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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., Competing Interests: Dr. Kemeny received research support for this trial from Amgen. The authors declare no other conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: This study investigated the effect of the reduced dose of systemic chemotherapy (SYS) on recurrence patterns in patients receiving adjuvant hepatic artery infusion (HAI) chemotherapy after complete colorectal liver metastases (CRLM) resection., Methods: Patients undergoing complete CRLM resection between 2000 and 2007 were selected from a prospectively maintained database and categorized as receiving SYS or HAI + SYS. Those with pre and/or intraoperative extrahepatic disease, documented death, or recurrence within 30 days of CRLM resection were excluded. Competing risk, Fine and Gray's tests were used to compare SYS versus HAI + SYS for time-to-organ recurrence., Results: Of 361 study patients, 153 (42.4%) received SYS and 208 (57.6%) received HAI + SYS. The median follow-up for survivors was 100 (range = 12-185) and 156 months (range = 18-217) for SYS and HAI + SYS, respectively. The 5-year cumulative incidence (CI) of any liver recurrence was greater for those receiving SYS (SYS = 41.9% vs. HAI + SYS = 28.6%, p = .005). The 5-year CI of developing any lung or extrahepatic recurrence for SYS patients was 36.2% and 47.9% compared with 44.5% (p = .242) and 51.7% (p = .551), respectively, in patients receiving HAI + SYS., Conclusion: Despite the reduced dose of SYS, adjuvant HAI + SYS after CRLM resection is not associated with a significantly increased risk of extrahepatic recurrence., (© 2020 Wiley Periodicals LLC.)

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.

Purpose: SMAD4 has shown promise in identifying patients with colorectal cancer at high risk of recurrence or death. Experimental Design: A discovery cohort and independent validation cohort were classified by SMAD4 status. SMAD4 status and immune infiltrate measurements were tested for association with recurrence-free survival (RFS). Patient-derived xenografts from SMAD4-deficient and SMAD4-retained tumors were used to examine chemoresistance., Results: The discovery cohort consisted of 364 patients with stage I-IV colorectal cancer. Median age at diagnosis was 53 years. The cohort consisted of 61% left-sided tumors and 62% stage II/III patients. Median follow-up was 5.4 years (interquartile range, 2.3-8.2). SMAD4 loss, noted in 13% of tumors, was associated with higher tumor and nodal stage, adjuvant therapy use, fewer tumor-infiltrating lymphocytes (TIL), and lower peritumoral lymphocyte aggregate (PLA) scores (all P < 0.04). SMAD4 loss was associated with worse RFS ( P = 0.02). When stratified by SMAD4 and immune infiltrate status, patients with SMAD4 loss and low TIL or PLA had worse RFS ( P = 0.002 and P = 0.006, respectively). Among patients receiving 5-fluorouracil (5-FU)-based systemic chemotherapy, those with SMAD4 loss had a median RFS of 3.8 years compared with 13 years for patients with SMAD4 retained. In xenografted mice, the SMAD4-lost tumors displayed resistance to 5-FU. An independent cohort replicated our findings, in particular, the association of SMAD4 loss with decreased immune infiltrate, as well as worse disease-specific survival., Conclusions: Our data show SMAD4 loss correlates with worse clinical outcome, resistance to chemotherapy, and decreased immune infiltrate, supporting its use as a prognostic marker in patients with colorectal cancer., (©2018 American Association for Cancer Research.)

Background/objectives: Combination hepatic artery infusion (HAI) and systemic (SYS) chemotherapy for unresectable CRLM results in high tumor-response rates. This study represents an update of long-term survival and conversion to resectability in patients with unresectable CRLM treated with HAI and SYS chemotherapy in a phase II study., Method: The primary endpoint was complete resection. Multivariate and landmark analysis assessed the effect of complete resection on progression-free (PFS) and overall survival (OS)., Results: From 2007 to 2012, 64 patients with median of 13 tumors were enrolled; 67% had prior chemotherapy. 33 patients (52%) were converted to resection. Median follow-up among survivors was 81 months. Median PFS and OS were 13 and 38 months, respectively, with 5-year-OS of 36%. Chemotherapy-naïve patients had 5-year-OS of 51%. Conversion to resection was the only independent factor prognostic of improved PFS and OS. Nine of 64 patients (14%) are NED (five since initial resection, three after resection of recurrent disease, one from chemotherapy alone) at median follow-up of 86 months from treatment initiation, and 72 months from last operative intervention., Conclusion: Combination HAI and SYS is an effective therapy for high-volume unresectable CRLM, resulting in a high rate of resection, long-term survival, and the potential for cure., (© 2017 Wiley Periodicals, Inc.)

