CXCR4 Expression Predicts Patient Outcome and Recurrence Patterns after Hepatic Resection for Colorectal Liver Metastases

Background

The purpose of this study was to determine if the expression of the chemokine receptors, CXCR4 and CCR7, and the chemokine ligand, CXCL12, in completely resected colorectal cancer hepatic metastases are predictive of disease-specific survival, recurrence-free survival and patterns of recurrence.

Methods

Immunohistochemical analysis of CXCR4, CCR7 and CXCL12 expression within resected hepatic metastases was performed and correlated with clinicopathological variables, disease-specific survival, recurrence-free survival and patterns of recurrence.

Results

Seventy-five patients who underwent partial hepatectomy with curative intent were studied. CXCR4 expression (hazard ratio [HR] 3.6, 95% confidence interval [95% CI] 1.4–9.1) and clinical risk score >2 (HR 2.3, 95% CI 1.1–4.7) were independently associated with disease-specific survival by multivariate analysis. The 5-year estimated disease-specific survival rates for positive and negative CXCR4 tumor expression were 44 and 77%, respectively (P = 0.005). CXCR4 expression (HR 2.2, 95% CI 1.2–4.2) and clinical risk score >2 (HR 1.9, 95% CI 1.1–3.4) were independently associated with recurrence-free survival by multivariate analysis. The five year estimated recurrence-free survival rates for positive and negative CXCR4 tumor expression were 20 and 50%, respectively (P = 0.004). Neither CXCL12 nor CCR7 expression in tumors predicted disease-specific survival or recurrence-free survival. Forty-nine patients (65%) developed recurrent disease after initial hepatectomy. Negative CXCR4 tumor expression was associated with favorable recurrence patterns amenable to salvage resection and/or ablation.

Conclusions

Negative CXCR4 expression in resected colorectal cancer hepatic metastases is independently associated with improved disease-specific and recurrence-free survival and favorable patterns of recurrence.

     

Strong YB-1 Expression Predicts Liver Recurrence Following Resection for Colorectal Metastases

Introduction

The Y-box binding protein-1 (YB-1) is a multifunctional oncoprotein involved in the proliferation and aggressiveness of cancer cells. The aim of this study was to determine whether strong YB-1 expression in neoplastic cells of colorectal liver metastases (CRLM) may have an impact on liver disease-free survival following liver resection.

Materials and Methods

Immunohistochemistry was performed to evaluate YB-1 in 66 patients who underwent liver resection for CRLM. YB-1 expression was classified as weak (low-staining intensity) and strong (high-staining intensity).

Results

YB-1 expression was observed in the cytoplasm of all CRLM. YB-1 expression was weak in 17 patients (25.8 %) and strong in 49 patients (74.2 %). Liver recurrence rate was significantly higher in the strong than in the weak expression group: 55.1 vs. 23.5 % (p?=?0.023). Multivariable logistic regression analysis showed that YB-1 strong expression was the only independent risk factor for liver recurrence. The 5-year specific liver disease-free survival rate was 76.0 % in the weak expression group and 41.5 % in the strong expression group (p?=?0.034). These results were not influenced by clinical prognostic factors of tumor recurrence.

Conclusions

This is the first study showing that the degree of YB-1 expression in tissue specimens of CRLM predicts liver recurrence following liver resection.     

Patterns of Recurrence after Resection of Colorectal Liver Metastases: Prediction by Models of Outcome Analysis

Various series have reported similar survival and recurrence rates after resection of colorectal liver metastases (CRLM). If outcomes were predictable, indications for surgery could be improved. This hypothesis was tested in 135 consecutive patients with CRLM who underwent “curative” resection from 1977 to 1997. Among the 132 patients available for follow-up, three groups were identified on the basis of outcome: (1) survival of more than 5 years disease-free (n= 32; 24%); (2) diffuse recurrences within the first 6 months (n= 24; 18%); and (3) discrete recurrences for which reresection was performed (n= 16; 12%). As our results are similar to those reported in the literature, we assumed that about 50% of patients with resectable lesions have recognizable patterns of recurrence. At multivariate analysis, factors significant for disease-free survival (DFS) were the percentage of liver invasion, metastases to lymph nodes at the primary site, number of metastases, preoperative glutamic pyruvic transaminase (GPT) level, and type of liver resection. On the basis of the relative risk (RR) expressed by significant prognostic factors, a score model was developed, and three prognostic groups were defined: Group A, with the best prognostic score, included 23 of 32 (72%) patients who survived more than 5 years, and that with the worst prognostic score (group C) included 22 of 24 (92%) patients with early diffuse recurrences. Extreme (especially unfavorable) outcomes can therefore be predicted. By using improved models of outcome analysis, many patients could be spared surgery as first-line treatment, and stratification criteria could be worked out for future trials.     

Recurrence and Survival Outcomes after Hepatic Resection with or without Cryotherapy for Liver Metastases from Colorectal Carcinoma

Background Some reports support resection combined with cryotherapy for patients with multiple bilobar colorectal liver metastases (CRLM) that would otherwise be ineligible for curative treatments. This series demonstrates long-term results of 415 patients with CRLM who underwent resection with or without cryotherapy. Methods Between April 1990 and January 2006, 291 patients were treated with resection only and 124 patients with combined resection and cryotherapy. Recurrence and survival outcomes were compared. Kaplan-Meier and Cox-regression analyses were used to identify significant prognostic indicators for survival. Results Median length of follow-up was 25 months (range 1–124 months). The 30-day perioperative mortality rate was 3.1%. