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

Purpose: Lymph node metastasis (LNM) drastically reduces survival after resection of intrahepatic cholangiocarcinoma (IHC). Optimal treatment is ill defined, and it is unclear whether tumor mutational profiling can support treatment decisions. Experimental Design: Patients with liver-limited IHC with or without LNM treated with resection (N = 237), hepatic arterial infusion chemotherapy (HAIC; N = 196), or systemic chemotherapy alone (SYS; N = 140) at our institution between 2000 and 2018 were included. Genomic sequencing was analyzed to determine whether genetic alterations could stratify outcomes for patients with LNM. Results: For node-negative patients, resection was associated with the longest median overall survival [OS, 59.9 months; 95% confidence interval (CI), 47.2–74.31], followed by HAIC (24.9 months; 95% CI, 20.3–29.6), and SYS (13.7 months; 95% CI, 8.9–15.9; P < 0.001). There was no difference in survival for node-positive patients treated with resection (median OS, 19.7 months; 95% CI, 12.1–27.2) or HAIC (18.1 months; 95% CI, 14.1–26.6; P = 0.560); however, survival in both groups was greater than SYS (11.2 months; 95% CI, 14.1–26.6; P = 0.024). Node-positive patients with at least one high-risk genetic alteration (TP53 mutation, KRAS mutation, CDKN2A/B deletion) had worse survival compared to wild-type patients (median OS, 12.1 months; 95% CI, 5.7–21.5; P = 0.002), regardless of treatment. Conversely, there was no difference in survival for node-positive patients with IDH1/2 mutations compared to wild-type patients. Conclusions: There was no difference in OS for patients with node-positive IHC treated by resection versus HAIC, and both treatments had better survival than SYS alone. The presence of high-risk genetic alterations provides valuable prognostic information that may help guide treatment.

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

Purpose: The prevalence and clinical characteristics of small bowel adenocarcinomas (SBA) in the setting of Lynch syndrome have not been well studied. We characterized SBA according to DNA mismatch repair and/or microsatellite instability (MMR/MSI) and germline mutation status and compared clinical outcomes. Experimental Design: A single-institution review identified 100 SBAs. Tumors were evaluated for MSI via MSIsensor and/or corresponding MMR protein expression via IHC staining. Germline DNA was analyzed for mutations in known cancer predisposition genes, including MMR (MLH1, MSH2, MSH6, PMS2, and EPCAM). Clinical variables were correlated with MMR/MSI status. Results: Twenty-six percent (26/100; 95% confidence interval, 18.4–35.4) of SBAs exhibited MMR deficiency (MMR-D). Lynch syndrome prevalence was 10% overall and 38.5% among MMR-D SBAs. Median age at SBA diagnosis was similar in non-Lynch syndrome MMR-D versus MMR-proficient (MMR-P) SBAs (65 vs. 61; P = 0.75), but significantly younger in Lynch syndrome (47.5 vs. 61; P = 0.03). The prevalence of synchronous/metachronous cancers was 9% (6/67) in MMR-P versus 34.6% (9/26) in MMR-D SBA, with 66.7% (6/9) of these in Lynch syndrome (P = 0.0002). In the MMR-P group, 52.2% (35/67) of patients presented with metastatic disease, compared with 23.1% (6/26) in the MMR-D group (P = 0.008). In MMR-P stage I/II patients, 88.2% (15/17) recurred, compared with 18.2% (2/11) in the MMR-D group (P = 0.0002). Conclusions: When compared with MMR-P SBA, MMR-D SBA was associated with earlier stage disease and lower recurrence rates, similar to observations in colorectal cancer. With a 38.5% prevalence in MMR-D SBA, germline Lynch syndrome testing in MMR-D SBA is warranted.

PURPOSE: To evaluate safety and efficacy of radiation segmentectomy (RS) with (90)Y glass microspheres in patients with limited metastatic liver disease not amenable to resection or percutaneous ablation. METHODS: Patients with ≤3 tumors treated with RS from 6/2015–12/2017 were included. Target tumor radiation dose was > 190 Gy based on Medical Internal Radiation Dose (MIRD) dosimetry. Tumor response, local tumor progression (LTP), LTP-free survival (LTPFS) and disease progression rate in the treated segment were defined using Choi and RECIST 1.1 criteria. Toxicities were evaluated using modified SIR criteria. RESULTS: Ten patients with 14 tumors underwent 12 RS. Median tumor size was 3 cm (range, 1.4–5.6). Median follow-up was 17.8 months (range, 1.6–37.3). Response rates per Choi and RECIST 1.1 criteria were 8/8 (100%) and 4/9 (44%), respectively. Overall LTP rate was 3/14 (21%) during the study period. One-, two- and three -year LTPFS was 83%, 83% and 69%, respectively. Median LTPFS was not reached. Disease progression rate in the treated segment was 6/18 (33%). Median overal survival was 41.5 months (IQR, 16.7–41.5). Median delivered tumor radiation dose was 293 Gy (range, 163–1303). One major complication was recorded in a patient post-Whipple procedure who suffered anaphylactic reaction to prophylactic cefotetan and liver abscess in RS region 6.5 months post-RS. All patients were alive on last follow-up. CONCLUSION: RS of ≤ 3 hepatic segments can safely provide a two-year local tumor control rate of 83% in selected patients with limited metastatic liver disease and limited treatment options. Optimal dosimetry methodology requires further investigation.