Background and Objectives: To evaluate the role of hepatic arterial infusion (HAI) in patients with metastatic colorectal cancer (mCRC) liver metastases (LM) refractory to oxaliplatin, irinotecan, and fluorouracil-based treatments., Methods: A search identified patients with mCRC treated after tumor progression on at least three standard systemic therapies., Results: One hundred and ten patients met criteria for inclusion (i.e., progression on at least three standard agents). Fifty seven patients had LM-only and 53 patients had LM and low volume extrahepatic metastases (LME). Patients with LM-only and LME had a response rate (RR) of 33% and 36%, median survival of 20 months and 11.4 months, respectively. Patients with LM-only had progression free survival of 6 months and hepatic progression free survival of 7.56 months. In a secondary analysis, 46 patients were RECIST-refractory to all standard therapies: LM-only (n = 24) and LME (n = 22). LM-only and LME had a RR of 29% and 36%, and median survival 17.2 months and 9.1 months, respectively., Conclusions: Patients with refractory mCRC LM can achieve a response to HAI resulting in antitumor activity and improvement in survival. Responses are rarely seen in such heavily treated patients with systemic therapy alone, suggesting a regional directed approach is useful. J. Surg. Oncol. 2016;114:655-663. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Purpose: Oxaliplatin at a dose of 85 mg/m(2) traditionally has been administered over 120 min in the standard FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin) regimen. CapeOx (capecitabine plus oxaliplatin), in which the dose of oxaliplatin is 130 mg/m(2), has also been infused over 120 min. Maintenance of a prolonged infusion time has been largely based on the concern for a potential hypersensitivity reaction (HSR) if administered too quickly., Methods: We first performed a retrospective review of our institutional experience to assess whether HSR rates were similar in FOLFOX and CapeOx by using computerized pharmacy records between January 1, 2011, and December 31, 2013. We then instituted a new policy to infuse all nonresearch doses of oxaliplatin at a set rate of 1 mg/m(2)/min (85 mg/m(2) given over 85 min; 68 mg/m(2) over 68 min, etc). The incidence of HSRs with the new infusion rate was actively monitored., Results: Of 2,097 patients who previously received oxaliplatin over 120 min, 1,936 received a dose of 85 mg/m(2) (± 10%), and 161 received a dose of 130 mg/m(2). The incidence of HSRs in the 85 mg/m(2) group was 11% versus 7% in the 130 mg/m(2) group (P = .13). Then between December 1, 2014, and June 4, 2015, 667 patients received oxaliplatin at a rate of 1 mg/m(2)/min for all doses. The incidence of HSRs in patients treated at this fixed infusion rate was 8%., Conclusion: Infusing oxaliplatin at a rate of 1 mg/m(2)/min does not increase the rate of HSRs and does not compromise patient safety. This infusion rate is safe for use in routine practice., (Copyright © 2016 by American Society of Clinical Oncology.)

Background and Objectives: Patients who undergo liver resection for metastatic colorectal cancer (mCRC) have reported 5-year survivals ranging from 25% to 50%. The current study updated long-term survival for patients with resected liver metastases treated with adjuvant hepatic arterial infusion (HAI) and systemic (SYS) chemotherapy., Methods: Updated survival and recurrence free survival for patients treated on four consecutive adjuvant protocols with HAI and SYS from 1991 to 2009. Patients were divided into two groups: those treated on protocols before 2003 and after 2003. Median follow-up for all patients was 11 years., Results: All 287 patients enrolled in four prospective protocols after liver resection are included. Patients treated before 2003 had a median follow-up of 15 years, 5 and 10-year survivals of 56% [95%CI: 49-64%] and 40% [95%CI: 32-47%], respectively, and median survival of 71 months. Patients treated after 2003 had a median follow-up of 9 years, 5 and 10-year survivals of 78% [95%CI: 70-84%] and 61% [95%CI: 51-70%], respectively, and median survival has not been reached., Conclusions: Survival is improving for patients with mCRC who undergo liver resection. These data support the durability of long-term survival in patients who undergo resection followed by adjuvant HAI and SYS therapy. J. Surg. Oncol. 2016;113:477-484. © 2016 Wiley Periodicals, Inc., Competing Interests: The authors disclose no conflict of interest, (© 2016 Wiley Periodicals, Inc.)

