Primary Tumor Nodal Status Research Articles

Long-term Oncological Outcomes after Resection and Thermal Ablation of Colorectal Liver Metastases: A Propensity Score Matched Analysis

Introduction: Thermal ablation of colorectal liver metastases is mostly used where resection is not possible, but has recently emerged as a parenchyma-sparing alternative to resection. High-quality data comparing oncological outcomes after resection and ablation of colorectal liver metastases are wanting. Method: Data for patient with colorectal liver metastases treated with laparoscopic resection at Oslo University Hospital between 2007 and 2020 was extracted from a prospectively maintained database and compared to patients undergoing ablation (radiofrequency or microwave). The primary endpoint was overall survival (OS). An average treatment effect (ATE) and potential-outcome means analysis using inverse-probability assignment and censoring using prognostic variables (CEA, largest tumor size, synchronous disease, primary tumor nodal status and sidedness, chemotherapy, previous liver surgery and others). Results: We identified 223 ablation sessions and 765 resection sessions available for comparison. The 5-year OS was 53% in the ablation group and 51% in the resection group. Median OS was 62,4 months (ablation) and 61,6 months (resection). The ATE for ablation versus resection was estimated to be 0,47 months (95% CI -8,1 to 9,9; P=0,92), meaning if every patient was treated with ablation, the average time to death would be 0,47 months longer than if every patient was treated with resection. A complete dataset including local recurrence will be presented at the meeting. Conclusion: Thermal ablation in patients with colorectal liver metastases was associated with rates of OS similar to surgical resection. Our results indicate adequate equipoise for a randomized trial to overcome selection bias.

Extended Molecular Profiling Improves Stratification and Prediction of Survival After Resection of Colorectal Liver Metastases.

The aim of this study was to assess the effect of cancer-related genes and their mutations analyzed by next-generation sequencing (NGS) on the oncological outcome after resection of colorectal liver metastases (CRLM). Traditional prognostic scores include clinical and pathological parameters of primary tumor and metastases. The modified clinical risk score (m-CS), based on size of metastases, primary tumor nodal status, and RAS mutation status outperformed traditional scores. We hypothesized to further improve the scoring system based on the results of NGS. Cancer tissues of 139 patients with CRLM were used for NGS. The work-up included the analysis of recurrent somatic mutations and copy number changes of 720 genes. Clinical data were extracted from a prospectively collected institutional liver database. Depending on significance, the following cancer-related genes and their alterations (%) were further investigated: APC (86%), TP53 (78%), KRAS (29%), SMAD4 (15%), PIK3CA (14%), BRAF (8%), ERBB2 (6%), SMAD3 (5%), SMAD2 (4%), and NRAS (4%). The most predictive parameters for poor oncological outcome were alterations in the SMAD family (P = 0.0186) and RAS-RAF pathway (P = 0.032). Refining the m-CS by replacing RAS with RAS-RAF pathway and adding SMAD family resulted in an extended clinical risk score which is highly predictive for oncological outcome (P < 0.0001). In conclusion, mutations of the SMAD family revealed a strong prognostic effect after surgery for CRLM. Integration of alterations of the SMAD family as well as the RAS/RAF pathway resulted in a new, still simple but highly prognostic score.

RAS Mutation Clinical Risk Score to Predict Survival After Resection of Colorectal Liver Metastases.

To determine the impact of RAS mutation status on the traditional clinical score (t-CS) to predict survival after resection of colorectal liver metastases (CLM). The t-CS relies on the following factors: primary tumor nodal status, disease-free interval, number and size of CLM, and carcinoembryonic antigen level. We hypothesized that the addition of RAS mutation status could create a modified clinical score (m-CS) that would outperform the t-CS. Patients who underwent resection of CLM from 2005 through 2013 and had RAS mutation status and t-CS factors available were included. Multivariate analysis was used to identify prognostic factors to include in the m-CS. Log-rank survival analyses were used to compare the t-CS and the m-CS. The m-CS was validated in an international multicenter cohort of 608 patients. A total of 564 patients were eligible for analysis. RAS mutation was detected in 205 (36.3%) of patients. On multivariate analysis, RAS mutation was associated with poor overall survival, as were positive primary tumor lymph node status and diameter of the largest liver metastasis >50 mm. Each factor was assigned 1 point to produce a m-CS. The m-CS accurately stratified patients by overall and recurrence-free survival in both the initial patient series and validation cohort, whereas the t-CS did not. Modifying the t-CS by replacing disease-free interval, number of metastases, and CEA level with RAS mutation status produced an m-CS that outperformed the t-CS. The m-CS is therefore a simple validated tool that predicts survival after resection of CLM.