BackgroundHepatic artery infusion (HAI) chemotherapy is associated with overall survival (OS) in patients with resected colon cancer liver metastases (CLM). The prognostic impact of primary tumor location in CLM following hepatic resection in patients receiving regional HAI is unknown. This study seeks to investigate the prognostic impact of HAI in relation to laterality in this patient population.MethodsConsecutive patients with resected CLM, with known primary tumor site treated with and without HAI, were reviewed from a prospective institutional database. Correlations between HAI, laterality, other clinicopathological factors, and survival were analyzed, and Cox proportional hazard regressionwas used to determine whether laterality was an independent prognostic factor.ResultsFrom 1993 to 2012, 487 patients [182 with right colon cancer (RCC),305 with left colon cancer (LCC)] were evaluated with a median follow-up of 6.5years. Fifty-seven percent(n = 275) received adjuvant HAI. Patients with RCC had inferior 5-year OS compared with LCC (56% vs. 67%,P = 0.01). HAI was associated with improved 5-year OS in both RCC (68% vs. 45%;P

OBJECTIVE: To examine genomic correlates of conversion to resection (CTR) and overall survival (OS) in patients with initially unresectable colorectal liver metastasis (IU-CRLM) treated with combination systemic and hepatic artery infusion (HAI) chemotherapy. BACKGROUND: In patients presenting with IU-CRLM, combination systemic and HAI chemotherapy enables CTR with associated long-term OS in a subset of patients. Genomic correlates of CTR and OS in IU-CRLM have not been previously explored. METHODS: Specimens from IU-CRLM patients receiving systemic/HAI chemotherapy (2003-2017) were submitted for next-generation sequencing. Fisher’s Exact test assessed associations with CTR, and Kaplan-Meier/Cox methods assessed associations with OS from HAI initiation. RESULTS: Of 128 IU-CRLM patients, 51 (40%) underwent CTR at median 6 months (range:3-35) from HAI initiation. CTR and persistently unresectable (PU) cohorts differed significantly in preoperative systemic chemotherapy exposure, node-positive primary status, and size of largest liver metastasis. Median and 5-year OS was 66 months and 51%. CTR was associated with prolonged survival (time-dependent HR 0.23, 95%CI:0.12-0.46, p

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.

BACKGROUND: The objective was to investigate the impact of adjuvant hepatic arterial infusion pump (HAIP) chemotherapy on the rates and patterns of recurrence and survival in patients with resected colorectal liver metastases (CRLM).METHODS: Recurrence rates, patterns, and survival were compared between patients treated with and without adjuvant HAIP using competing risk analyses.RESULTS: 2128 patients were included, of which 601 patients (28.2%) received adjuvant HAIP and systemic chemotherapy (HAIP + SYS). The overall recurrence rate was similar with HAIP + SYS or SYS (63.5% versus 64.2%,p = 0.74). The 5-year cumulative incidence of initial intrahepatic recurrences was lower with HAIP + SYS (22.9% versus 38.4%,p < 0.001). The 5-year cumulative incidence of initial extrahepatic recurrences was higher with HAIP + SYS (48.5% versus 40.3%,p = 0.005), because patients remained at risk for extrahepatic recurrence in the absence of intrahepatic recurrence, which was largely attributable to more pulmonary recurrences with HAIP + SYS (33.6% versus 23.7%,p < 0.001). HAIP was an independent prognostic factor for DFS (adjusted HR 0.69, 95% CI 0.60-0.79, p < 0.001), and OS (adjusted HR 0.67, 95% CI 0.57-0.78,p < 0.001).CONCLUSION: Adjuvant HAIP chemotherapy is associated with lower intrahepatic recurrence rates and better DFS and OS after resection of CRLM.

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: After resection of colorectal liver metastases (CRLM), recurrent disease in the liver is a major cause of death, but may be reduced with the addition of adjuvant hepatic arterial infusion (HAI) chemotherapy to systemic chemotherapy (SYS). OBJECTIVE: This study investigates organ-specific causes of death in patients receiving adjuvant HAI and SYS compared with adjuvant SYS alone. METHODS: Between 2000 and 2007, patients undergoing complete CRLM resection were identified from a prospectively maintained liver resection database and categorized as receiving HAI+SYS or SYS only. Using newly constructed definitions, mortality was attributed to specific organs (liver, lung, peritoneum, and brain) or infection. Univariate models and cumulative incidence functions were generated using competing risks methods. RESULTS: Of 361 eligible patients, 208 (57.6%) received HAI+SYS and 153 (42.4%) received SYS. The median follow-up among survivors was 142 months (range= 12–217 months). Ten-year overall survival was 50.6% in the HAI+SYS group compared to 30.9% in those receiving SYS (p= 0.004). The 5-year cumulative incidence of liver-related mortality was 6.8% in the HAI+SYS group compared to 14.3% in SYS group (p= 0.007). CONCLUSION: The addition of HAI to systemic chemotherapy after CRLM resection is associated with a 50% reduction in liver-related mortality at 5 years.

Purpose: We aimed to investigate genomic correlates underlying extremes of survivorship in metastatic colorectal cancer and their applicability in informing survival in distinct subsets of patients with metastatic colorectal cancer. Experimental Design: We examined differences in oncogenic somatic alterations between metastatic colorectal cancer cohorts demonstrating extremes of survivorship following complete metastasectomy: ≤2-year (n = 17) and ≥10-year (n = 18) survivors. Relevant genomic findings, and their association with overall survival (OS), were validated in two independent datasets of 935 stage IV and 443 resected stage I–IV patients. Results: In the extremes-of-survivorship cohort, significant co-occurrence of KRAS hotspot mutations and TP53 alterations was observed in ≤2-year survivors (P < 0.001). When validating these findings in the independent cohort of 935 stage IV patients, incorporation of the cumulative effect of any oncogenic Ras/B-raf (i.e., either KRAS, NRAS, or BRAF) and TP53 alteration generated three prognostic clusters: (i) TP53-altered alone (median OS, 132 months); (ii) Ras/B-raf–altered alone (65 months) or Ras/B-raf- and TP53 pan-wild-type (60 months); and (iii) coaltered Ras/B-raf–TP53 (40 months; P < 0.0001). Coaltered Ras/B-raf–TP53 was independently associated with mortality (HR, 2.47; 95% confidence interval, 1.91–3.21; P < 0.001). This molecular profile predicted survival in the second independent cohort of 443 resected stage I–IV patients. Coaltered Ras/B-raf–TP53 was associated with worse OS in patients with liver (n = 490) and lung (n = 172) but not peritoneal surface (n = 149) metastases. Moreover, coaltered Ras/B-raf–TP53 tumors were significantly more likely to involve extrahepatic metastatic sites with limited salvage options. Conclusions: Genomic analysis of extremes of survivorship following colorectal cancer metastasectomy identifies a prognostic role for coaltered Ras/B-raf–TP53 and its association with distinct patterns of colorectal cancer metastasis.

