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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.

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

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 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.

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.

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.

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.

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: 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.

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.

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.

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.

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 .

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

role of liver-directed chemotherapy and loco-regional interventions in managing colorectal cancer liver metastases

To review outcomes following microwave ablation (MWA) of colorectal cancer pulmonary metastases and assess predictors of oncologic outcomes.Technical success, primary and secondary technique efficacy rates were evaluated for 50 patients with 90 colorectal cancer pulmonary metastases at immediate, 4-8 weeks post-MWA and subsequent follow-up CT and/or F-18-FDG PET/CT. Local tumor progression (LTP) rate, LTP-free survival (LTPFS), cancer-specific and overall survivals were assessed. Complications were recorded according to SIR classification.Median follow-up was 25.6 months. Median tumor size was 1 cm (0.3-3.2 cm). Technical success, primary and secondary technique efficacy rates were 99, 90 and 92%, respectively. LTP rate was 10%. One-, 2- and 3-year LTPFS were: 93, 86 and 86%, respectively, with median LTPFS not reached. Median overall survival was 58.6 months, and median cancer-specific survival (CSS) was not reached. One-, 2- and 3-year overall and CSS were 94% and 98, 82 and 90%, 61 and 70%, respectively. On univariate analysis, minimal ablation margin (p = 5 mm and/or tumor size 10 ng/ml (p = 0.046) and >= 3 prior chemotherapy lines predicted decreased CSS (p = 0.02). There was no 90-day death. Major complications rate was 13%.MWA with minimal ablation margin >= 5 mm is essential for local control of colorectal cancer pulmonary metastases. Pleural-based metastases and larger tumor size were associated with higher risk of LTP. CEA level and pre-MWA chemotherapy impacted CSS.

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.

Colorectal liver metastases (CRLM) receive their blood supply predominantly through the hepatic artery. Intra-arterial drug delivery can optimize the dose and time exposure of chemotherapy to tumor cells while limiting systemic toxicity. Chemotherapy is most commonly administered through a catheter surgically placed in the gastroduodenal artery and connected to a subcutaneous pump. Due to its pharmacokinetics features, floxuridine is the most commonly used drug in the USA with hepatic arterial infusional (HAI) chemotherapy. To date, many clinical trials have shown the positive impact of HAI in the management of CRLM. Hence, in unresectable patients, HAI is associated with high response rates and commonly enables subsequent resection in both chemonaive and previously treated patients. Outcomes in patients converted to complete resection are similar to patients who present with initially resectable disease. In the adjuvant setting, HAI with floxuridine improves survival as well as hepatic and overall disease-free survival after complete resection of CRLM, as compared with 5-FU alone, in three of four randomized studies. To date, no trials have compared HAI combined with modern chemotherapy alone to modern chemotherapy alone in the adjuvant setting.

Evaluate conversion rate of patients with unresectable colorectal-liver metastasis to complete resection with hepatic-arterial infusion plus systemic chemotherapy including bevacizumab (Bev).Forty-nine patients with unresectable colorectal liver metastases (CRLM) were included in a single-institution phase II trial. Conversion to resection was the primary outcome. Secondary outcomes included overall survival (OS), progression-free survival, and response rates. Multivariate and landmark analyses were performed to evaluate survival differences between resected and nonresected patients.Median number of tumors was 14 and 65% were previously treated patients. A high biliary toxicity rate was found in the first 24 patients whose treatment included Bev. The remaining 25 patients were treated without Bev. Overall response rates were 76% (4 complete responses). Twenty-three patients (47%) achieved conversion to resection at a median of 6 months from treatment initiation. Median OS and progression-free survival for all patients were 38 (95% confidence interval: 28 to not reached) and 13 months (95% confidence interval: 7-16). Bev administration did not impact outcome. Conversion was the only factor associated with prolonged OS and progression-free survival in multivariate analysis. On landmark analysis, patients who had undergone resection had longer OS than those who did not undergo resection (3-year OS: 80% vs 26%). Currently, 10 of 49 (20%) patients have no evidence of disease (NED) at a median follow-up of 39 months (32-65 months).In patients with extensive unresectable CRLM, the majority of whom were previously treated, 47% were able to undergo complete resection after combined HAI and systemic therapy. Conversion to resection is associated with prolonged survival.