Survival Impact of Primary Tumor Lymph Node Status and Circulating Tumor Cells in Patients with Colorectal Liver Metastases

ObjectiveThe aim of this study was to analyse the survival impact of primary tumor nodal status (N0/N+) in patients with resectable colorectal liver metastases (CLM), and to determine the value of circulating and disseminated tumor cells (CTCs/DTCs) in this setting.MethodsIn this prospective study of patients undergoing resection of CLM from 2008 to 2011, peripheral blood was analyzed for CTCs using the CellSearch System®, and bone marrow was sampled for DTC analyses just prior to hepatic resection. The presence of one or more tumor cells was scored as CTC/DTC-positive. Following resection of the primary tumor, the lymph nodes (LNs) were examined by routine histopathological examination.ResultsA total of 140 patients were included in this study; 38 patients (27.1%) were negative at the primary colorectal LN examination (N0). CTCs were detected in 12.1% of all patients; 5.3% of patients in the N0 group and 14.7% of patients in the LN-positive (N+) group (p = 0.156), with the LN-positive group (N+) consisting of both N1 and N2 patients. There was a significant difference in recurrence-free survival (RFS) when analysing the N0 group versus the N+ group (p = 0.007) and CTC-positive versus CTC-negative patients (p = 0.029). In multivariate analysis, CTC positivity was also significantly associated with impaired overall survival (OS) [p = 0.05], whereas DTC positivity was not associated with survival.ConclusionIn this cohort of resectable CLM patients, 27% had primary N0 colorectal cancer. Assessment of CTC in addition to nodal status may contribute to improved classification of patients into high- and low-risk groups, which has the potential to guide and improve treatment strategies.

The Prognostic Value of the Primary Tumor's Nodal Status after Surgery for Colorectal Liver Metastases in the Era of Effective Systemic Therapy

Background: The nodal status of primary colorectal cancer is of prognostic value for survival after the resection for colorectal liver metastases (CRLM). However, in the past decade, effective adjuvant chemotherapy for lymph node positive primary colon cancer was introduced. This study evaluated the prognostic value of primary lymph node status in patients with resectable metachronous CRLM in the era of effective systemic therapy. Methods: Between January 2000 and December 2011, all consecutive patients undergoing curative liver resection for CRLM were retrospectively analyzed. Overall survival (OS) was analyzed by the localization of the primary tumor (colon vs. rectum) and by lymph node status (positive vs. negative) of the primary tumor. Results: A total of 286 patients with metachronous CRLM's were selected. Five-year OS was similar for colon and rectal primaries (42 and 40%, p = 0.62). Lymph node positivity was only a prognostic factor in rectal primaries (N+ 32% vs. N0 49%, p = 0.04) and not in colon primaries (N+ 42% vs. N0 41%, p = 0.99). In multivariate analysis, these results were confirmed. Conclusion: The current study demonstrates that the nodal status of primary colon malignancies does not have prognostic value in patients undergoing resection for metachronous CRLM. A possible explanation might be the administration of effective adjuvant chemotherapy in node positive colon cancer.

An optimized five-gene multi-platform predictor of hormone receptor negative and triple negative breast cancer metastatic risk

IntroductionOutcome predictors in use today are prognostic only for hormone receptor-positive (HRpos) breast cancer. Although microarray-derived multigene predictors of hormone receptor-negative (HRneg) and/or triple negative (Tneg) breast cancer recurrence risk are emerging, to date none have been transferred to clinically suitable assay platforms (for example, RT-PCR) or validated against formalin-fixed paraffin-embedded (FFPE) HRneg/Tneg samples.MethodsMultiplexed RT-PCR was used to assay two microarray-derived HRneg/Tneg prognostic signatures IR-7 and Buck-4) in a pooled FFPE collection of 139 chemotherapy-naïve HRneg breast cancers. The prognostic value of the RT-PCR measured gene signatures were evaluated as continuous and dichotomous variables, and in conditional risk models incorporating clinical parameters. An optimized five-gene index was derived by evaluating gene combinations from both signatures.ResultsRT-PCR measured IR-7 and Buck-4 signatures proved prognostic as continuous variables; and conditional risk modeling chose nodal status, the IR-7 signature, and tumor grade as significant predictors of distant recurrence (DR). From the Buck-4 and IR-7 signatures, an optimized five-gene (TNFRSF17, CLIC5, HLA-F, CXCL13, XCL2) predictor was generated, referred to as the Integrated Cytokine Score (ICS) based on its functional pathway linkage through interferon-γ and IL-10. Across all FFPE cases, the ICS was prognostic as either a continuous or dichotomous variable, and conditional risk modeling selected nodal status and ICS as DR predictors. Further dichotomization of node-negative/ICS-low FFPE cases identified a subset of low-grade HRneg tumors with <10% 5-year DR risk. The prognostic value of ICS was reaffirmed in two previously studied microarray assayed cohorts containing 274 node-negative and chemotherapy naive HRneg breast cancers, including 95 Tneg cases where it proved prognostically independent of Tneg molecular subtyping. In additional HRneg/Tneg microarray assayed cohorts, the five-gene ICS also proved prognostic irrespective of primary tumor nodal status and adjuvant chemotherapy intervention.ConclusionWe advanced the measurement of two previously reported microarray-derived HRneg/Tneg breast cancer prognostic signatures for use in FFPE samples, and derived an optimized five-gene Integrated Cytokine Score (ICS) with multi-platform capability of predicting metastatic outcome from primary HRneg/Tneg tumors independent of nodal status, adjuvant chemotherapy use, and Tneg molecular subtype.