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: 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 non-alcoholic 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 to the NAS. Fisher’s exact test examined 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 incidence 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 a median follow-up of 127 months (range=4-175), 10-year RFS was 22% (95%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 (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. CONCLUSION: Severe HPD was associated with increased IHR risk and decreased EHR risk. Future investigation into whether improving hepatic parenchymal disease from reversible etiologies can reduce the risk for intrahepatic recurrence is warranted.

Locally advanced hepatocellular carcinoma and intrahepatic cholangiocarcinoma are associated with a grim prognosis. The development of highly effective systemic therapies for these tumors has been challenging; however, numerous locoregional treatment alternatives have emerged, including transarterial hepatic embolization (TAE), transarterial chemoembolization (TACE), drug-eluting bead TACE (DEB-TACE), hepatic arterial infusion chemotherapy (HAI), radioembolization, and stereotactic body radiation therapy. Although there is potential for long-term disease control for these therapies, the evidence to guide adequate patient selection and choose among different treatment alternatives is still limited. This review focuses on the rationale and data supporting TAE, TACE, DEB-TACE, and HAI in hepatobiliary cancers.

Background Resection of colorectal liver metastases (CLM) can cure disease, but many patients with extensive disease cannot be fully resected and others recur following surgery. Hepatic arterial infusion (HAI) chemotherapy can convert extensive liver disease to a resectable state or decrease recurrence risk, but response varies and no biomarkers currently exist to identify patients most likely to benefit. Methods We performed a retrospective cohort study of CLM patients receiving HAI chemotherapy whose tumors underwent MSK‐IMPACT sequencing. The frequency of oncogenic alterations and their association with overall survival (OS) and objective response rate were analyzed at the individual gene and signaling pathway levels. Results Three hundred and seventy patients met inclusion criteria: 189 (51.1%) who underwent colorectal liver metastasectomy followed by HAI + systemic therapy (Adjuvant cohort), and 181 (48.9%) with unresectable CLM (Metastatic cohort) who received HAI + systemic therapy, consisting of 63 (34.8%) with extrahepatic disease and 118 (65.2%) with liver‐restricted disease. Genomic alterations were similar in each cohort, and no individual gene or pathway was significantly associated with objective response. Patients in the adjuvant cohort with concurrent Ras/B‐Raf alteration and SMAD4 inactivation had worse prognosis while in the metastatic cohort patients with co‐alteration of Ras/B‐Raf and TP53 had worse OS. Similar findings were observed in a validation cohort. Conclusions Concurrently altered Ras/B‐Raf and SMAD4 mutations were associated with worse survival in resectable patients, while concurrent Ras/B‐Raf and TP53 alterations were associated with worse survival in unresectable patients. The mutual exclusivity of Ras/B‐Raf, SMAD4, and TP53 may have prognostic value for CLM patients receiving HAI., Patients with colorectal liver metastases receiving hepatic arterial infusion chemotherapy who have either resectable disease with concurrently altered Ras/B‐Raf and SMAD4 mutations, or unresectable disease with concurrent Ras/B‐Raf and TP53 alterations had worse survival. Mutual exclusivity of Ras/B‐Raf, SMAD4, and TP53 status may be useful for prognostic stratification in these patients.

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

Background The causative factors for the recent increase in early-onset colorectal cancer (EO-CRC) incidence are unknown. We sought to determine if early-onset disease is clinically or genomically distinct from average-onset colorectal cancer (AO-CRC). Methods Clinical, histopathologic, and genomic characteristics of EO-CRC patients (2014-2019), divided into age 35 years and younger and 36-49 years at diagnosis, were compared with AO-CRC (50 years and older). Patients with mismatch repair deficient tumors, CRC-related hereditary syndromes, and inflammatory bowel disease were excluded from all but the germline analysis. All statistical tests were 2-sided. Results In total, 759 patients with EO-CRC (35 years, n = 151; 36-49 years, n = 608) and AO-CRC (n = 687) were included. Left-sided tumors (35 years and younger = 80.8%; 36-49 years = 83.7%; AO = 63.9%; P Conclusions EO-CRCs are more commonly left-sided and present with rectal bleeding and abdominal pain but are otherwise clinically and genomically indistinguishable from AO-CRCs. Aggressive treatment regimens based solely on the age at CRC diagnosis are not warranted.

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.

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

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

Purpose:Immune checkpoint inhibition (ICI) alone is not active in mismatch repair–proficient (MMR-P) metastatic colorectal cancer (mCRC), nor does radiotherapy alone result in objective systemic benefit. However, combined radiotherapy plus ICI can induce systemic antitumor immunity in preclinical and clinical models.Patients and Methods:In this single-center, phase II study, patients with chemotherapy-refractory MMR-P mCRC received durvalumab 1,500 mg plus tremelimumab 75 mg every 4 weeks plus radiotherapy. The primary endpoint was objective response rate (ORR) in nonirradiated lesions. Treatment and efficacy were correlated with peripheral immune cell profiles.Results:We enrolled 24 patients, and report outcomes after a median follow-up of 21.8 (range: 15.9–26.3) months. The ORR was 8.3% (2 patients) [95% confidence interval (CI), 1.0–27.0]. The median progression-free survival was 1.8 (95% CI, 1.7–1.9) months, median overall survival was 11.4 (95% CI, 10.1–17.4) months. Twenty five percent of patients (n = 6) had treatment-related grade 3–4 adverse events. We observed increased circulating CD8+ T lymphocyte activation, differentiation, and proliferation in patients with objective response.Conclusions:This combination of radiotherapy plus ICI study did not meet the prespecified endpoint criteria to be considered worthwhile for further study. However, rare instances of systemic immune augmentation and regression in nonirradiated lesions were observed (an abscopal response). Combination durvalumab and tremelimumab plus radiotherapy is feasible in MMR-P mCRC with a manageable safety profile. Further studies of novel immunotherapy combinations, and identification of biomarkers predictive of abscopal response are warranted.

Colorectal cancer (CRC) is one of the leading cancers globally in terms of both incidence and cancer-related mortality. Liver metastatic disease is the main prognostic driver for patients with CRC. The management options for liver metastatic CRC continue to evolve, particularly with the incorporation of locoregional therapies into the treatment paradigm. Hepatic arterial infusion (HAI) chemotherapy is one such liver directed approach used with the goal of converting patients to liver resection, reducing the risk of recurrence, treating recurrent disease, and most importantly improving overall survival. This article summarizes the role of HAI chemotherapy in the treatment of liver metastatic CRC.

