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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., (© 2023. The Author(s).)

Background: Histopathological growth patterns (HGPs) are a prognostic biomarker in colorectal liver metastases (CRLM). Desmoplastic HGP (dHGP) is associated with liver-only recurrence and superior overall survival (OS), while non-dHGP is associated with multi-organ recurrence and inferior OS. This study investigated the predictive value of HGPs for adjuvant hepatic arterial infusion pump (HAIP) chemotherapy in CRLM., Methods: Patients undergoing resection of CRLM and perioperative systemic chemotherapy in two centers were included. Survival outcomes and the predictive value of HAIP versus no HAIP per HGP group were evaluated through Kaplan-Meier and Cox regression methods, respectively., Results: We included 1233 patients. In the dHGP group (n = 291, 24%), HAIP chemotherapy was administered in 75 patients (26%). In the non-dHGP group (n = 942, 76%), HAIP chemotherapy was administered in 247 patients (26%). dHGP was associated with improved overall survival (OS, HR 0.49, 95% CI 0.32-0.73, p < 0.001). HAIP chemotherapy was associated with improved OS (HR 0.61, 95% CI 0.45-0.82, p < 0.001). No interaction could be demonstrated between HGP and HAIP on OS (HR 1.29, 95% CI 0.72-2.32, p = 0.40)., Conclusions: There is no evidence that HGPs of CRLM modify the survival benefit of adjuvant HAIP chemotherapy in patients with resected CRLM., (© 2023. The Author(s).)

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., (© 2023. Society of Surgical Oncology.)

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., (© 2022. Society of Surgical Oncology.)

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., (© 2021. Society of Surgical Oncology.)

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.

Background: Obesity and metabolic syndrome are associated with inflammatory hepatic parenchymal disease (HPD) and increased risk for recurrence after resection of colorectal liver metastases (CRLM). The independent impact of HPD on recurrence patterns has not been well defined., Methods: The nonalcoholic fatty liver disease activity score (NAS) was used to quantify HPD including steatosis and fibrosis for all patients with completely resected CRLM between April 2003 and March 2007. Clinicopathologic factors, perioperative history, and outcomes were compared with the NAS. Fisher's exact test was used to examine the association between severe HPD (NAS ≥ 3) with clinical and perioperative characteristics. Kaplan-Meier methods were used to estimate recurrence-free survival (RFS). The cumulative incidences of recurrence [any intrahepatic recurrence (IHR), extrahepatic recurrence only (EHR), and death without recurrence (DWR)] were estimated using competing risks methods., Results: Among the 357 patients included in this study, microsteatosis was noted in 124 (35%) patients, severe HPD in 31 (9%), steatohepatitis in 14 (4%), and sinusoidal injury in 36 (10%). After median follow-up of 127 months (range 4-175 months), 10-year RFS was 22% [95% confidence interval (CI) 17-27%]. Ten-year cumulative incidence for IHR, EHR, and DWR was 37%, 30%, and 12%, respectively. After controlling for confounders, NAS ≥ 3 was independently associated with higher risk of IHR [hazard ratio (HR) 1.76, 95% CI 1.07-2.90, p = 0.027] and lower risk of EHR (HR 0.18, 95% CI 0.04-0.75, p = 0.019) on multivariable analysis., Conclusions: Severe HPD was associated with increased IHR risk and decreased EHR risk. Future investigation into whether improving HPD from reversible etiologies can reduce the risk for IHR is warranted.