Background: Intrahepatic cholangiocarcinoma (ICC) is associated with poor survival. This study compared the outcomes of patients with unresectable ICC treated with hepatic arterial infusion (HAI) plus systemic chemotherapy (SYS) with the outcomes of patients treated with SYS alone., Methods: Consecutive patients with ICC were retrospectively reviewed. Clinicopathologic data were reviewed. Survival rates were compared by Kaplan-Meier analysis and log-rank testing., Results: Between January 2000 and August 2012, 525 patients with ICC were evaluated at Memorial Sloan Kettering Cancer Center, and 236 patients with unresectable tumors (locally advanced or metastatic) were analyzed. Disease was confined to the liver in 104 patients, who underwent treatment with combined HAI and SYS (n = 78 or 75%) or SYS alone (n = 26 or 25%). The response rate in the combined group was better than the rate in the group receiving SYS alone, although this did not reach statistical significance (59% vs 39%, P = .11). Overall survival for the combined group was longer than overall survival for the patients who received SYS alone (30.8 vs 18.4 months, P < .001), and this difference was maintained when patients with portal lymph node disease were included in the survival analysis (29.6 months with HAI and SYS [n = 93] vs 15.9 months with SYS [n = 74], P < .001). Eight patients who initially presented with unresectable tumors responded enough to undergo complete resection and had a median overall survival of 37 months (range, 10.4-92.3 months)., Conclusions: In patients with unresectable ICC confined to the liver or with limited regional nodal disease, a combination of SYS and HAI chemotherapy is associated with greater survival than SYS alone. Cancer 2016;122:758-765. © 2015 American Cancer Society., (© 2015 American Cancer Society.)

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.

Acinar cell carcinoma of the pancreas is an uncommon malignancy for which there are no prospective, randomized data to guide therapy. We describe the clinical course and management of a patient with advanced pancreatic acinar cell carcinoma who is alive seven years after diagnosis using systemic and regional chemotherapies as well as molecularly targeted agents.

Hepatic steatosis is a hallmark of chemotherapy-induced liver injury. We made serial (1) H MRS measurements of hepatic lipids in patients over the time course of a 24-week chemotherapeutic regimen to determine whether (1) H MRS could be used to monitor the progression of chemotherapy-induced steatosis. Thirty-four patients with stage III or IV colorectal cancer receiving 5-fluorouracil, folinic acid and oxaliplatin (n=21) or hepatic arterial infusion of floxuridine with systemic irinotecan (n=13) were studied prospectively. (1) H MRS studies were performed at baseline and after 6 and 24 weeks of treatment. A (1) H MR spectrum was acquired from the liver during a breath hold and the ratio of fat to fat+water (FFW) was calculated to give a measure of hepatic triglycerides (HTGCs). The methodology was histologically validated in 18 patients and the reproducibility was assessed in 16 normal volunteers. Twenty-seven patients completed baseline, 6-week and 24-week (1) H MRS examinations and one was censored. Thirteen of 26 patients (50%) showed an increase in FFW after completion of treatment. Six patients (23%) developed hepatic steatosis and two patients converted from steatosis to nonsteatotic liver. Patients whose 6-week hepatic lipid levels had increased significantly relative to baseline also had a high probability of lipid elevation relative to baseline at the completion of treatment. Serial (1) H MRS is effective for the monitoring of HTGC changes during chemotherapy and for the detection of chemotherapy-associated steatosis. Six of 26 patients developed steatosis during chemotherapy. Lipid changes were observable at 6 weeks., (Copyright © 2012 John Wiley & Sons, Ltd.)