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

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.

Thermal ablation of colorectal cancer liver metastases with minimum margin > 10 mm offers the best local tumor control. Biliary complications occurred only in patients that received hepatic artery infusion especially in the face of pre-existing biliary dilatation, exposure to bevacizumab, and ablation with minimum margin > 10 mm. For patients at risk, such as those in the hepatic artery infusion group, a margin of 6 to 10 mm offers 76% local tumor control rate and 4% major biliary complications incidence.Introduction: The purpose of this study was to identify risk factors associated with local tumor progression-free survival (LTPFS) and complications after colorectal liver metastases (CLM) thermal ablation (TA). Patients and Methods: This retrospective analysis included 286 patients with 415 CLM undergoing TA (radiofrequency and microwave ablation) in 378 procedures from January 2003 to July 2017. Prior hepatic artery infusion (HAI), bevacizumab, pre-existing biliary dilatation, ablation modality, minimal ablation margin (MM), prior hepatectomy, CLM number, and size were analyzed as factors influencing complications and LTPFS. Statistical analysis included the Kaplan-Meier method, Cox proportional hazards model, competing risk analysis, univariate/multivariate logistic/exact logistic regressions, and the Fisher exact test. Complications were reported according to modified Society of Interventional Radiology guidelines. Results: The median follow-up was 31 months. There was no LTP for MM > 10 mm. Smaller tumor size, increased MM, and prior hepatectomy correlated with longer LTPFS. The major complications occurred following 28 (7%) of 378 procedures. There were no biliary complications in HAI-naive patients, versus 11% in HAI patients (P 10 mm. In HAI patients, ablation with 6 to 10 mm and > 10 mm MM resulted in major biliary complication rates of 4% and 21% (P = .0011), with corresponding LTP rates of 24% and 0% (P = .0033). In HAI-naive patients, the LTP rates for 6 to 10 mm and > 10 mm MM were 27% and 0%, respectively. Conclusions: No LTP was seen for MM > 10 mm. Biliary complications occurred only in HAI patients, especially in those with biliary dilatation, bevacizumab, and MM > 10 mm. In HAI patients, MM of 6 to 10 mm resulted in 76% local tumor control and 4% major biliary complications incidence. (C) 2020 Published by Elsevier Inc.

Purpose/Objective(s) Patients with pelvic or retroperitoneal recurrences of colorectal cancer (CRC) have poor overall survival, with retrospective studies suggesting a possible survival benefit with local therapy. However, many patients present with disease that is either unresectable, or in which resection will result in significant morbidity or margin positivity. We sought to examine the local control, overall survival (OS), and toxicity of minimally invasive CT-guided low dose-rate (LDR) brachytherapy in this setting, for which there is limited published data. Materials/Methods This study was a retrospective analysis of all patients at our institution who have undergone CT-guided LDR brachytherapy for recurrent CRC. Patient, tumor, and treatment characteristics were collected, along with physician-reported symptoms in the medical record. Patients underwent dose calculation based on pre-implantation CT imaging and contouring of gross tumor volume (GTV), followed by CT-guided percutaneous interstitial needle placement of either Iodine-125 or Palladium-103 permanent seed implants prescribed to the GTV. Response Evaluation Criteria in Solid Tumors (RECIST) criteria were used to interpret treatment response, and the Kaplan-Meier method was used to estimate rates of overall survival (OS) and in-field control (IFC). IFC was defined as a lack of progression of disease within the pre-implantation defined target volume. Results Between December 2016 and August 2020, 13 patients underwent 18 CT-guided LDR seed implantations (6 I-125, 12 Pd-103) for pelvic or retroperitoneal recurrences of CRC at our institution, with a median follow-up of 17 months. 17 treatments were for pelvic recurrences, while one treatment was for a retrocaval nodal recurrence. The median prescribed dose to the target volume was 80 Gy (range 40-110 Gy), with a median target volume of 5.0 cc (range 0.6-25.5 cc). The 1-year estimated rates of OS and IFC were 94.4% (CI 84.4-100%) and 82.4% (CI 66.1-100%), respectively. All in-field failures occurred in targets above the median target volume of 5 cc. All patients previously received definitive treatment for either initially locally advanced (8 patients) or limited metastatic disease (5 patients). Of the 18 implantations, four were performed for isolated pelvic recurrences and 13 for either oligo-progressive or oligo-recurrent metastatic disease, with a median of two active sites of disease at the time of seed implantation. One patient received palliative brachytherapy after a poly-metastatic recurrence. No patients experienced grade 2 or higher toxicities. Three patients experienced a grade 1 toxicity (proctitis, pain, and fatigue), and one patient developed an asymptomatic recto-vaginal fistula detected on imaging, which was outside of the brachytherapy field. Conclusion CT-guided interstitial LDR brachytherapy achieved high rates of control and overall survival with minimal long-term toxicity in patients with pelvic and retroperitoneal recurrences of CRC.

Optimal clinical development of new cancer therapies targeting tumor vasculature requires new target-specific response assays. This clinical study examined the test-retest repeatability of SPECT as an in vivo assay of angiogenic hepatic tumor microvasculature using an intraarterial infusion ofPatients with primary or secondary cancerous liver tumors with HAI pump-catheter implants placed for HAI chemotherapy underwent hepatic SPECT after separate arterial infusions of 37 and 185 MBq ofTest-retest HAI pump SPECT yielded highly repeatable measurements in quantitative indexes of tumor microvasculature. Variability in repeat test-retest measurements was small relative to the range of observed measurements between different tumors. The total hepatic tumor microvascular MAA accumulation (percentage injected dose) proved most repeatable, with test-retest value quotients near unity (quotients: median, 1.10 ± 0.09 [SD]; range, 1.03-1.32; 95% CI, 1.07-1.19) and 1.6% CR. Tumor MAA uptake values ranged from 5% to 18% injected dose.This article describes the precision of HAI SPECT as a quantitative biomarker of tumor microvasculature under conditions of repeatability. The results support clinical testing of HAI SPECT as a radiologic response biomarker for angiotropic tumor therapy.