Two Decades of Experience with Hepatic Cryotherapy for Advanced Colorectal Metastases

Only 15% of patients with colorectal liver metastases (CLM) are candidates for curative hepatectomy at time of diagnosis, limited by anatomical location and tumor burden. Ablative therapies may extend this. This study reports a single institution's long-term experience with hepatic cryotherapy for advanced CLM. Between April 1990 and June 2009, 304 patients were curatively treated with cryotherapy. Survival was estimated by Kaplan-Meier method. Prognostic factors for survivals were determined by using univariate and multivariate analyses. A total of 293 patients were included into analysis. The median number of lesions treated per patient was three (range, 1-13). The median overall survival was 29 (range, 3-220) months. The 1-, 3-, 5-, and 10-year survivals were 87%, 41.8%, 24.2%, and 13.3%, respectively. A total of 161 patients developed intrahepatic recurrences: cryosite (23%); edge recurrence (14%); and within the liver remnant (78%). The median disease-free survival (DFS) was 9 (range, 1-220) months. The 1-, 3-, 5-, and 10-year DFS rates were 37.9%, 17.2%, 13.4%, and 10.8%, respectively. Univariate analysis identified four factors that significantly affect survival: node-positive primary tumor (p=0.001), preoperative CEA level (p<0.001), number of lesions (p<0.001), and use of neoadjuvant chemotherapy (p<0.001). However, only primary tumor nodal status was independently prognostic (hazards ratio=2.023; 95% confidence interval, 1.444-2.835; p<0.001). Hepatic cryotherapy seems to be a safe and effective ablative technique for the treatment of colorectal liver metastases and may offer long-term survival in otherwise unresectable disease.

Hepatic resection for colorectal metastases

Hepatic resection affords the best hope of survival for patients with colorectal carcinoma metastatic to the liver. However, recurrences are observed in about 60 percent of patients after curative hepatic resection. The purpose of this study was to examine the prognostic factors of patients undergoing curative hepatic resection for colorectal metastases. Between April 1984 and September 1997, 168 patients underwent curative hepatic resection for colorectal metastases. The clinicopathologic factors studied for prognostic value were gender, age, primary site, nodal status of primary tumor, time of metastases, preoperative serum level of carcinoembryonic antigen, hepatic tumor size and distribution, number of metastases, type of hepatic resection, resection margin, presence of micrometastases in resected specimen and microscopic fibrous pseudocapsule between the hepatic tumor and surrounding hepatic parenchyma, nodal status of hepatoduodenal ligament, adjuvant regional chemotherapy, and perioperative transfusion. The overall survival was 42 percent at three years and 26 percent at five years, including a 3.5 percent 60-day surgical mortality rate. Thirty-one percent of patients had micrometastases located at a median distance of 3 mm from the metastatic tumor edge. Presence of microscopic fibrous pseudocapsule was observed in 28 percent of patients. Univariate and multivariate analyses showed that significant prognostic factors for survival were nodal status of primary tumor, number of metastases, resection margin, microscopic fibrous pseudocapsule, and adjuvant regional chemotherapy. We conclude that 1) hepatic resection is effective in select patients with colorectal metastases; 2) adequate resection margin and adjuvant regional chemotherapy can improve outcome; and 3) microscopic fibrous pseudocapsule may offer additional postoperative information as an independent prognostic factor.