Background and Objectives: Hepatic arterial infusional (HAI) chemotherapy combined with systemic chemotherapy is effective palliative therapy for unresectable colorectal cancer liver metastases (CRLM). Some patients considered for HAI have evidence of minimal extrahepatic disease (EHD), and the role of HAI in these situations is unknown., Methods: All patients with unresectable CRLM treated with HAI and systemic chemotherapy from 2000 to 2009 were included. Survival of patients who were ultimately proven to have low-volume EHD was compared to those without EHD., Results: Three hundred seventy-three patients were included in this study. Seventy-nine percent of patients were previously treated with chemotherapy. One hundred forty-five patients (39%) ultimately proved to have EHD. Median overall survival from HAI pump placement in patients without EHD was 32 months compared to 16 months for patients with EHD, P < 0.001. Median overall survival from HAI pump placement in patients with a single site of EHD was 18 months compared to 9 months for those with multiple sites of EHD, P = 0.01., Conclusions: In this study of heavily pre-treated patients, overall survival was favorable in patients who proved to have EHD at one site., (Copyright © 2012 Wiley Periodicals, Inc.)

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: The potential benefit of adjuvant hepatic arterial infusional floxuridine (HAI-FUDR) in addition to modern systemic chemotherapy using oxaliplatin or irinotecan remains unknown for patients with resected liver-confined colorectal metastases (CRLM). The principle aim of this study was to compare outcomes in patients receiving modern systemic chemotherapy with or without HAI-FUDR., Methods: Between 2000 and 2005, 125 patients underwent resection of CRLM followed by adjuvant HAI-FUDR plus dexamethasone (Dex) and concurrent systemic chemotherapy including oxaliplatin or irinotecan. These patients were compared retrospectively to 125 consecutive patients who received modern systemic chemotherapy alone after liver resection., Results: The median follow-up for all patients was 43 months. There were no differences in clinical risk score, disease-free interval, size of largest CRLM, number of CRLM, or prehepatectomy CEA level between the 2 groups. Adjuvant HAI-FUDR was associated with an improved overall and liver recurrence-free survival (liver RFS) and disease-specific survival (DSS). For the adjuvant HAI-FUDR group, the 5-year liver RFS, overall RFS, and DSS were 75%, 48%, and 79%, respectively, compared to 55%, 25%, and 55% for the systemic alone group (P < 0.01). On multivariate analysis, adjuvant treatment including HAI-FUDR was independently associated with improved liver RFS (HR = 0.34), overall RFS (HR = 0.65), and DSS (HR = 0.39), P < 0.01., Conclusions: Adjuvant HAI-FUDR combined with modern systemic chemotherapy is independently associated with improved survival compared to adjuvant systemic chemotherapy alone. A randomized clinical trial between these 2 regimens is justified.

Resection of colorectal liver metastases (CLM) is the ultimate aim of treatment strategies in most patients with liver-confined metastatic colorectal cancer. Long-term survival is possible in selected patients with initially resectable or unresectable CLM. As a majority of patients have unresectable liver disease at the outset, there is a clear role for chemotherapy to downstage liver disease making resection possible. Studies of systemic chemotherapy with or without biologic therapy in patients with unresectable CLM have resulted in increased response rates, liver resection rates and survival. A sound physiologic rationale exists for the use of hepatic arterial infusion (HAI) therapy. Studies have shown that HAI with floxuridine combined with systemic chemotherapy increases response rates and liver resection rates in those patients with initially unresectable CLM. Toxicity from preoperative chemotherapy, biologic therapy and HAI therapy may adversely affect hepatic resection but can be kept minimal with appropriate monitoring. All conversion strategies should be decided by a multidisciplinary team., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Add systemic bevacizumab (Bev) to adjuvant hepatic arterial infusion (HAI) plus systemic therapy after liver resection to increase recurrence-free survival (RFS)., Patients and Methods: Patients were randomly assigned to HAI plus systemic therapy with or without Bev. If 1-year RFS of ≥ 80% was obtained in Bev arm, then the regimen would be studied further. HAI with fluorodeoxyuridine plus dexamethasone was given on days 1 to 14 of a 5-week cycle. Systemic therapy and Bev 5 mg/kg was delivered on days 15 and 29: oxaliplatin 85 mg/m², leucovorin 400 mg/m², and fluorouracil 2,000 mg/m² infusion for 2 days (if patients received prior oxaliplatin, then irinotecan 150 mg/m² was used). RFS and survival were estimated by using the Kaplan-Meier method and compared by using the log-rank test., Results: The two arms had similar characteristics: synchronous disease (66% v 63%), more than one metastasis (84% v 74%), and clinical risk score ≥ 3 (50% v 46%) for no Bev versus Bev arms, respectively. With a median follow-up of 30 months, 4-year survival was 85% and 81% (P = .5), and 4-year RFS was 46% versus 37%; 1-year RFS was 83% and 71% (P = .4) for no Bev versus Bev arms. Bilirubin > 3 mg/dL was seen in zero of 38 versus five of 35 patients (P = .02) and biliary stents were placed in zero versus four patients (P = .05) in no Bev versus Bev arms., Conclusion: The addition of Bev to adjuvant HAI plus systemic therapy after liver resection did not seem to increase RFS or survival but appeared to increase biliary toxicity. Four-year survival was 85% and 81% for no Bev and Bev arms, respectively.