Background A continued rise of hepatocellular carcinoma (HCC) incidence is noted. HCC main risk factors are hepatitis B, C, alcohol, and nonalcoholic steatohepatitis. The majority of biliary tumors are adenocarcinomas. Biliary tumors have been classically understood as three different diseases: gallbladder cancer, extrahepatic, and intrahepatic biliary tumors, with different clinical and biological characteristics. Methods Presenting the basic scientific components and clinical premises is supplemented by a thorough review of the new oncoming data especially for advanced disease is reported. This particularly true for the incredible advents in the treatment of advanced HCC. Results Surgery, liver transplantation, and radiofrequency ablation (RFA), are the sole proven curative therapies for HCC. Locally advanced disease is generally treated with different forms of local therapies, including but not limited to, transarterial embolization, chemoembolization, radioembolization, and radiation therapy. Novel five tyrosine kinase inhibitors are now added to sorafenib, and two of them are already FDA approved, being lenvatinib and regorafenib. Checkpoint inhibitors and combination of checkpoint inhibitors is another key advent. For biliary cancers, a novel approach to differentiate the three diseases based on biology and pathways is evolving. Surgery remain the sole curative approach. Capecitabine is now validated as an adjuvant treatment after resection. Several mutational taregts are being further investigated for the treatment of biliary cancers, particularly cholangiocarcinoma and gallbladder cancer. Principal conclusions Screening programs for HCC continue to evolve. Pathology evaluation may help distinguish variants or combined HCC and cholangiocarcinoma. Novel therapies are helping move the field forward at a fast pace.

Colorectal cancer represents a significant global health burden, with the liver as the most common site of metastases. In patients with metastatic disease, 60% will develop liver metastases, and this is a major cause of morbidity and mortality. Historically, liver metastatic colorectal cancer carried a poor prognosis. With modern systemic chemotherapy regimens and use of liver-directed therapies, great advances have been made.

Hepatic arterial infusion (HAI) chemotherapy has been used over the last 30 years in patients with liver metastases from colorectal cancer and intrahepatic cholangiocarcinoma. Its rationale has been well established and is based on the preferential blood supply of these tumors from the hepatic artery and the first-pass extraction by the liver of some chemotherapy drugs. However, the generation of high-quality evidence for HAI treatment and the technical expertise required for administration have limited its widespread adoption. In this review, we will describe the relevant aspects of HAI treatment and summarize the evidence supporting its use in the treatment of colorectal cancer and intrahepatic cholangiocarcinoma. We will also review the complications associated with HAI and the precautions to minimize their incidence. Based on the current evidence, HAI has emerged as an effective and safe treatment alternative leading to renewed enthusiasm toward this therapeutic strategy. Future research will refine the selection of patients and the optimal combination with systemic treatments.

PURPOSE Chemotherapy-induced thrombocytopenia (CIT) leads to delay or reduction in cancer treatment. There is no approved treatment. METHODS We conducted a phase II randomized trial of romiplostim versus untreated observation in patients with solid tumors with CIT. Before enrollment, patients had platelets less than 100,000/μL for at least 4 weeks, despite delay or dose reduction of chemotherapy. Patients received weekly titrated romiplostim with a target platelet count of 100,000/μL or more, or were monitored with usual care. The primary end point was correction of platelet count within 3 weeks. Twenty-three patients were treated in a randomization phase, and an additional 37 patients were treated in a single-arm, romiplostim phase. Resumption of chemotherapy without recurrent CIT was a secondary end point. RESULTS The mean platelet count at enrollment was 62,000/μL. In the randomization phase, 14 of 15 romiplostim-treated patients (93%) experienced correction of their platelet count within 3 weeks, compared with one of eight control patients (12.5%; P < .001). Including all romiplostim-treated patients (N = 52), the mean platelet count at 2 weeks of treatment was 141,000/μL. The mean platelet count in the eight observation patients at 3 weeks was 57,000/μL. Forty-four patients who achieved platelet correction with romiplostim resumed chemotherapy with weekly romiplostim. Only three patients (6.8%) experienced recurrent reduction or delay of chemotherapy because of isolated CIT. CONCLUSION This prospective trial evaluated treatment of CIT with romiplostim. Romiplostim is effective in correcting CIT, and maintenance allows for resumption of chemotherapy without recurrence of CIT in most patients.

Importance Although liver metastasis develops in more than half of patients with colorectal cancer, only 15% to 20% of these patients have resectable liver metastasis at presentation. Moreover, patients with initially unresectable colorectal liver metastasis (IU-CRLM) who progress on first-line systemic chemotherapy have limited treatment options. Hepatic arterial infusion chemotherapy (HAIC), in combination with systemic chemotherapy, leverages a multimodality approach to achieving control of hepatic disease and/or expanding resectability in patients with liver-only disease or liver-dominant disease. Observations Intra-arterial delivery of agents with high first-pass hepatic extraction (eg, floxuridine) limits systemic toxic effects and allows for administration of systemic chemotherapy at near-full doses. Hepatic arterial infusion chemotherapy in conjunction with systemic chemotherapy augments response rates up to 92% in patients who are chemotherapy naive, and up to 85% in pretreated patients with IU-CRLM. In turn, these responses translate into encouraging rates of conversion to resectability (CTR). Prospective trials have reported CTR rates as high as 52% in heavily pretreated patients with IU-CRLM who have an extensive hepatic disease burden. As such, CTR remains a compelling indication for liver-directed chemotherapy in this subset of patients. This review discusses the biological rationale for HAIC, evolution of rational combinations with systemic chemotherapy, contemporary evidence for CTR using HAIC and systemic chemotherapy, juxtaposition with rates of CTR using systemic chemotherapy alone, and morbidity and toxic effect profiles of HAIC. Conclusions and Relevance The argument is made for consideration of earlier initiation of HAIC in patients with IU-CRLM who are chemotherapy naive and for adoption of HAIC strategies to augment rates of resectability in patients who have failed first-line systemic chemotherapy before proceeding to second-line or third-line regimens.