Patients with recurrence after complete resection of colorectal liver metastases (CLM) are considered for repeat resection as a potential salvage therapy (PST). However, outcomes for this approach are not well defined. We sought to analyze the natural history of recurrence and PST in a large cohort of patients with long-term follow-up. Recurrence patterns, treatments, and outcomes in consecutive patients undergoing resection for colorectal liver metastases were analyzed retrospectively. PST was defined as repeat resection of all recurrent disease and effective salvage therapy (EST) as free of disease for 36 months after last PST. Factors associated with PST, EST, and outcomes were analyzed. Of 952 patients who underwent resection, 594 (62 %) experienced recurrence (median interval = 13 months). Initial recurrences involved liver (n = 157,26 %), lung (n = 167,28 %), multiple sites (n = 171,29 %), and other single sites (n = 99,17 %). PST was performed in 160 (27 %) of 594, most commonly with a single site of recurrence (n = 149). Young age (p = 0.01), negative initial resection margin (p = 0.003), initial tumor size

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

Metastatic colorectal cancers (mCRCs) are clinically heterogeneous, but the genomic basis of this variability remains poorly understood. We performed prospective targeted sequencing of 1,134 CRCs. We identified splice alterations in intronic regions of APC and large in-frame deletions in CTNNB1, increasing oncogenic WNT pathway alterations to 96% of CRCs. Right-sided primary site in microsatellite stable mCRC was associated with shorter survival, older age at diagnosis, increased mutations, and enrichment of oncogenic alterations in KRAS, BRAF, PIK3CA, AKT1, RNF43, and SMAD4 compared with left-sided primaries. Left-sided tumors frequently had no identifiable genetic alteration in mitogenic signaling, but exhibited higher mitogenic ligand expression. Our results suggest different pathways to tumorigenesis in right- and left-sided microsatellite stable CRC that may underlie clinical differences.

Colorectal cancer is a significant global health issue with over 1 million cases diagnosed annually throughout the world. 15% of patients diagnosed with colorectal cancer will have liver metastases and 60% will develop liver metastases if they have metastatic disease. Oligometastatic colorectal cancer confined to the liver represents an intermediate state in the evolution of metastatic capacity that opens the opportunity for local interventions. Areas covered: The literature supports long-term survival if patients undergo liver resection of colorectal metastases. This article reviews the liver-directed therapeutic strategies available for the management of metastatic liver disease including hepatic arterial infusion therapy, radiofrequency ablation, radiation therapy and transarterial chemoembolization. Expert commentary: Great advances have been made with the use of liver directed therapies. In the USA using hepatic arterial infusions with FUDR and Decadron along with systemic therapy, 5 year survivals after liver resection have improved. In Europe with the use of HAI of Oxaliplatin, more patients have been able to get to resection and have obtained higher survival rates, even in second line therapy. New advances in ablative therapy have improved results to get all disease treated at resection for the treatment of reccurrence.