Objectives: This study investigated the efficacy and safety of adding systemic (IV) bevacizumab (Bev) to hepatic arterial infusion (HAI) with floxuridine (FUDR)/dexamethasone (Dex) in unresectable primary liver cancer., Methods: Patients with unresectable intrahepatic cholangiocarcinoma (ICC) or hepatocellular carcinoma (HCC) were treated with HAI FUDR/Dex plus IV Bev. Results were compared to a recent study of HAI without Bev in a similar patient population., Results: Twenty-two patients (18 ICC, 4 HCC) were treated with HAI FUDR/Dex plus Bev; 7 (31.8%) had partial response and 15 (68.2%) had stable disease. Median survival was 31.1 months (CI 14.14-33.59), progression-free survival (PFS) 8.45 months (CI 5.53-11.05), and hepatic PFS 11.3 months (CI 7.93-15.69). In the previous trial with HAI alone (no Bev), the response was 50%; median survival, PFS, and hepatic PFS were 29.5, 7.3, and 10.1 months. In the present trial, bilirubin elevation (>2 mg/dl) was seen in 24% of patients and biliary stents were placed in 13.6%, versus 5.8 and 0%, respectively, in the HAI trial without Bev. Due to increased biliary toxicity, the trial was prematurely terminated., Conclusion: Adding Bev to HAI FUDR/Dex appeared to increase biliary toxicity without clear improvement in outcome (median PFS 8.45 vs. 7.3 months, and median survival 31.1 vs. 29.5 months, for HAI + Bev vs. HAI alone groups, respectively)., (Copyright © 2011 S. Karger AG, Basel.)

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.

Liver resection is the goal of treatment strategies for liver-confined metastatic colorectal cancer. However, after resection the majority of patients will experience recurrence. Chemotherapy seems to improve outcomes compared with surgery alone. We reviewed the data of the role of adjuvant chemotherapy after resection of liver- confined metastatic colorectal cancer. Optimal regimens and sequencing of chemotherapies when liver resection is an option are unclear. Some suggest that resectable liver metastases, in the absence of high-risk features, should begin with surgery and consideration given to adjuvant chemotherapy after surgery. If high-risk features are present, most physicians prefer a short course of systemic preoperative chemotherapy. Perioperative therapy and regional therapy with hepatic arterial infusion (HAI) both increase disease-free survival (DFS) when compared with surgery alone. In unresectable disease, consideration should be given to systemic chemotherapy with or without a biologic agent or HAI with systemic therapy. If the disease becomes resectable, adjuvant treatment should follow surgery. Adjuvant chemotherapy is usually FOLFOX, but HAI combined with systemic chemotherapy is also an option. The role of adjuvant treatment post-liver resection should not be viewed in isolation but rather in the context of prior treatment, surgical preference, and individual patient characteristics. Perioperative therapy and regional therapy have both shown an increase in DFS. Conducting randomized trials examining the role of adjuvant chemotherapy has been difficult because of rapidly changing chemotherapies.