Background Although gemcitabine plus platinum chemotherapy is the established first-line regimen for advanced biliary cancer (ABC), there is no standard second-line therapy. This study evaluated current practice and outcomes for second-line chemotherapy in patients with ABC across 3 US academic medical centers. Methods Institutional registries were reviewed to identify patients who had received second-line chemotherapy for ABC from April 2010 to March 2015 along with their demographics, diagnoses and staging, treatment histories, and clinical outcomes. Overall survival from the initiation of second-line chemotherapy (OS2) was estimated with Kaplan-Meier methods. Results This study identified 198 patients with cholangiocarcinoma (intrahepatic [61.1%] or extrahepatic [14.1%]) or gallbladder carcinoma (24.8%); 52% received at least 3 lines of systemic chemotherapy. The median OS2 was 11 months (95% confidence interval [CI], 8.8-13.1 months). The median OS2 for patients with intrahepatic cholangiocarcinoma was 13.4 months (95% CI, 10.7-17.8 months), which was longer than that for patients with extrahepatic cholangiocarcinoma (6.8 months; 95% CI, 5-10.6 months) or gallbladder carcinoma (9.4 months; 95% CI, 7.2-12.3 months; P = .018). The median time to second-line treatment failure was 2.2 months (95% CI, 1.8-2.7 months), and it was similar across tumor locations (P = .60). Conclusions In this large cohort of patients with ABC treated across 3 academic medical centers after the failure of first-line chemotherapy, the time to treatment failure on standard therapies was short, although the median OS2 was longer than has been reported previously, and more than half of the patients received additional lines of treatment. This multicenter collaboration represents the largest cohort studied to date of second-line chemotherapy for ABC and provides a contemporary benchmark for future clinical trials.

BACKGROUND: Recurrences are reported in 70% of all patients after resection of colorectal liver metastases (CRLM), in which half are confined to the liver. Adjuvant hepatic arterial infusion pump (HAIP) chemotherapy aims to reduce the risk of intrahepatic recurrence. A large retrospective propensity score analysis demonstrated that HAIP chemotherapy is particularly effective in patients with low-risk oncological features. The aim of this randomized controlled trial (RCT) --the PUMP trial-- is to investigate the efficacy of adjuvant HAIP chemotherapy in low-risk patients with resectable CRLM.METHODS: This is an open label multicenter RCT. A total of 230 patients with resectable CRLM without extrahepatic disease will be included. Only patients with a clinical risk score (CRS) of 0 to 2 are eligible, meaning: patients are allowed to have no more than two out of five poor prognostic factors (disease-free interval less than 12 months, node-positive colorectal cancer, more than 1 CRLM, largest CRLM more than 5 cm in diameter, serum Carcinoembryonic Antigen above 200 μg/L). Patients randomized to arm A undergo complete resection of CRLM without any adjuvant treatment, which is the standard of care in the Netherlands. Patients in arm B receive an implantable pump at the time of CRLM resection and start adjuvant HAIP chemotherapy 4-12 weeks after surgery, with 6 cycles of floxuridine scheduled. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, hepatic PFS, safety, quality of life, and cost-effectiveness. Pharmacokinetics of intra-arterial administration of floxuridine will be investigated as well as predictive biomarkers for the efficacy of HAIP chemotherapy. In a side study, the accuracy of CT angiography will be compared to radionuclide scintigraphy to detect extrahepatic perfusion. We hypothesize that adjuvant HAIP chemotherapy leads to improved survival, improved quality of life, and a reduction of costs, compared to resection alone.DISCUSSION: If this PUMP trial demonstrates that adjuvant HAIP chemotherapy improves survival in low-risk patients, this treatment approach may be implemented in the standard of care of patients with resected CRLM since adjuvant systemic chemotherapy alone has not improved survival.TRIAL REGISTRATION: The PUMP trial is registered in the Netherlands Trial Register (NTR), number: 7493 . Date of registration September 23, 2018.

3602 Background: Lung chemoembolization (via the bronchial or pulmonary artery) is a new treatment option for unresectable and unablatable lung metastases. Methods: 10 patients with unresectable and unablatable lung, endobronchial, or mediastinal metastases, who failed systemic chemotherapy, were enrolled in this single center, single arm, phase I trial. Pulmonary and bronchial angiography was performed in all patients, to determine the blood supply to the lung metastases. Based on the angiographic findings, bronchial or pulmonary artery chemoembolization was performed, using a lipiodol / mitomycin emulsion, followed by spherical particles. Technical success, safety, efficacy, and pharmacokinetics were evaluated. Wilcoxon signed-rank test was used to compare change in size of treated versus untreated tumors. Results: On angiography, all patients had lung metastases that were hypervascular compared to normal lung. 90% of patients had lung metastases supplied by the bronchial artery, and 10% were supplied by the pulmonary artery. Technical success rate of intra-tumoral drug delivery was 100% (95% CI: 76-100%). There were no severe adverse events, and all patients met criteria for discharge 4 hours post procedure. Response rate of treated lesions was 10% by RECIST and 40% by PERCIST. Treated tumors were mostly stable to decreased in size after chemoembolization (median change in size: 0%; IQR: -11% to 2%; mean: -4%), and untreated tumors were mostly increased in size (median change in size: 10%; IQR: 0% to 17%; mean 9%; p= 0.02). Intra-tumoral lipiodol retention at 4-6 weeks was correlated with decreased tumor size and metabolic activity. Pharmacokinetics showed that 45% of the mitomycin dose underwent burst release in 2 minutes, and 55% of the dose was retained intratumorally with a half-life > 5 hours. Initial tumor-to-plasma ratio of mitomycin concentration was 380. Half-life of intratumoral lipiodol retention was 16 days. In vitro experiments showed 50% emulsion separation in 6.2 days, and 50% drug release in 7.1 hours. Conclusions: Lung chemoembolization can safely treat lung, mediastinal, and endobronchial metastases, with minimal systemic toxicity. High intratumoral drug concentrations after chemoembolization can overcome chemoresistance. Clinical trial information: NCT04200417.