Purpose: NRAS mutations are now routinely included in RAS testing prior to EGFR inhibitor therapy for metastatic colorectal cancer (mCRC). The clinical implications of NRAS mutation beyond lack of response to anti-EGFR therapy, however, are not known. We undertook this study to determine the clinical features and treatment outcomes of patients with NRAS-mutant mCRC. Experimental Design: We reviewed clinical characteristics, concurrent mutations, and outcomes for all mCRC cases with NRAS mutations undergoing standard genotyping at our institution from 2008 to 2015. Comparison groups consisted of RAS wild-type and KRAS-mutant mCRC consecutive cases genotyped from 2008 to 2012. Results: Three percent (87/2764) of mCRC patients had NRAS-mutant tumors (45% exon 2 and 55% exon 3), including three cases with concurrent NRAS and KRAS mutations. Left-sided primary site and African American self-reported race were associated with NRAS mutation (P < 0.01). Resection rate at 12 months was lower for NRAS-mutant mCRC than for RAS wild-type or KRAS-mutant mCRC. Median survival from time of first known metastasis was 33 months for NRAS-mutant, 47 months for KRAS-mutant, and 78 months for RAS wild-type cases (P < 0.001). Multivariate analysis assigned an HR for overall survival of 2.0 for NRAS mutation and 1.5 for KRAS mutation (P < 0.01). Conclusions: NRAS defines a molecular subset with distinct clinical characteristics from KRAS-mutant and wild-type mCRC. NRAS mutations are enriched in left-sided primary tumors and among African Americans. Mutations in NRAS are associated with poor survival and worse outcomes than either KRAS-mutant or wild-type mCRC. Clin Cancer Res; 23(16); 4753–60. ©2017 AACR.

BACKGROUND RAS and PIK3CA mutations in metastatic colorectal cancer (mCRC) have been associated with worse survival. We sought to evaluate the impact of RAS and PIK3CA mutations on cumulative incidence of metastasis to potentially curable sites of liver and lung and other sites such as bone and brain. METHODS We performed a computerized search of the electronic medical record of our institution for mCRC cases genotyped for RAS or PIK3CA mutations from 2008 to 2012. Cases were reviewed for patient characteristics, survival, and site-specific metastasis. RESULTS Among the 918 patients identified, 477 cases were RAS wild type, and 441 cases had a RAS mutation (394 at KRAS exon 2, 29 at KRAS exon 3 or 4, and 18 in NRAS). RAS mutation was significantly associated with shorter median overall survival (OS) and on multivariate analysis independently predicted worse OS (HR, 1.6; P

BACKGROUND The validity of the KRAS mutation as a predictor of recurrence-free survival (RFS) or overall survival (OS) is unclear. The current study investigated whether the presence of the KRAS mutation decreased RFS or OS in patients with colorectal cancer who underwent liver resection. METHODS Patients with resected colorectal liver metastases who received adjuvant hepatic arterial infusion plus systemic therapy and for whom KRAS data was available were evaluated. Correlation between KRAS and clinical factors was done using the Fisher exact test. Kaplan-Meier methods were used to estimate the median RFS and OS. RESULTS A total of 169 patients were evaluated, 118 of whom had KRAS wild-type (WT) and 51 had KRAS mutated (MUT) tumors. The 3-year RFS rate was 46% for patients with KRAS WT (95% confidence interval [95% CI], 35%-56%) and 30% (95% CI, 16%-44%) for patients with KRAS MUT (P =.005). The 3-year OS rate was 95% (95% CI, 87%-98%) and 81% (95% CI, 62%-95%), respectively, for patients with KRAS WT and KRAS MUT (P =.07). On multivariate analysis, KRAS remained a significant predictor of RFS (hazard ratio, 1.9). The 3-year cumulative recurrence rate by site of metastases was as follows: 2% versus 13.4% for bone (P≤.01), 2% versus 14.5% for brain (P =.05), 33.2% versus 58% for lung (P≤.01), and 30% versus 47% for liver (P =.10) in patients with KRAS WT versus KRAS MUT. CONCLUSIONS In the current study, among patients with resected colorectal liver metastases who were treated with adjuvant hepatic arterial infusion plus systemic therapy, patients with KRAS MUT were found to have a significantly worse 3-year RFS (30%) compared with KRAS WT (46%) p=.005. The cumulative incidence of bone, brain, and lung metastases was significantly higher for patients with KRAS MUT compared with those with KRAS WT. Cancer 2014;120:3965–3971. © 2014 American Cancer Society.