Background: During chemotherapy, some colorectal liver metastases (LMs) disappear on serial imaging. This disappearance may represent a complete response (CR) or a reduction in the sensitivity of imaging during chemotherapy. The objective of the current study was to determine the fate of disappearing LMs (DLMs) and the factors that predict a true CR., Methods: Between 2000 and 2003, 435 patients who were evaluated by hepatobiliary surgeons received chemotherapy before they were considered for resection. Inclusion criteria were <12 LMs before chemotherapy, at least 1 DLM on a computed tomography (CT) scan, and either surgical resection or 1 year of clinical follow-up after the disappearance of LMs. A true CR was defined as either a pathologic CR (no tumor detected in the resection specimen) or a durable clinical CR (did not reappear on follow-up imaging). Clinical and pathologic factors were analyzed to identify those associated with a true CR., Results: During chemotherapy, 39 patients (9%) had a total of 118 DLMs on follow-up CT scans. Sixty-eight DLMs were resected, and 50 were followed clinically. Overall, 75 DLMs (64%) were true CRs, including 44 pathologic CRs and 31 durable clinical CRs. On multivariate analysis, the use of hepatic arterial infusion (HAI) chemotherapy (odds ratio [OR], 6.2; P = .02), the inability to observe the DLM on a magnetic resonance image (OR, 4.7; P = .005), and normalization of serum carcinoembryonic antigen levels (OR, 4.6; P = .006) were associated independently with a true CR., Conclusions: Approximately 66% of DLMs represented a true CR according to assessment by resection or radiologic follow-up. Predictive factors may help to stratify patients who are likely to harbor residual disease.

Purpose: The purpose of this study was to describe the frequency of interventions necessary to palliate the intact primary tumor in patients who present with synchronous, stage IV colorectal cancer (CRC) and who receive up-front modern combination chemotherapy without prophylactic surgery., Patients and Methods: By using a prospective institutional database, we identified 233 consecutive patients from 2000 through 2006 with synchronous metastatic CRC and an unresected primary tumor who received oxaliplatin- or irinotecan-based, triple-drug chemotherapy (infusional fluorouracil, leucovorin, and oxaliplatin; bolus fluorouracil, leucovorin, and irinotecan; or fluorouracil, leucovorin, and irinotecan) with or without bevacizumab as their initial treatment. The incidence of subsequent use of surgery, radiotherapy, and/or endoluminal stenting to manage primary tumor complications was recorded., Results: Of 233 patients, 217 (93%) never required surgical palliation of their primary tumor. Sixteen patients (7%) required emergent surgery for primary tumor obstruction or perforation, 10 patients (4%) required nonoperative intervention (ie, stent or radiotherapy), and 213 (89%) never required any direct symptomatic management for their intact primary tumor. Of those 213 patients, 47 patients (20%) ultimately underwent elective colon resection at the time of metastasectomy, and eight patients (3%) underwent this resection during laparotomy for hepatic artery infusion pump placement. Use of bevacizumab, location of the primary tumor in the rectum, and metastatic disease burden were not associated with increased intervention rate., Conclusion: Most patients with synchronous, stage IV CRC who receive up-front modern combination chemotherapy never require palliative surgery for their intact primary tumor. These data support the use of chemotherapy, without routine prophylactic resection, as the appropriate standard practice for patients with neither obstructed nor hemorrhaging primary colorectal tumors in the setting of metastatic disease.

This review examines the development of hepatic arterial infusion (HAI) of chemotherapy over the past 40 years. Liver metastases are mainly supplied by the hepatic artery, and high levels of intratumoral drug delivery are achievable with the use of HAI. Floxuridine, 5-fluorodeoxyuridine is commonly used, but intra-arterial oxaliplatin and mitomycin- C also have advantages. The dramatic responses observed with HAI plus systemic therapy offer the possibility of resection and cure in select patients. Resectability of liver-limited colorectal cancer metastases should be considered as an endpoint for all patients. Hepatic arterial infusion may be used in palliative, neoadjuvant, and adjuvant settings. Herein, combinations of systemic chemotherapy with HAI are discussed, along with the role of newer cytotoxic and biologic agents. The first-pass extraction of some drugs given by regional perfusion in the liver limits systemic side effects. Toxicity includes catheter-related complications and biliary and gastrointestinal ulcers. The role of HAI therapy for the treatment of unresectable and resectable disease, as well as the use of other regional strategies such as embolization and ablation, are discussed.