Background: The 10-year overall survival with adjuvant hepatic arterial infusion pump (HAIP) chemotherapy after resection of colorectal liver metastases (CRLMs) was 61% in clinical trials from Memorial Sloan Kettering Cancer Center. A pilot study was performed to evaluate the safety and feasibility of adjuvant HAIP chemotherapy in patients with resectable CRLMs., Study Design: A phase II study was performed in two centers in The Netherlands. Patients with resectable CRLM without extrahepatic disease were eligible. All patients underwent complete resection and/or ablation of CRLMs and pump implantation. Safety was determined by the 90-day HAIP-related postoperative complications from the day of pump placement (Clavien-Dindo classification, grade III or higher) and feasibility by the successful administration of the first cycle of HAIP chemotherapy., Results: A total of 20 patients, with a median age of 57 years (interquartile range [IQR] 51-64) were included. Grade III or higher HAIP-related postoperative complications were found in two patients (10%), both of whom had a reoperation (without laparotomy) to replace a pump with a slow flow rate or to reposition a flipped pump. No arterial bleeding, arterial dissection, arterial thrombosis, extrahepatic perfusion, pump pocket hematoma, or pump pocket infections were found within 90 days after surgery. After a median of 43 days (IQR 29-52) following surgery, all patients received the first dose of HAIP chemotherapy, which was completed uneventfully in all patients., Conclusion: Pump implantation is safe, and administration of HAIP chemotherapy is feasible, in patients with resectable CRLMs, after training of a dedicated multidisciplinary team.

Background: Liver resection can be curative for well-selected metastatic colorectal cancer (CRC) patients. Circulating tumor DNA (ctDNA) has shown promise as a biomarker for tumor dynamics and recurrence following CRC resection. This prospective pilot study investigated the use of ctDNA to predict disease outcome in resected CRC patients., Methods: Between November 2014 and November 2015, 60 patients with CRC were identified and prospectively enrolled. During liver resection, blood was drawn from peripheral (PERIPH), portal (PV), and hepatic (HV) veins, and 3-4 weeks postoperatively from a peripheral vein (POSTOP). Kappa statistics were used to compare mutated (mt) genes in tissue and ctDNA. Disease-specific and disease-free survival (DSS and DFS) were assessed from surgery with Kaplan-Meier and Cox methods., Results: For the 59 eligible patients, the most commonly mutated genes were TP53 (mtTP53: 47.5%) and APC (mtAPC: 50.8%). Substantial to almost-perfect agreement was seen between ctDNA from PERIPH and PV (mtTP53: 89.8%, κ = 0.73, 95% confidence interval [CI] 0.53-0.93; mtAPC: 94.9%, κ = 0.83, 95% CI 0.64-1.00), as well as HV (mtTP53: 91.5%, κ = 0.78, 95% CI 0.60-0.96; mtAPC: 91.5%, κ = 0.73, 95% CI 0.51-0.95). Tumor mutations and PERIPH ctDNA had fair-to-moderate agreement (mtTP53: 72.9%, κ = 0.44, 95% CI 0.23-0.66; mtAPC: 61.0%, κ = 0.23, 95% CI 0.04-0.42). Detection of PERIPH mtTP53 was associated with worse 2-year DSS (mt+ 79% vs. mt- 90%, P = 0.024)., Conclusions: Peripheral blood reflects the perihepatic ctDNA signature. Disagreement between tissue and ctDNA mutations may reflect the true natural history of tumor genes or an assay limitation. Peripheral ctDNA detection before liver resection is associated with worse DSS.

Background: The impact of primary tumor location on overall survival (OS), recurrence-free survival (RFS), and long-term outcomes has not been well established in patients undergoing potentially curative resection of colorectal liver metastases (CRLM)., Methods: A single-institution database was queried for initial resections for CRLM 1992-2004. Primary tumor location determined by chart review (right = cecum to transverse; left = splenic flexure to sigmoid). Rectal cancer (distal 16 cm), multiple primaries, and unknown location were excluded. Kaplan-Meier and Cox regression methods were used. Cure was defined as actual 10-year survival with either no recurrence or resected recurrence with at least 3 years of disease-free follow-up., Results: A total of 907 patients were included with a median follow-up of 11 years; 578 patients (64%) had left-sided and 329 (36%) right-sided primaries. Median OS for patients with a left-sided primary was 5.2 years (95% confidence interval [CI] 4.6-6.0) versus 3.6 years (95% CI 3.2-4.2) for right-sided (p = 0.004). On multivariable analysis, the hazard ratio for right-sided tumors was 1.22 (95% CI 1.02-1.45, p = 0.028) after adjusting for common clinicopathologic factors. Median RFS was marginally different stratified by primary location (1.3 vs. 1.7 years; p = 0.065). On multivariable analysis, location of primary was not significantly associated with RFS (p = 0.105). Observed cure rates were 22% for left-sided and 20% for right-sided tumors., Conclusions: Among patients undergoing resection of CRLM, left-sided primary tumors were associated with improved median OS. However, long-term survival and recurrence-free survival were not significantly different stratified by primary location. Patients with left-sided primary tumors displayed a prolonged clinical course suggestive of more indolent biology.

