radiologists familiarize themselves with various aspects of HAI pumps.

Updated Management of Colorectal Cancer Liver Metastases: Scientific Advances Driving Modern Therapeutic Innovations.

Colorectal cancer is the second leading cause of cancer-related deaths in the United States and accounts for an estimated 1 million deaths annually worldwide. The liver is the most common site of metastatic spread from colorectal cancer, significantly driving both morbidity and mortality. Although remarkable advances have been made in recent years in the management for patients with colorectal cancer liver metastases, significant challenges remain in early detection, prevention of progression and recurrence, and in the development of more effective therapeutics. In 2017, our group held a multidisciplinary state-of-the-science symposium to discuss the rapidly evolving clinical and scientific advances in the field of colorectal liver metastases, including novel early detection and prognostic liquid biomarkers, identification of high-risk cohorts, advances in tumor-immune therapy, and different regional and systemic therapeutic strategies. Since that time, there have been scientific discoveries translating into therapeutic innovations addressing the current management challenges. These innovations are currently reshaping the treatment paradigms and spurring further scientific discovery. Herein, we present an updated discussion of both the scientific and clinical advances and future directions in the management of colorectal liver metastases, including adoptive T-cell therapies, novel blood-based biomarkers, and the role of the tumor microbiome. In addition, we provide a comprehensive overview detailing the role of modern multidisciplinary clinical approaches used in the management of patients with colorectal liver metastases, including considerations toward specific molecular tumor profiles identified on next generation sequencing, as well as quality of life implications for these innovative treatments.

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.

Phase 2 study of preoperative chemotherapy with nab-paclitaxel and gemcitabine followed by chemoradiation for borderline resectable or node-positive pancreatic ductal adenocarcinoma.

BACKGROUND: Neoadjuvant treatment with nab-paclitaxel and gemcitabine for potentially operable pancreatic adenocarcinoma has not been well studied in a prospective interventional trial and could down-stage tumors to achieve negative surgical margins. METHODS: A single-arm, open-label phase 2 trial (NCT02427841) enrolled patients with pancreatic adenocarcinoma deemed to be borderline resectable or clinically node-positive from March 17, 2016 to October 5, 2019. Patients received preoperative gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on Days 1, 8, 15, every 28 days for two cycles followed by chemoradiation with 50.4 Gy intensity-modulated radiation over 28 fractions with concurrent fluoropyrimidine chemotherapy. After definitive resection, patients received four additional cycles of gemcitabine and nab-paclitaxel. The primary endpoint was R0 resection rate. Other endpoints included treatment completion rate, resection rate, radiographic response rate, survival, and adverse events. RESULTS: Nineteen patients were enrolled, with the majority having head of pancreas primary tumors, both arterial and venous vasculature involvement, and clinically positive nodes on imaging. Among them, 11 (58%) underwent definitive resection and eight of 19 (42%) achieved R0 resection. Disease progression and functional decline were primary reasons for deferring surgical resection after neoadjuvant treatment. Pathologic near-complete response was observed in two of 11 (18%) resection specimens. Among the 19 patients, the 12-month progression-free survival was 58%, and 12-month overall survival was 79%. Common adverse events were alopecia, nausea, vomiting, fatigue, myalgia, peripheral neuropathy, rash, and neutropenia. CONCLUSION: Gemcitabine and nab-paclitaxel followed by long-course chemoradiation represents a feasible neoadjuvant treatment strategy for borderline resectable or node-positive pancreatic cancer.

The genomics of liver metastases from colon and rectal cancer: An Invited Commentary (invitation from Lee Ocuin, MD and Kevin Behrns, MD) for the special issue of "Management of Advanced Primary and Secondary Liver Malignancies".