The mechanisms that allow colon cancer cells to form liver and lung metastases, and whether KRAS mutation influences where and when metastasis occurs, are unknown. We provide clinical and molecular evidence showing that different MAPK signalling pathways are implicated in this process. Whereas ERK2 activation provides colon cancer cells with the ability to seed and colonize the liver, reduced p38 MAPK signalling endows cancer cells with the ability to form lung metastasis from previously established liver lesions. Downregulation of p38 MAPK signalling results in increased expression of the cytokine PTHLH, which contributes to colon cancer cell extravasation to the lung by inducing caspase-independent death in endothelial cells of the lung microvasculature. The concerted acquisition of metastatic traits in the colon cancer cells together with the sequential colonization of liver and lung highlights the importance of metastatic lesions as a platform for further dissemination.

BACKGROUND BRAF mutations occur in 5% to 11% of patients with metastatic colorectal cancer (mCRC) and have been associated with poor prognosis. The current study was undertaken to determine the clinicopathologic characteristics, PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) mutation frequency, and outcomes after metastasectomy in patients with BRAF-mutant mCRC. METHODS Data from 1941 consecutive patients with mCRC who underwent KRAS/BRAF mutation testing between 2009 and 2012 at a single institution were identified to identify BRAF-mutant mCRC cases (92 cases). BRAF wild-type mCRC cases from 2011 (423 cases) served as a control group. RESULTS BRAF-mutated mCRC was found to be significantly associated with older age at diagnosis, female sex, right-sided location, poorly differentiated morphology, and mucinous histology compared with wild-type cases. BRAF-mutant cases more frequently progressed from stage III disease (32% vs 17%; P = .003) and among those patients with stage III disease, T4 disease was more common (48% vs 27%; P = .05). PIK3CA was found to be co-mutated in 5% of BRAF-mutant tumors versus 17% of KRAS-mutant tumors (P

3555 Background: HAI therapy has improved recurrence free (RF) survival in several randomized trials after resection of CRLM. The purpose of this trial was to determine whether systemic Pmab added to adjuvant HAI + FOLFIRI in RAS WT pts increases 15 months RF survival (RFS) after liver resection. Secondary endpoints are evaluation of overall survival, toxicity, and predictive biomarkers. Methods: RAS WT pts with resected liver mets were randomized to HAI + SYS (+/-) Pmab after stratification by clinical risk score (≥ 3 or < 3) and previous chemotherapy (Y/N). For a particular arm, if 24 or more patients (pts) were alive and RF at 15 months, the regimen in that arm would be considered worthy of further investigation. The initial dose of HAI FUDR 0.12mg/Kg + dexamethasone was infused over the first 2 weeks of a 5-week cycle. Systemic chemotherapy was delivered on days 15 and 29 (irinotecan 125 mg/m2, LV 400 mg/ m2, 5FU 1000 mg/m2 48-hour continuous infusion and +/- Pmab 6mg/kg). Patient characteristics were compared between arms using Fisher’s exact test and Wilcoxon rank-sum test. Survival curves were estimated using the Kaplan-Meier method and compared by the log-rank test. Results: After randomization of 75 pts, the arm receiving + Pmab met the decision rule of having ≥ 24 patients alive and RF at 15 months. The two arms had similar pt characteristics and toxicity, with the exception of Pmab related rash (Table). The 15-month RFS is 79% and 67% in +/- Pmab arms, respectively. With a median follow-up of 45 months, 3-year RFS is 65% [CL 0.45-0.78] and 42% [CL 0.24-0.57], and 3-year survival is 96% and 90% in +/-Pmab arms, respectively. Conclusions: In this trial, the addition of Pmab to HAI and SYS showed promising activity without increase in biliary toxicity and should be further investigated in a larger study. Predictive biomarkers will be presented. Clinical trial information: NCT01312857. [Table: see text]