Background: Recurrence after resection of colorectal liver metastases (CRLMs) occurs in up to 75% of patients. Preoperative prediction of hepatic recurrence may inform therapeutic strategies at the time of initial resection. Texture analysis (TA) is an established technique that quantifies pixel intensity variations (heterogeneity) on cross-sectional imaging. We hypothesized that tumoral and parenchymal changes that are predictive of overall survival (OS) and recurrence in the future liver remnant (FLR) can be detected using TA on preoperative computed tomography (CT) images., Methods: Patients who underwent resection for CRLM between 2003 and 2007 with appropriate preoperative CT scans were included (n = 198) in this retrospective study. Texture features extracted from the tumor and FLR, and clinicopathologic variables, were incorporated into a multivariable survival model., Results: Quantitative imaging features of the FLR were an independent predictor of both OS and hepatic disease-free survival (HDFS). Tumor texture showed significant association with OS. TA of the FLR allowed patient stratification into two groups, with significantly different risks of hepatic recurrence (hazard ratio 2.09, 95% confidence interval 1.33-3.28; p = 0.001). Patients with homogeneous parenchyma had approximately twice the risk of hepatic recurrence (41 vs. 20%)., Conclusion: TA of the tumor and FLR are independently associated with OS, and TA of the FLR is independently associated with HDFS. Patients with homogeneous parenchyma had a significantly higher risk of hepatic recurrence. Preoperative TA of the liver represents a potential biomarker to identify patients at risk of liver recurrence after resection for CRLM.

Purpose: Patients with recurrence after complete resection of colorectal liver metastases (CLM) are considered for repeat resection as a potential salvage therapy (PST). However, outcomes for this approach are not well defined. We sought to analyze the natural history of recurrence and PST in a large cohort of patients with long-term follow-up., Methods: Recurrence patterns, treatments, and outcomes in consecutive patients undergoing resection for colorectal liver metastases were analyzed retrospectively. PST was defined as repeat resection of all recurrent disease and effective salvage therapy (EST) as free of disease for 36 months after last PST. Factors associated with PST, EST, and outcomes were analyzed., Results: Of 952 patients who underwent resection, 594 (62 %) experienced recurrence (median interval = 13 months). Initial recurrences involved liver (n = 157,26 %), lung (n = 167,28 %), multiple sites (n = 171,29 %), and other single sites (n = 99,17 %). PST was performed in 160 (27 %) of 594, most commonly with a single site of recurrence (n = 149). Young age (p = 0.01), negative initial resection margin (p = 0.003), initial tumor size <5 cm (p = 0.006), and recurrence pattern (p < 0.001) were independently associated with PST. Thirty-six patients experienced EST (25 % of PSTs). Overall median survival was 61 and 43 months in those with recurrence. Median survival of patients undergoing PST was 87 months compared to 34 months for those who did not., Conclusions: Recurrence is common after CLM resection, but 27 % of patients were able to undergo PST. Approximately one-quarter of these experienced EST and may be cured. PST is associated with long-term survival and possible cure, and therefore active surveillance after CLM resection is justified.