Over the past two decades, the treatment of patients with cancer has become increasingly structured around the identification of cancer mutations genetically driving the disease. Upfront knowledge of these data has implications for both the selection and omission of certain cytotoxic and targeted therapies. For patients with colon or rectal cancer metastatic to the liver, next-generation sequencing to identify these key mutational drivers should be done at the outset of diagnosis to understand the full spectrum of treatment options available to a patient. Mutational profiling for patients with colorectal liver metastasis initially led to the recognition of treatment resistance to epidermal growth factor inhibitors in patients with a KRAS mutation and now has expanded to include other targeted options. As the treatment options for patients with colorectal liver metastasis continue to evolve, it is increasingly important to integrate genomic data into selecting patients who will benefit from hepatic resection, ablative techniques, and liver-directed therapy. Herein, we review the most common mutations encountered in treating patients with colorectal liver metastasis, focusing specifically on epidermal growth factor receptor, KRAS/NRAS, BRAF, and the mismatch repair pathway with resultant implications to the medical and surgical treatment for these patients.

Neoadjuvant therapy does not impact the biliary microbiome in patients with pancreatic cancer.

BACKGROUND: Pancreatic adenocarcinoma (PDAC) often impinges on the biliary tree and obstruction necessitates stent placement increasing the risk of surgical site infections (SSIs). We sought to explore the impact of neoadjuvant therapy on the biliary microbiome and SSI risk in patients undergoing resection. METHODS: A retrospective analysis was performed on 346 patients with PDAC who underwent resection at our institution from 2008 to 2021. Univariate and multivariate methods were utilized for analysis. RESULTS: Biliary stenting rates were similar between groups but resulted in increased bile culture positivity (97% vs. 15%, p < 0.001). Culture positivity did not differ between upfront resection or neoadjuvant chemotherapy (NAC) (77% vs. 80%, p = 0.60). NAC-alone versus neoadjuvant chemoradiotherapy did not impact biliary positivity (80% vs. 79%, p = 0.91), nor did 5-fluorouracil versus gemcitabine-based regimens (73% vs. 85%, p = 0.19). While biliary stenting increased incisional SSI risk (odds ratios [OR]: 3.87, p = 0.001), NAC did not (OR: 0.83, p = 0.54). Upfront resection, NAC, and chemoradiotherapy were not associated with biliary organism-specific changes or antibiotic resistance patterns. CONCLUSIONS: Biliary stenting is the greatest predictor for positive biliary cultures and SSIs in resected PDAC patients. Neither NAC nor radiotherapy impact bile culture positivity, speciation, rates, or antibiotic resistance patterns, and perioperative antibiotic prophylaxis should not differ.

Socioeconomic and Geographic Disparities in the Referral and Treatment of Pancreatic Cancer at High-Volume Centers.

Importance: Treatment at high-volume centers (HVCs) has been associated with improved overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC); however, it is unclear how patterns of referral affect these findings. Objective: To understand the relative contributions of treatment site and selection bias in driving differences in outcomes in patients with PDAC and to characterize socioeconomic factors associated with referral to HVCs. Design, Setting, Participants: A population-based retrospective review of the Oregon State Cancer Registry was performed from 1997 to 2019 with a median 4.3 months of follow-up. Study participants were all patients diagnosed with PDAC in Oregon from 1997 to 2018 (n = 8026). Exposures: The primary exposures studied were diagnosis and treatment at HVCs (20 or more pancreatectomies for PDAC per year), low-volume centers ([LVCs] less than 20 per year), or both. Main Outcomes and Measures: OS and treatment patterns (eg, receipt of chemotherapy and primary site surgery) were evaluated with Kaplan-Meier analysis and logistic regression, respectively. Results: Eight thousand twenty-six patients (male, 4142 [52%]; mean age, 71 years) were identified (n = 3419 locoregional, n = 4607 metastatic). Patients receiving first-course treatment at a combination of HVCs and LVCs demonstrated improved median OS for locoregional and metastatic disease (16.6 [95% CI, 15.3-17.9] and 6.1 [95% CI, 4.9-7.3] months, respectively) vs patients receiving HVC only (11.5 [95% CI, 10.7-12.3] and 3.9 [95% CI, 3.5-4.3] months, respectively) or LVC-only treatment (8.2 [95% CI, 7.7-8.7] and 2.1 [95% CI, 1.9-2.3] months, respectively; all P < .001). No differences existed in disease burden by volume status of diagnosing institution. When stratifying by site of diagnosis, HVC-associated improvements in median OS were smaller (locoregional: 10.4 [95% CI, 9.5-11.2] vs 9.9 [95% CI, 9.4-10.4] months; P = .03; metastatic: 3.6 vs 2.7 months, P < .001) than when stratifying by the volume status of treating centers, indicating selection bias during referral. A total of 94% (n = 1103) of patients diagnosed at an HVC received HVC treatment vs 18% (n = 985) of LVC diagnoses. Among patients diagnosed at LVCs, later year of diagnosis and higher estimated income were independently associated with higher odds of subsequent HVC treatment, while older age, metastatic disease, and farther distance from HVC were independently associated with lower odds. Conclusions and Relevance: LVC-to-HVC referrals for PDAC experienced improved OS vs HVC- or LVC-only care. While disease-related features prompting referral may partially account for this finding, socioeconomic and geographic disparities in referral worsen OS for disadvantaged patients. Measures to improve access to HVCs are encouraged.