3585 Background: We assembled a large series of consecutive patients with unresectable metastatic colorectal cancer (mCRC) to identify genomic biomarkers of response and survival. Methods: Patients with unresectable mCRC treated at Memorial Sloan Kettering with genomic tumor profiling between 2014 and 2017 were included. Patients who underwent upfront metastasectomy or received neoadjuvant/conversion chemotherapy were excluded. Clinical information was retrieved from electronic medical records, and we evaluated associations between genomic profiles with progression free survival (PFS) on first-line chemotherapy and overall survival (OS). Categorical data were analyzed by Fisher exact test and time-to-event data were analyzed by Cox proportional hazards models. Results: Of 1453 mCRCs profiled in this period, 471 patients met the study criteria. Median age was 59 years (range, 18 to 95), and 73% of patients were stage IV at diagnosis. Most tumors (91%) were microsatellite stable (MSS). The most frequent first-line regimen was FOLFOX +/- bevacizumab (66%). Among MSS patients treated with oxaliplatin-containing regimens (n = 305), 7% harbored alterations in genes associated with DNA damage response (DDR) (BRCA1, BRCA2, ATM, PALB2). DDR gene alterations were not associated with PFS (P = 0.94) nor were different quartiles of large-state transitions (P = 0.54). Genomic alterations that significantly varied by duration of response included BRAF (16%, 10%, and 5% for PFS < 6 months, 6-12 months, and > 12 months, respectively) and APC (62%, 74%, and 80% for PFS < 6 months, 6-12 months, and > 12 months, respectively). APC mutation, single or dual, was associated with significantly longer PFS (HR 0.67) and OS (HR 0.59) in multivariate analysis versus no WNT pathway alteration or alterations in other WNT pathway genes (RNF43, AXIN2, CTNNB1). Conclusions: In unresectable mCRC patients, mutations in APC were associated with better outcomes; absence of an APC alteration or the occurrence of other WNT pathway alterations was associated with shorter survival. Somatic alterations in DDR genes were not associated with outcomes in mCRC patients receiving oxaliplatin-containing regimen.

Introduction This prospective study assessed the safety and outcomes of selective internal radiation therapy (SIRT) using yttrium-90 ( 90 Y) resin microspheres as a salvage therapy for liver-predominant metastases of colorectal cancer in patients with documented progression after hepatic arterial chemotherapy (HAC) and systemic chemotherapy. Patients and Methods We recruited 19 patients who had received a mean of 2.9 prior lines of chemotherapy and ≥ 1 line of HAC. Dose-limiting toxicities (grade 3 or higher) were catalogued using Common Terminology Criteria for Adverse Events version 3.0. At 4 to 8 weeks and 3 to 4 months post SIRT, responses were assessed by carcinoembryonic antigen (CEA), and quantitative imaging using Response Evaluation Criteria in Solid Tumors (RECIST) and PET Response Criteria in Solid Tumors (PERCIST). Liver progression-free survival (LPFS), progression-free survival (PFS), and overall survival (OS) were calculated using Kaplan-Meier methodology. Results Median follow-up was 31.2 months after SIRT. Within 6 weeks of SIRT, 3 patients (15.8%) experienced grade 3 toxicity. There was no incidence of radiation-induced liver disease. Responses by RECIST, PERCIST, and CEA were, respectively, 0%, 20%, and 32% at 4 to 8 weeks and 5%, 33%, and 21% at 3 to 4 months post SIRT; 53% of patients had stable disease (by RECIST) at 3 to 4 months. Of 19 patients, 4 (21.1%) had liver ablation, 9 (47%) received additional HAC, and 17 (89%) received systemic chemotherapy after SIRT. Median LPFS, PFS, and OS after SIRT were 5.2 months, 2.0 months, and 14.9 months, respectively. Conclusion SIRT was well tolerated and did not prohibit subsequent treatment, resulting in a median OS of 14.9 months in this heavily pretreated population.