Background: For patients with unresectable intrahepatic cholangiocarcinoma (ICC), treatment options are limited and survival is poor. This study summarizes the long-term outcome of two previously reported clinical trials using hepatic arterial infusion (HAI) with floxuridine and dexamethasone (with or without bevacizumab) in advanced ICC., Methods: Prospectively collected clinicopathologic and survival data were retrospectively reviewed. Response was based on Response Evaluation Criteria in Solid Tumors (RECIST). Pre-HAI dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) images were reviewed, and tumor perfusion data correlated with outcome., Results: Forty-four patients were analyzed (floxuridine, 26; floxuridine/bevacizumab, 18). At a median follow-up of 29.3 months, 41 patients had died of disease. Partial response by RECIST was observed in 48 %, and 50 % had stable disease. Three patients underwent resection after response, and 82 % received additional HAI after removal from the trials. Median survival was similar in both trials (floxuridine 29.3 months vs. floxuridine/bevacizumab 28.5 months; p = 0.96). Ten (23 %) patients survived ≥3 years, including 5 (11 %) who survived ≥5 years. Tumor perfusion measured on pre-treatment DCE-MRI [area under the gadolinium concentration curve at 90 and 180 s (AUC90 and AUC180, respectively)] was significantly higher in ≥3-year survivors and was the only factor that distinguished this group from <3-year survivors (mean AUC90 22.6 vs. 15.9 mM s, p = 0.025, and mean AUC180 48.9 vs. 32.3 mM s, p = 0.003, respectively). Median hepatic progression-free survival was longer in ≥3-year survivors (12.9 vs. 9.3 months, respectively; p = 0.008)., Conclusions: HAI chemotherapy can result in prolonged survival in unresectable ICC. Pre-HAI DCE-MRI may predict treatment outcome.

Background: Two-stage hepatectomy (TSH) has been adopted as a treatment modality for resection of advanced colorectal liver metastases (CRLM). This study analyzed the recurrence pattern, salvage rate, and survival after TSH combined with systemic and regional chemotherapy., Methods: A retrospective review of a prospective database identified patients who underwent a TSH for CRLM was performed and outcome data analyzed., Results: From September 2000 to May 2009, a total of 40 patients were eligible for TSH, and 88 % completed both resections. Of the 35 resected patients, the median number of tumors was 8, with 38 % having a tumor >5 cm and 35 % having a carcinoembryonic antigen value >200 ng/ml. All patients received systemic chemotherapy, and 86 % received regional therapy with hepatic artery infusion. Median follow-up for survivors was 40 months; median disease-specific survival was 52 months, and 5-year disease-specific survival was 49 %. The combined rate of major complication for all procedures was 45 % with no operative deaths. Median recurrence-free survival was 11 months with a 3-year probability of recurrence of 81 %. Disease recurrence occurred in 27 patients (77 %), with the liver (42 %) and lung (37 %) being the most common sites. Sixteen of these patients (60 %) underwent salvage therapy via either surgery and/or ablation, 7 (44 %) of whom were free of disease at a median follow-up of 54 months., Conclusions: TSH combined with systemic and hepatic artery infusion chemotherapy is an effective treatment strategy for selected patients with advanced CRLM. These patients are at considerable risk of local and distant recurrence; however, the majority can be salvaged, and long-term survival can be achieved.

Purpose: Systemic bevacizumab (Bev) was added to hepatic arterial infusion (HAI) floxuridine (FUDR)-based chemotherapy in three studies in an attempt to improve outcomes. A specific review of biliary toxicity was carried out., Methods: This analysis included 203 patients from three prospective studies. The first (study A) was an adjuvant study after liver resection of colorectal metastases in which patients received HAI and systemic chemotherapy (Sys) with or without Bev. Study B comprised unresectable colorectal patients who received HAI and Sys plus Bev. Study C included patients with unresectable cholangiocarcinoma or hepatocellular carcinoma who received HAI plus systematic Bev. The outcome and toxicity of patients in studies B and C were compared with historical controls., Results: In all three studies, the incidence of hyperbilirubinemia and biliary stent placement within 1 year of treatment was increased with the addition of Bev. In the no-Bev versus Bev groups, the placement of biliary stents was as follows: study A, 0 of 38 versus 4 of 35 patients (p = 0.05); study B, 0 of 49 versus 3 of 24 (p = 0.06); and study C, 0 of 34 versus 3 of 22 (p = 0.15). Elevation in bilirubin was noted in the no-Bev versus Bev groups: study A, 0 of 38 versus 5 of 35 patients (p = 0.02); study B, 1 of 49 versus 7 of 24 (p = 0.005); and study C, 2 of 34 versus 5 of 22 (p = 0.10). The addition of Bev did not seem to be associated with improved progression-free or overall survival., Conclusions: The addition of Bev to HAI FUDR resulted in increased biliary toxicity in three separate studies. Although the sample sizes were small, there was no evidence of improved PFS or OS with the addition of Bev. Bev should not be combined with HAI FUDR.