Metastatic colorectal cancer (CRC) is most frequently seen in the liver. Resection of metastases remains the treatment of choice; however, the majority of patients are ineligible for surgery due to unfavorable location, size, or number of metastases; insufficient liver reserve; or extrahepatic disease. The activity of irinotecan- and oxaliplatin-based regimens as first-line therapy has prompted the investigation of these agents as neoadjuvant therapy in patients with resectable and unresectable disease. Although studies suggest considerable promise for a neoadjuvant strategy in patients with unresectable liver metastases, the heterogeneity, small size, and retrospective nature of many of these studies precludes drawing firm clinical conclusions at this time, especially in patients with resectable disease. Therefore large, prospective trials that examine the impact of preoperative chemotherapy in patients with initially unresectable or resectable liver metastases are needed. These trials must include well-defined criteria for resectability and clear reporting of the extent of resection.

Background and Objectives: Few studies have addressed the optimal duration of chemotherapy, particularly prior to liver resection for colorectal liver metastases (CLM). The purpose of this retrospective analysis was to evaluate time to maximal response in patients receiving systemic +/- hepatic arterial infusion (HAI) chemotherapy alone for the treatment of CLM., Methods: We reviewed 35 patients with CLM on clinical trials of HAI floxuridine/dexamethasone plus systemic oxaliplatin with 5-fluorouracil/leucovorin or irinotecan (PUMP + SYSTEMIC). We retrospectively identified 35 patients with CLM who received first-line systemic 5FU/leucovorin/oxaliplatin (FOLFOX) +/- bevacizumab (SYSTEMIC) during the same time period. Measurable disease was evaluated on CT scans performed at 2-month intervals. The sum of the products of bi-dimensional tumor measurements for representative lesions was compared both to baseline imaging and between consecutive time points., Results: In responders to therapy, mean cumulative tumor reduction increased from 61% at 2 months to 73% at 4 months in the PUMP + SYSTEMIC group (P < 0.01) and from 39% to 56% in the SYSTEMIC group (P < 0.01). No significant incremental tumor reduction occurred between 4 and 6 months in either group., Conclusions: In responders to preoperative therapy, surgical resection should be considered after 2-4 months, when most patients have achieved maximal response.

Purpose: We evaluated the safety and efficacy of concurrent administration of two monoclonal antibodies, cetuximab and bevacizumab, in patients with metastatic colorectal cancer., Patients and Methods: This was a randomized phase II study in patients with irinotecan-refractory colorectal cancer. All patients were naïve to both bevacizumab and cetuximab. Patients in arm A received irinotecan at the same dose and schedule as last received before study entry, plus cetuximab 400 mg/m2 loading dose, then weekly cetuximab 250 mg/m2, plus bevacizumab 5 mg/kg administered every other week. Patients in arm B received the same cetuximab and bevacizumab as those in arm A but without irinotecan., Results: Forty-three patients received cetuximab, bevacizumab, and irinotecan (CBI) and 40 patients received cetuximab and bevacizumab alone (CB). Toxicities were as would have been expected from the single agents. For the CBI arm, time to tumor progression (TTP) was 7.3 months and the response rate was 37%; for the CB arm, TTP was 4.9 months and the response rate was 20%. The overall survival for the CBI arm was 14.5 months and the overall survival for the CB-alone arm was 11.4 months., Conclusion: Cetuximab and bevacizumab can be administered concurrently, with a toxicity pattern that seems to be similar to that which would be expected from the two agents alone. This combination plus irinotecan also seems to be feasible. The activity seen with the addition of bevacizumab to cetuximab, or to cetuximab plus irinotecan, seems to be favorable when compared with historical controls of cetuximab or cetuximab/irinotecan in patients who are naïve to bevacizumab.

Purpose: Hepatic metastases derive most of their blood supply from the hepatic artery; therefore, for patients with hepatic metastases from colorectal cancer, hepatic arterial infusion (HAI) of chemotherapy may improve outcome., Methods: In a multi-institutional trial, 135 patients were randomly assigned to receive HAI versus systemic bolus fluorouracil and leucovorin. The primary end point was survival; secondary end points were response, recurrence, toxicity, quality of life, cost, and the influence of molecular markers., Results: Overall survival was significantly longer for HAI versus systemic treatment (median, 24.4 v 20 months; P = .0034), as were response rates (47% and 24%; P = .012) and time to hepatic progression (THP; 9.8 v 7.3 months; P = .034). Time to extrahepatic progression (7.7 v 14.8 months; P = .029) was significantly shorter in the HAI group. Quality-of-life measurements showed improved physical functioning in the HAI group at the 3- and 6-month follow-up assessments. Toxicity included grade > or = 3 neutropenia (2% and 45%; P < .01), stomatitis (0% and 24%; P < .01), and bilirubin elevation (18.6% and 0; P < .01) in the HAI and systemic treatment groups, respectively. A greater proportion of men versus women receiving HAI experienced biliary toxicity (37% and 15%, respectively; P = .05). For HAI patients with thymidylate synthase levels in tumor less than or > or = 4, the median survival was 24 and 14 months, respectively (P = .17)., Conclusion: HAI therapy increased overall survival, response rate, THP, and was associated with better physical functioning compared with systemic therapy. Additional studies need to address the overall benefit and cost of new chemotherapy agents versus HAI alone or the combination of HAI with new agents.