Past, Present, and Future Management of Localized Biliary Tract Malignancies.

Most of the patients with gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (iCCA), and peri-hilar cholangiocarcinoma (pCCA) present with advanced disease. Complete staging with multiphasic liver imaging is essential to determine the extent of disease. Operative goals should include a margin-negative resection, portal lymphadenectomy for staging, and sufficient remnant liver volume. Biliary tract malignancies have distinct mutational drivers (GBC and pCCA = ERBB2 in 20%; iCCA = fibroblast growth factor receptor 2 or isocitrate dehydrogenase 1 in 20%) amenable to therapy with inhibitors. Clinical trials assessing neoadjuvant, peri-operative, and adjuvant treatments continue to evolve and now include targeted inhibitors and the integration of hepatic arterial infusion.

Hepatectomy is associated with improved oncologic outcomes in recurrent colorectal liver metastases: A propensity-matched analysis.

BACKGROUND: Following resection of colorectal liver metastasis, most patients have disease recurrence, most commonly intrahepatic. Although the role of resection in colorectal liver metastasis is well-established, there have been limited investigations assessing the benefit of repeat hepatic resection compared with systemic treatment alone for intrahepatic recurrence. METHODS: A retrospective single-institution cohort study of patients with recurrent colorectal liver metastasis following curative-intent hepatectomy was performed from 2003 to 2019. The oncologic outcomes, including post-recurrence overall survival, were evaluated using Kaplan-Meier and Cox proportional hazards modeling. Patients undergoing repeat hepatic resection were propensity-matched with patients receiving systemic treatment alone based on relevant clinicopathologic variables. RESULTS: There were 338 patients treated with hepatic resection for colorectal liver metastasis over the study period. Liver recurrence was observed in 147 (43%) patients at a median time of 10 months from prior resection, with a median post-recurrence overall survival of 29 months. There were 37 patients managed with repeat hepatic resection; 33 (89%) received perioperative chemotherapy. On propensity matching, there were no significant clinicopathologic differences between 37 patients having repeat hepatic resection and 37 patients treated with systemic treatment alone. Repeat hepatic resection was independently associated with improved 5-year post-recurrence overall survival compared with systemic treatment alone (median overall survival 41 vs 35 months, 5-year overall survival 19% vs 3%, P = .048). CONCLUSION: Disease characteristics of patients with intrahepatic recurrence of colorectal liver metastasis, specifically the number of liver lesions and size of the largest lesion, are most predictive of survival and response to systemic therapy. Patients who recur with oligometastatic liver disease experience improved outcomes and derive benefit from curative-intent repeat hepatic resection with integrated perioperative systemic therapy.