Background: When feasible, surgical treatment of colorectal liver metastases (CRLM) is the treatment of choice. Regional hepatic artery infusional (HAI) chemotherapy effectively treats CRLM. The combination of HAI and systemic chemotherapy may downsize tumors and allow for complete resection and/or ablation (R/A). This study analyzes the combination of HAI and systemic chemotherapy for treating unresectable CRLM, focusing on conversion to complete R/A., Methods: All patients with unresectable CRLM treated with HAI and systemic chemotherapy from 2000 to 2009 were included. Patients who responded sufficiently to undergo complete R/A were compared to those who did not convert. Survival was compared using a landmark analysis to account for bias., Results: A total of 373 patients were included; 93 patients (25%) subsequently underwent complete R/A. The percentage of patients submitted to complete R/A increased from 16% during 2000-2003 to 30% during 2004-2009. Factors associated with conversion on multivariate analysis were more recent treatment (2004-2009), no prior chemotherapy, clinical risk score<3, treatment on clinical protocol, and younger age. Median and predicted 5-year survival from the time of HAI pump placement was 59 months and 47%, respectively, in the patients who converted to complete R/A, compared with 16 months and 6%, respectively in those who did not (p<0.001)., Conclusions: Despite extensive disease, 25% of patients with unresectable CRLM responded sufficiently to undergo complete R/A following HAI plus systemic chemotherapy. Combination HAI and systemic chemotherapy is an effective strategy to convert patients to complete resection with an associated excellent long-term survival.

Background: Perioperative outcomes, such as blood loss, transfusions, and morbidity, have been linked to cancer-specific survival, but this is largely unsupported by prospective data., Methods: Patients from a previous, randomized trial that evaluated acute normovolemic hemodilution during major hepatectomy (≥3 segments) were reevaluated and those with metastatic colorectal cancer (n = 90) were selected for analysis. Survival data were obtained from the medical record. Disease extent was measured using a clinical-risk score (CRS). Log-rank test and Cox proportional hazard model were used to evaluate recurrence-free survival (RFS) and overall survival (OS)., Results: Median follow-up was 71 months. The CRS was ≥3 in 45 % of patients; 59 % had extrahepatic procedures. Morbidity and mortality were 33 and 2 %, respectively. Postoperative chemotherapy was given to 87 % of patients (78/90) starting at a median of 6 weeks. RFS and OS were 29 and 60 months, respectively. Postoperative morbidity significantly reduced RFS (23 vs. 69 months; P < 0.001) and OS (28 vs. 74 months; P < 0.001) on uni- and multi-variate analysis; positive resection margins and high CRS also were significant factors. Delayed initiation of postoperative chemotherapy (≥8 weeks) was common in patients with complications (37 vs. 12 %; P = 0.01)., Conclusions: In this selected cohort of patients from a previous RCT, perioperative morbidity was strongly (and independently) associated with cancer-specific outcome. It also was associated with delayed initiation of postoperative chemotherapy, the impact of which on survival is unclear.