The treatment of metastatic colorectal cancer by chemotherapy alone was considered palliative and without the potential to cure patients unless patients were rendered resectable. We report two patients with metastatic colorectal cancer involving the liver who were considered inoperable and were treated with systemic chemotherapy using biomodulated 5-fluorouracil. Both patients received 5-fluorouracil and N-(phosphonoacetyl)-l-aspartic acid; one also received methotrexate, leucovorin, and triacetyluridine with the N-(phosphonoacetyl)-l-aspartic acid and 5-fluorouracil. Both patients had a complete remission with chemotherapy and are still alive with no evidence of cancer ten years after the diagnosis of unresectable metastatic disease. These patients provide evidence that prolonged survival can be achieved withsystemic chemotherapy without the use of surgery or other forms of local therapy. These patients also confirm the importance of continued investigation of fluorouracil modulating agents, which may further enhance the recent progress made with fluorouracil-based combination chemotherapy for colorectal cancer.

Purpose: Two consecutive compassionate use studies of oxaliplatin were conducted in the United States and Canada in more than 5000 patients with locally advanced or metastatic colorectal carcinoma who had experienced treatment failure after at least one prior chemotherapy regimen., Patients and Methods: The main focus was safety. Patients were assigned to treatment with either single-agent oxaliplatin or oxaliplatin in combination with fluorouracil (FU) and with or without leucovorin (LV) in various regimens. Response data collection was not a trial objective, but time to treatment failure (TTF) was recorded in the first cohort (1370 patients)., Results: All treatment regimens were well tolerated, with an overall incidence of grade 3 or 4 hematologic toxicity of 23.2%, grade 3 or 4 treatment-related gastrointestinal toxicity of 26.4% (including diarrhea, vomiting, and mucositis), and grade 3 neurosensory toxicity 3.9%. Similar results were reported in the second cohort (3806 patients), in which the eligibility criteria were much less restrictive. In the first cohort (in which 83% received prior irinotecan), median TTF was 14 weeks, and was similar for the five regimens combining oxaliplatin and FU with or without LV, but significantly shorter for the single-agent oxaliplatin arm. The overall dose-intensity of oxaliplatin was maintained at 85.5% (range, 80.6% to 94.3%) of that prescribed by protocol (average 36.7 mg/m2/wk)., Conclusion: These data in a heavily pretreated patient population confirm that oxaliplatin is safe when used as a single agent or with a variety of FU-based regimens as salvage therapy in patients with advanced colorectal cancer.

Hepatic metastases are a frequent complication of colorectal cancer (CRC), affecting over half of all CRC patients. Resection of isolated metastases can result in long-term survival, but the majority of patients relapse, and most have unresectable disease. Hepatic arterial infusion (HAI) chemotherapy delivers high concentrations of cytotoxic agents directly to liver metastases with minimal systemic toxicities. Advances in surgical techniques, development of fully implantable pumps, and modification of drug regimens have decreased complications and improved patient tolerability. Randomized trials comparing HAI with systemic chemotherapy have demonstrated superior response rates and times to hepatic progression for unresectable disease, and have shown better times to progression and overall survival rates in the adjuvant setting following hepatic resection. HAI chemotherapy has unique toxicities, including chemical hepatitis and biliary sclerosis, which can be mitigated by the addition of dexamethasone to therapy. In an attempt to prevent extrahepatic progression, combinations of HAI with systemic chemotherapy, including newer agents such as irinotecan and oxaliplatin, are currently being investigated, with promising early results.