Background: The liver is the most common site for metastases from colorectal cancer (CRC) with the majority of these patients having unresectable disease. Methods: This is a retrospective review of studies using hepatic arterial infusion (HAI) therapy to treat liver metastasis from CRC. A PubMed search of randomized controlled trials and retrospective studies from 2006 to present was conducted using the search terms ‘hepatic arterial infusion (HAI) therapy', ‘colorectal cancer', and ‘treatment of liver metastases'. Results: The first randomized studies comparing HAI to systemic therapy with 5-fluorouracil/leucovorin produced significantly higher response rates of 41 versus 14%. Systemic therapy has improved with the addition of irinotecan and oxaliplatin; however, the responses with HAI and these modern agents have also increased, with responses as high as 80%. For patients with wild-type KRAS, HAI and systemic therapy produced a median survival of 68 months. In patients with refractory disease, response rates are in the 30% range with a median survival of 20 months. Adjuvant HAI after liver resection has shown an increase of hepatic disease-free survival and overall disease-free survival when compared to systemic therapy alone in three of four randomized trials. A recent update of the adjuvant trials after liver resection at Memorial Sloan Kettering Cancer Center has shown a 5-year survival of 78%. Conclusion: HAI therapy has a role in treating hepatic metastases from CRC in both the resectable and unresectable setting.

BACKGROUND Ovarian metastases from colorectal cancer (OM-CRC) often are unresponsive to chemotherapy and are associated with poor survival. To the authors' knowledge, the clinicopathologic and genomic predictors of OM-CRC are poorly characterized and optimal clinical management remains unclear. METHODS Women with a histopathological diagnosis of OM-CRC who were treated at Memorial Sloan Kettering Cancer Center from 1999 to 2015 were identified. Next-generation somatic mutation profiling (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT]) was performed on 38 OM-CRC cases, including 21 matched tumor pairs/trios. Regression models were used to analyze variables associated with progression-free survival and overall survival (OS). RESULTS Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), SMAD family member 4 (SMAD4), and neurotrophic receptor tyrosine kinase 1 (NTRK1) mutations were more frequent in cases of OM-CRC than in instances of CRC occurring without OM. SMAD4 and lysine methyltransferase 2D (KMT2D) mutations were associated with reduced OS. Matched multisite tumor sequencing did not identify OM-specific genomic alterations. Of the 195 patients who underwent oophorectomy for OM-CRC (median age, 49 years with a progression-free survival of 9.4 months and an OS of 23 months from oophorectomy), 76% had extraovarian metastasis (EOM). In multivariable analysis, residual disease after surgery (R2 resection) was associated with worse survival. Patients with EOM were less likely to achieve R0/R1 surgical resection status (complete macroscopic resection without clinical/radiological evidence of disease) (48% vs 94%). However, if R0/R1 resection status was achieved, both patients with (35.9 months vs 12 months) and without (43.2 months vs 14.5 months) EOM were found to have better OS. Among 114 patients with R0/R1 resection status, 23 (20%) had no disease recurrence, including 10 patients (9%) with > 3 years of follow-up. CONCLUSIONS Loss-of-function alterations in SMAD4 are frequent and predictive of worse survival in patients with OM-CRC. Similar to oligometastatic CRC to the lung or liver, surgical resection of OM-CRC is associated with a better outcome only if all macroscopic metastatic disease is resected. Cancer 2016. © 2016 American Cancer Society.

Purpose To establish the prognostic value of biopsy of the central and marginal ablation zones for time to local tumor progression (LTP) after radiofrequency (RF) ablation of colorectal cancer liver metastasis (CLM). Materials and Methods A total of 47 patients with 67 CLMs were enrolled in this prospective institutional review board-approved and HIPAA-compliant study between November 2009 and August 2012. Mean tumor size was 2.1 cm (range, 0.6-4.3 cm). Biopsy of the center and margin of the ablation zone was performed immediately after RF ablation (mean number of biopsy samples per ablation zone, 1.9) and was evaluated for the presence of viable tumor cells. Samples containing tumor cells at morphologic evaluation were further interrogated with immunohistochemistry and were classified as either positive, viable tumor (V) or negative, necrotic (N). Minimal ablation margin size was evaluated in the first postablation CT study performed 4-8 weeks after ablation. Variables were evaluated as predictors of time to LTP with the competing-risks model (uni- and multivariate analyses). Results Technical effectiveness was evident in 66 of 67 (98%) ablated lesions on the first contrast material-enhanced CT images at 4-8-week follow-up. The cumulative incidence of LTP at 12-month follow-up was 22% (95% confidence interval [CI]: 12, 32). Samples from 16 (24%) of 67 ablation zones were classified as viable tumor. At univariate analysis, tumor size, minimal margin size, and biopsy results were significant in predicting LTP. When these variables were subsequently entered in a multivariate model, margin size of less than 5 mm (P < .001; hazard ratio [HR], 6.7) and positive biopsy results (P = .008; HR, 3.4) were significant. LTP within 12 months after RF ablation was noted in 3% (95% CI: 0, 9) of necrotic CLMs with margins of at least 5 mm. Conclusion Biopsy proof of complete tumor ablation and minimal ablation margins of at least 5 mm are independent predictors of LTP and yield the best oncologic outcomes. (©) RSNA, 2016.

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.

Purpose: Oxaliplatin at a dose of 85 mg/m2 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/m2, 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/m2/min (85 mg/m2 given over 85 min; 68 mg/m2 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/m2 (± 10%), and 161 received a dose of 130 mg/m2. The incidence of HSRs in the 85 mg/m2 group was 11% versus 7% in the 130 mg/m2 group (P = .13). Then between December 1, 2014, and June 4, 2015, 667 patients received oxaliplatin at a rate of 1 mg/m2/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/m2/min does not increase the rate of HSRs and does not compromise patient safety. This infusion rate is safe for use in routine practice.

BACKGROUND An increasing proportion of patients are presenting with colorectal cancer at an early age. A proportion of these occur with genetic syndromes; however the majority present as sporadic. The purpose of this study is to investigate the prognosis and treatment of young patients with sporadic metastatic colorectal cancer. METHODS Following IRB approval, patients with sporadic metastatic colorectal cancer at 40 years or under were identified. Patient charts and pathology reports were analyzed retrospectively for clinical and pathological factors. RESULTS Three hundred and two patients were identified; 148 with liver metastases only, and 154 with extra-hepatic disease. Five-year overall survival was 19%, 28% for liver only disease, and 12% for extrahepatic disease. For patients with liver metastases only, factors associated with survival on univariable analysis included diagnosis in the 2000's, unilobular hepatic disease, smaller volume liver metastases, intrahepatic pump chemotherapy, resection of the primary, and resection of liver metastases. On multivariable analysis factors associated with survival included resection of the primary, resection of liver metastases, and diagnosis in the 2000's. CONCLUSION Sporadic metastatic colorectal cancer in young patients appears to have a similar prognosis to that in older patients. The most significant prognostic factor was the ability to resect all sites of disease. J. Surg. Oncol. 2016;113:473-476. © 2016 Wiley Periodicals, Inc.