Purpose: To assess the predictive value of examinations of tissue adherent to multitined electrodes on local tumor progression-free survival (LPFS) and overall survival (OS) after liver tumor radiofrequency ablation (RFA)., Methods: An institutional review board-approved, Health Insurance Portability and Accountability Act-compliant review identified 68 liver tumors treated with RFA in 63 patients with at least 3 years' follow-up. Tissue adherent to the electrode after liver tumor RFA was evaluated with proliferation (Ki-67) and apoptotic (caspase-3) markers. LPFS and OS were evaluated by Kaplan-Meier methodology and the log-rank test. Multivariate analysis assessed the effect of tumor size, pathology, and post-RFA tissue characteristics on LPFS and OS., Results: Post-RFA tissue examination classified 55 of the 68 tumors as completely ablated with coagulation necrosis, with cells positive for caspase-3 and negative for Ki-67 (CN). Thirteen had viable Ki-67-positive tumor cells. Mean liver tumor size was larger in the viable (V) group versus the CN group (3.4 vs. 2.5 cm, respectively; P = .017). For the V and CN groups, respectively, local tumor progression occurred in 12 (92 %) of 13 and 23 (42 %) of 55 specimens. One, 3-, and 5-year LPFS was 8 %, 8 %, and 8 %, and 79 %, 47 %, and 47 % (P < .001) for the V and CN groups, respectively. During a 63-month median follow-up, 92 % of patients in the V group and 58 % in the CN group died, resulting in 1-, 3-, and 5-year OS of 92 %, 25 %, and 8 % vs. 92 %, 59 %, and 33 % (P = .032), respectively., Conclusions: Ki-67-positive tumor cells on the electrode after liver tumor RFA is an independent predictor of LPFS and OS. Size, initially thought to be an independent risk factor for local tumor progression in tumors 3-5 cm, does not hold its significance at long follow-up.

Background: Pathologic response to preoperative chemotherapy for colorectal liver metastases (CLM) is associated with survival after hepatectomy. Histologically, dominant response patterns include fibrosis, necrosis and/or acellular mucin, but some of these changes can appear without previous chemotherapy and their individual correlation with outcome is unknown., Methods: Pathology slides from patients who underwent CLM resection (irrespective of preoperative chemotherapy status) were rereviewed by a blinded pathologist. Pathologic response was recorded as the summation of percentage necrosis, fibrosis and acellular mucin. Associations between pathologic response, its components, preoperative chemotherapy, and survival were analyzed., Results: Pathology slides were rereviewed in 366 patients undergoing CLM resection from 2003 to 2007. Preoperative chemotherapy was administered in 249 (68 %) patients, who, when compared to no preoperative chemotherapy patients, had higher rates of overall pathologic response (57 vs. 46 %, P < .01), fibrosis (21 vs. 12 %, P < .01) and acellular mucin (6 vs. 3 %, P = .05) but similar rates of necrosis (30 vs. 31 %, P = .30). In patients receiving preoperative chemotherapy, overall pathologic response ≥ 75 % (5 year, 83 vs. 47 %, P < .01) and fibrosis ≥ 40 % (5 year, 87 vs. 51 %, P < .01) independently correlated with disease-specific survival after hepatectomy. Preoperative hepatic artery infusion chemotherapy (P = .04) and bevacizumab (P = .05) were marginally associated with overall pathologic response and fibrosis, respectively., Conclusions: Fibrosis is the predominant chemotherapy-related pathologic alteration driving the association of treatment response with survival after CLM resection. Necrosis in CLM is not related to chemotherapy or outcome.