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. 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. 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

In the 1950s, colon cancer was the poor stepchild for chemotherapists, with a median survival of 12 months for patients with metastatic disease. Now patients with metastatic disease, even hepatic metastases, can survive 5 years when surgical techniques for liver resection and new chemotherapy, with or without targeted agents, are used. In the article that accompanies this editorial, Ye et al prospectively randomly assigned patients with unresectable, liver-limited metastases (KRAS wild type) to systemic chemotherapy with or without cetuximab (Cetx). The primary end point was the number of patients converted to hepatic resection. The patients receiving chemotherapy plus Cetx had a significantly higher resection rate: 25% versus 7.4%. The patients were well matched for individual prognostic factors, but the two study groups differed slightly: high clinical risk score of 25% versus 35%; rectal primaries, 38% versus 48%; lesion larger than 5 cm, 44% versus 55%; and major vessel involvement, 37% versus 44%, for the chemotherapy plus Cetx group versus chemotherapy group, respectively. Overall, the chemotherapy plus Cetx group had 22% fewer patients with poor prognostic indicators. This may explain why patients who underwent resection and did not receive Cetx had a shorter survival than those who received chemotherapy plus Cetx (median survival, 22 months v 34.8 months, respectively). The 5-year survival rates obtained with liver resection, 30% to 50%, are superior to rates of survival obtained with systemic chemotherapy alone. Early studies showed a 30% 5-year survival for patients who had resection of one to three liver metastases. More recent studies have shown that resection is possible in patients with a greater volume of disease. Currently, the main consideration is not the total number of liver metastases but whether enough viable liver can be preserved to provide adequate liver function. What about patients with initially unresectable disease that becomes resectable after chemotherapy— what is their survival? French investigators have shown that patients withunresectablediseasewhosediseasebecomesresectableafterchemotherapy have a similar prognosis as those whose disease was initially resectable, with 5-year survivals of 33% for the converted group. To examine long-term outcomes: of 184 patients with unresectable disease whose disease became resectable and who were followed for 5 years or more, 33% had a 5-year survival and 27% had a 10-year survival. There was a greater chance of achieving long-term survival with fewer than three metastases. Others have reported a 23% actual 5-year survival in downstaged patients. In patients with resectable disease, trials should address whether neoadjuvant therapy is useful and, if so, what type of therapy should be used. A European Organisation for Research and Treatment of Cancer (EORTC) study that used both preoperative and postoperative therapy stated that preoperative chemotherapy was beneficial, given that there was an increase in 3-year disease-free survival (DFS) in the treated group versus the surgery alone group (36.2% v 27.8%, respectively, for eligible patients). There was no difference in 5-year survival (51.2% v 47.8%). The benefit of preoperative chemotherapy is not clear because patients received both preand postoperative therapy. Ninety-four percent of these patients had one to three liver metastases and other favorable characteristics. Do patients with good characteristics need preoperative chemotherapy? Are there poor-risk groups who would be helped by preoperative chemotherapy? In patients with unresectable hepatic metastases whose disease can be converted to resectable disease, what is the best preoperative chemotherapy regimen? The article by Ye et al attempts to answer this conversion question. For this type of trial, what is the definition of resectability? A multidisciplinary hepatobiliary team is needed to address this question. Are certain types of patients less likely to have disease that can be made resectable, such as patients with involvement of hepatic veins or inferior vena cava involvement? A Memorial SloanKettering Cancer Center trial outlined the reasons for unresectability for each patient and then reported which of these patients had disease that was made resectable, thus providing a framework to compare studies. Are there patients whose disease can be made resectable but who do not benefit from resection? Do some patients have a higher recurrence rate? Do techniques that enable more patients to undergo resection, such as portal vein embolization, two-stage resection, and radiofrequency ablation, produce a higher rate of recurrence? These are questions that need to be addressed in future trials. Is adjuvant chemotherapy after hepatic resection useful? The initial randomized trials of fluorouracil/leucovorin versus no treatment did not show a clear increase in progression-free survival, but a multivariable pooled analysis of two studies showed a significant benefit. Adding irinotecan to fluorouracil/leucovorin did not increase overall survival or DFS. Infusional fluorouracil, leucovorin, and oxaliplatin after resection has not been tested in a randomized study. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 16 JUNE 1 2013