4602 Background: Thermal ablation (TA) is used as a local cure for selected colorectal liver metastases (CLM) with minimal risk. A critical limitation of TA has been early local tumor progression (LTP). The goal of this study is to establish the role of ablation zone (AZ) biopsy in predicting LTP. Methods: This institutional review board-approved prospective study included patients with CLM of 5cm or less in maximum diameter, with confined liver disease or stable, limited extrahepatic disease. Both radiofrequency(RF) and microwave(MW) ablation modalities were used. A biopsy of the center and margin of the AZ was performed immediately after ablation. The applicators were also examined for the presence of viable tumor cells. All samples containing morphologically identified tumor cells were further interrogated with immunohistochemistry to determine the proliferative and viability potential of the detected tumor cells. Ablation margin size was evaluated on the first CT scan performed 4–8 weeks after ablation and was confirmed by 3D assessment with Ablation Confirmation Software (Neuwave™). Variables were evaluated as predictors of time to LTP with the competing-risks model (uni- and multivariate analyses). Results: Between November 2009 and February 2019, 102 patients with 182 CLMs were enrolled. Mean tumor size was 2.0 cm (range, 0.6–4.8 cm). MW was used in 95/182 (52%) tumors and RF in 87/182 (48%). Median follow-up was 19 months. Technical effectiveness was evident in 178/182 (97%) ablated tumors on the first contrast material–enhanced CT at 4–8-weeks post-ablation. The cumulative incidence of LTP at 12 months was 19% (95% confidence interval [CI]: 14, 27). Samples from 64 (35%) of the 178 technically successful cases contained viable tumor. At univariate analysis, tumor size, minimal margin size, and biopsy results were significant in predicting LTP. In a multivariate model, margin size of less than 5 mm (P < .001; hazard ratio [HR], 4.3), and positive biopsy results (P = .02; HR, 1.8) remained significant. LTP within 12 months after TA was noted in 3% (95% CI: 1, 6) of tumor-negative biopsy CLMs with margins of at least 5 mm. Conclusions: Biopsy and pathologic examination of the AZ predicts LTP regardless of TA modality used. This can optimize ablation as a potential local cure for patients with limited CLM.

e16007 Background: Due to the termination of the Codman pump, in order to administer hepatic arterial infusion (HAI) chemotherapy, the Medtronic pump has been used with the Codman catheter at MSKCC since 2018. Methods: Retrospective review of patients(pts) receiving HAI therapy via Medtronic pumps. Expected versus actual dose delivery of HAI FUDR, response rates and safety were reviewed. Results: Pts included; unresectable colorectal liver metastases (CRLM) (94 pts), resected CLRM (66 pts) and unresectable intrahepatic cholangiocarcinoma (ICC) (11 pts). Baseline characteristics of the 171 evaluable pts are shown in Table. In 120 pts with mCRC, 51.8% (n = 58) had 10 or more hepatic tumors and 23.2%( n = 26) had 50% or more liver involvement by metastases. 52 out of 171 pts (30.4%) had 100% of the expected FUDR doses by completion of the 3rdcycle. Another 49.7% (85/171) had greater than or equal to 50% of the expected FUDR dose. 96 pts had measurable disease (unresectable CLRM and ICC subgroups) evaluated by RECIST 1.1 with an MSK radiologist. The partial response for unresectable CRLM pts was 47% (41/87), and 28% (24/87) were stable. The partial response for ICC pts was 22% (2/9), and 33% (3/9) were stable. Conclusions: We evaluated 171 pts who were heavily pretreated and had extensive disease prior to pump placement. Partial response by RECIST 1.1 of 47% was evident in those pts with CRLM and 22% for pts with ICC. Dose delivery of HAI FUDR was compatible with that seen with the Codman pump and no increase in toxicity was noted. An updated analysis with additional evaluable pts will be presented at the meeting. [Table: see text]

TPS4123 Background: The treatment of patients with locally advanced rectal cancer includes total neoadjuvant therapy with chemotherapy, chemoradiation followed by surgery. While most rectal cancers respond to combination induction chemotherapy, patients with mismatch repair deficient (dMMR) or MSI-H tumors have a significantly higher chance of progression with this treatment regimen. dMMR or MSI-H tumors have shown remarkable responses to PD-1 blockade, but the effect of neoadjuvant checkpoint inhibition has not been well studied. In this trial we will determine the pathologic complete response rate (pCR) of neoadjuvant anti-PD-1 blockade followed by standard chemoradiation in dMMR or MSI-H locally advanced rectal cancer. We hypothesize that treatment naïve dMMR or MSI-H rectal cancers will achieve a robust clinical response to PD-1 blockade and that the total neodjuvant therapy with PD-1 blockade followed by chemoradiation will improve pCR rates. Methods: Eligible patients ≥18 years of age with Stage II (T3-4, N-) or Stage III (any T, N+) histologically confirmed dMMR or MSI-H (by NGS) rectal adenocarcinoma will be enrolled. Patients will receive TSR-042 (500mg IV) every 3 weeks for a maximum of 8 cycles (6 months of treatment). Imaging, internal endoscopic exam and ctDNA blood draw will be performed at 6 weeks and every 3 months during induction anti-PD-1 treatment. Adverse events and surgical complications will be graded according to the NCI CTCAE v5 and the Clavien-Dindo classification, respectively. Following neoadjuvant checkpoint blockade, patients will undergo conventional chemoradiotherapy followed by surgical resection. The primary endpoint is pathologic complete response compared with historical control in pMMR patients. Patients will be followed up every 6 months for assessment of disease-free survival for up to five years. Clinical trial information: NCT04165772 .