Background: Hepatic arterial infusion pump chemotherapy (HAIPC) contributes to the prolonged survival of selected patients with colorectal cancer liver metastases (CRCLM). The most clinically important adverse event after HAIPC with floxuridine (FUDR) is biliary sclerosis (BS). Little is known about the etiology of BS., Methods: HAIPC was administered to 475 consecutive patients who received HAIPC on prospective protocols from 1991 to 2008. The incidence, clinical features, variables related to demographics, comorbidity, medical history, CRCLM, surgery, chemotherapy, and laboratory data were reviewed. An analysis of factors potentially associated with BS, defined as a biliary stricture related to HAIPC requiring stent placement, was performed., Results: The incidence of BS was 5.5% (16 of 293) in patients receiving HAIPC as an adjuvant therapy after hepatectomy, and 2% (2 of 100) in patients receiving HAIPC with FUDR for unresectable disease. The common hepatic duct was the site most frequently affected (87.5%). In patients receiving adjuvant HAIPC, BS was associated with abnormal postoperative flow scans (18.8% vs. 1.8%, P = 0.006), postoperative infectious complications (50.0% vs. 14.8%, P = 0.002), and larger dose/cycle/weight of FUDR (2.6 vs. 2.0 mg/cycle/kg, P = 0.025) than patients without BS. No patient died directly of BS. Median survival was not compromised by the development of BS (BS vs. non-BS: 61.0 months [range 6.2-171.6 months] vs. 47.2 months [range 2.4-200.8 months], P = 0.316, respectively)., Conclusions: BS is an uncommon complication after HAIPC and does not compromise survival if adequately salvaged by stenting or dilatation. Surgical complications as well as type and dose of intra-arterial chemotherapy may contribute to the development of BS.

A 72-year-old man was diagnosed with a poorly differentiated hepatic flexure mass seen on routine screening colonoscopy. He underwent a right hemicolectomy and biopsy of a liver lesion noted at laparotomy. Pathology revealed a high-grade neuroendocrine carcinoma in the primary tumor and the liver lesion. Post-operative imaging revealed an isolated FDG avid liver metastases which had not been appreciated pre-operatively. He was treated with combination platinum and etoposide for extensive stage small-cell carcinoma of the colon. After 6 cycles of chemotherapy, the isolated liver lesion remained FDG avid, albeit less than baseline. Radiofrequency ablation of the avid liver lesion was performed. Further, chemotherapy was given as the lesion remained FDG avid. Ablation was repeated and a subsequent biopsy was positive. Chemotherapy resumed for a total of 10 cycles. Repeat PET scan became negative and the patient remains disease-free 7 years from an initial diagnosis of extensive stage small-cell colon cancer with a negative PET scan. Aggressive locoregional treatment is an option in patients with extensive stage small-cell carcinoma of the colon who are left with an oligometastasis after platinum-based systemic chemotherapy.

The use of targeted/biologic therapies is now commonplace in the treatment of malignant and non-malignant diseases. The novel mode of action of these drugs has resulted in unpredictable and in some cases unexpected side effects. Given the widespread use of bevacizumab and its distinct mode of action, it is important that oncologists report any unexpected adverse events that may be associated with the drug. Herein, we report three cases of spontaneous nasal septum perforation secondary to bevacizumab. We hypothesize an etiology for this rare event and reasons why it is reasonable to rechallenge the patient.

There are two highly selective antibodies to the epidermal growth factor receptor (EGFR) now available for use in metastatic colorectal cancer (mCRC). In KRAS wild type patients, cetuximab (Cmab)-an IgG1 chimeric molecule--has activity alone and in combination with chemotherapy for the first, second and third-line settings. Panitumumab (Pmab)--a fully humanized IgG2 molecule--has activity as a single agent in chemorefractory mCRC and shows promising activity in combination with chemotherapy. It remains unclear which antibody to use. This retrospective review of our experience with Pmab in 13 EGFR antibody-naive patients and in 22 patients previously treated with Cmab for mCRC highlights a lack of hypersensitivity reactions (HSR) with Pmab, even in patients who experienced HSR to Cmab. In patients who received Cmab, 22% developed grade 3-4 HSR. There were no HSR on subsequent treatment with Pmab. We demonstrate similar activity in 95% of cases, between Cmab and Pmab both alone and in combination with chemotherapy in the treatment of mCRC. In one case we report unique sensitivity to Pmab after progression with Cmab.