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

While the significance of carcinoembryonic antigen (CEA), lactate dehydrogenase (LDH), and Kirsten rat sarcoma (KRAS) status as individual prognostic factors for patients with metastatic colorectal cancer has been addressed, the relationship and interdependence between these prognostic factors on survival is limited.Patients with unresectable colorectal liver metastases with known KRAS status, and with baseline CEA and LDH levels who were treated with hepatic arterial infusion and systemic chemotherapy were identified. Patients were divided into two groups: hepatic-only disease and extra-hepatic disease.A total of 193 patients were included: 121 with hepatic-only and 72 with extra-hepatic disease. In the hepatic-only group, median overall survival (OS) was 55 months. On multivariate analysis, KRAS mutated tumors (HR 1.7, P 0.05), LDH200 U/L (HR 2.0, P 0.05), and prior chemotherapy (HR 2.1, P 0.05) had lower OS. In patients with extra-hepatic disease, median OS was 32 months. On multivariate analysis, baseline CEA200 ng/mL (HR 2.1, P = 0.051), LDH200 U/L (HR 3.8, P 0.05), and right-sided tumors (HR 2.8, P 0.05) had lower OS.This analysis verifies two distinct patterns in terms of biomarkers in patients with unresectable colorectal liver metastases. In patients with hepatic-only disease, KRAS mutation and elevated LDH negatively influenced survival. In patients with extra-hepatic disease, elevated LDH negatively impacted survival.

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

This study was designed to evaluate the relationship between the minimal margin size and local tumor progression (LTP) following CT-guided radiofrequency ablation (RFA) of colorectal cancer liver metastases (CLM).An institutional review board-approved, HIPPA-compliant review identified 73 patients with 94 previously untreated CLM that underwent RFA between March 2003 and May 2010, resulting in an ablation zone completely covering the tumor 4-8 weeks after RFA dynamic CT. Comparing the pre- with the post-RFA CT, the minimal margin size was categorized to 0, 1-5, 6-10, and 11-15 mm. Follow-up included CT every 2-4 months. Kaplan-Meier methodology and Cox regression analysis were used to evaluate the effect of the minimal margin size, tumor location, size, and proximity to a vessel on LTP.Forty-five of 94 (47.9 %) CLM progressed locally. Median LTP-free survival (LPFS) was 16 months. Two-year LPFS rates for ablated CLM with minimal margin of 0, 1-5 mm, 6-10 mm, 11-15 mm were 26, 46, 74, and 80 % (p 0.011). Minimal margin (p = 0.002) and tumor size (p = 0.028) were independent risk factors for LTP. The risk for LTP decreased by 46 % for each 5-mm increase in minimal margin size, whereas each additional 5-mm increase in tumor size increased the risk of LTP by 22 %.An ablation zone with a minimal margin uniformly larger than 5 mm 4-8 weeks postablation CT is associated with the best local tumor control.