Background: The optimal use of radical surgery to palliate primary rectal cancers presenting with synchronous distant metastases is poorly defined. We have reviewed stage IV rectal cancer patients to evaluate the effectiveness of radical surgery without radiation as local therapy., Methods: Eighty stage IV patients with resectable primary rectal tumors treated with radical rectal surgery without radiotherapy were identified. Sixty-one (76%) patients received chemotherapy; response information was available for 34 patients., Results: Radical resection was accomplished by low anterior resection (n = 65), abdominoperineal resection (n = 11), and Hartmann's resection (n = 4). Surgical complications were seen in 12 patients (15%), with 1 death and 4 reoperations. The local recurrence rate was 6% (n = 5), with a median time to local recurrence of 14 months. Only one patient received pelvic radiotherapy as salvage treatment. One patient required subsequent diverting colostomy. Median survival was 25 months. On multivariate analysis, the extent of metastasis and response to chemotherapy were determinants of prolonged survival., Conclusions: For patients who present with distant metastases and resectable primary rectal cancers, radical surgery without radiotherapy can provide durable local control with acceptable morbidity. The extent of metastatic disease and the response to chemotherapy are the major determinants of survival. Effective systemic chemotherapy should be given high priority in the treatment of stage IV rectal cancer.

Background: Aggressive treatment of peritoneal metastases from colon cancer by surgical cytoreduction and infusional intraperitoneal (IP) chemotherapy may benefit selected patients. We reviewed our institutional experience to assess patient selection, complications, and outcome., Methods: Patients having surgical debulking and IP 5-fluoro-2'-deoxyuridine (FUDR) plus leucovorin (LV) for peritoneal metastases from 1987 to 1999 were evaluated retrospectively., Results: There were 64 patients with a mean age of 50 years. Primary tumor sites were 47 in the colon and 17 in the appendix. Peritoneal metastases were synchronous in 48 patients and metachronous in 16 patients. Patients received IP FUDR (1000 mg/m2 daily for 3 days) and IP leucovorin (240 mg/m2) with a median cycle number of 4 (range, 1-28). The median number of complications was 1 (range, 0-5), with no treatment related mortality. Only six patients (9%) required termination of IP chemotherapy because of complications. The median follow-up was 17 months (range, 0-132 months). The median survival was 34 months (range, 2-132); 5-year survival was 28%. Lymph node status, tumor grade, and interval to peritoneal metastasis were not statistically significant prognostic factors for survival. Complete tumor resection was significant on multivariate analysis (P = .04), with a 5-year survival of 54% for complete (n = 19) and 16% for incomplete (n = 45) resection., Conclusions: Surgical debulking and IP FUDR for peritoneal metastases from colon cancer can be accomplished safely and has yielded an overall 5-year survival of 28%. Complete resection is associated with improved survival (54% at 5 years) and is the most important prognostic indicator.

Background: Hepatic resection is the standard treatment for hepatic colorectal metastases. The lung represents the next most likely site, after the liver, of metastatic disease. Computed tomography (CT) of the chest is more sensitive than is chest x-ray in detecting metastatic lung lesions. However, the usefulness of chest CT in the evaluation of patients before hepatic resection remains uncertain., Methods: One hundred consecutive patients with negative chest x-rays and potentially resectable hepatic colorectal metastases underwent chest CT. Patients with CT findings suggestive of metastatic disease were subjected to thoracotomy or video-assisted thoracic surgery (VATS) before laparotomy and attempted hepatic resection. The operative findings and clinical course were analyzed., Results: Eleven of 100 patients had a positive chest CT. Four of these 11 patients had malignant lesions of the lung (three metastatic colorectal cancers and one primary lung cancer). There was no difference in median total hospital stay (8.5 days [range 7 to 13 days] vs. 8.0 days [range 3 to 49 days]), number of perioperative deaths (0 vs. 2 deaths), or long-term outcome between those patients with a positive chest CT undergoing thoracotomy/VATS and those patients with a negative chest CT. Overall, chest CT provided a positive yield of 4% and a positive predictive value of 36% for the detection of malignant lesions of the lung., Conclusions: Chest CT only minimally improved detection of malignant lesions of the lung over chest x-ray. Thoracotomy/VATS and wedge resection of lung nodules did not adversely affect outcome. The low positive yield and low positive predictive value of chest CT in the setting of a negative chest x-ray places in question the usefulness of routinely performing chest CT as part of the extent-of-disease work-up before hepatic resection.