BACKGROUND: The optimal combination of available therapies for patients with resectable synchronous liver metastases from rectal cancer (SLMRC) is unknown, and the pattern of recurrence after resection has been poorly investigated. In this study, the authors examined recurrence patterns and survival after resection of SLMRC. METHODS: Consecutive patients with SLMRC (disease-free interval, ≤12 months) who underwent complete resection of the rectal primary and liver metastases between 1990 and 2008 were identified from a prospective database. Demographics, tumor-related variables, and treatment-related variables were correlated with recurrence patterns. Competing risk analysis was used to determine the risk of pelvic and extrapelvic recurrence. RESULTS: In total, 185 patients underwent complete resection of rectal primary and liver metastases. One hundred eighty patients (97%) received chemotherapy during their treatment course, and 91 patients (49%) received pelvic radiation therapy either before (N = 65; 71.4%), or after (N = 26; 28.6%) rectal resection. The 5-year disease-specific survival rate was 51% for the entire cohort with a median follow-up of 44 months for survivors. One hundred thirty patients (70%) developed a recurrence: Eighteen patients (10%) had recurrences in the pelvis in combination with other sites, and 7 of these (4%) had an isolated pelvic recurrence. Recurrence pattern did not correlate with survival. Competing risk analysis demonstrated that the likelihood of a pelvic recurrence was significantly lower than that of an extrapelvic recurrence (P < .001). CONCLUSIONS: Of the patients with SLMRC who developed recurrent disease, systemic sites were overwhelmingly more common than pelvic recurrences. The current results indicated that the selective exclusion of radiotherapy may be considered in patients who are diagnosed with simultaneous disease. Cancer 2012. © 2012 American Cancer Society.

Hepatic resection for limited metastatic colorectal cancer to the liver (CRLM) is a surgical success story. An associated long-term survival after resection of CRLM has been known for decades. Furthermore, it has now been demonstrated that complete resection of limited CRLM is associated with cure, meaning alive and free of disease 10 years after resection. In most modern series, 5-year survival rates after complete resection are more than 50 % with actual cure rates estimated to be as high as 20– 25 %. For example, at Memorial Sloan Kettering Cancer Center patients with limited CRLM treated on trial with adjuvant hepatic artery infusional (HAI) floxuridine (5FUDR) and systemic 5-fluorouracil (5-FU) had 5and 10year survival rates of 59 and 40 %, respectively. More recently, in our patients treated on trial with adjuvant HAI and modern systemic chemotherapy, the 5-year survival rate has increased to greater than 70 %. While selection bias has an impact on some of the overall survival statistics, the potential for cure truly drives the incentive to operate. An important point also is that hepatic resection is now a safe procedure. Many may recall the days of massive blood loss and high mortality rates, but currently hepatic resection for metastases is performed with low blood loss and mortality rates of approximately 1 %. Chemotherapy for metastatic colorectal cancer has significantly improved during the past two decades. Response rates in excess of 50 % are commonly reported and 5-year survival rates approaching 10 % are seen in selected patients on trials. Unfortunately, systemic chemotherapy alone does not cure patients with CRLM and mandates chronic therapy. Interestingly, this improvement in outcomes seen in patients with unresectable disease has not translated into an improved survival when systemic therapy is given as an adjuvant following hepatic resection. This has now been shown in four randomized trials. Therefore, hepatic resection for limited liver-only metastatic colorectal cancer is the only potentially curative treatment option. In this nicely written manuscript by Krell et al., it is well demonstrated that medical oncologists (at least in Michigan) are not consistent in their referral practices for patients with CRLM. The majority of the surveyed oncologists work in a community setting that is likely representative of most of the country. Another interesting point is that approximately one-third of the oncologists stated that they did not have a liver surgeon whom to refer patients. As in most good studies, the authors demonstrate some simple but important points. The heterogeneity in referral practices is staggering. Referral rates to liver surgeons range from nearly never to nearly always. Single prognostic factors are commonly used by these oncologists to help decide whether to refer a patient. Many (approximately 40 % of respondents) consider metastasis size and presence of bilateral disease each to be contraindications to hepatic resection. This is troubling, because neither of these findings alone precludes cure or long-term survival. As an example, if a patient presents 2 years after resection of a node-negative primary colon cancer with two or three small hepatic metastases that happen to be on both sides of the liver (bilateral), many of the surveyed oncologists stated that they would not refer to a surgeon. This patient’s disease is potentially curable and should be assessed by a hepatic surgeon. It is unclear why patients are not being referred; is it lack of a liver surgeon in the oncologist’s practice area? Is it misinformation or misconceptions about Society of Surgical Oncology 2015

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.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.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 (P0.01). 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), P0.01.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.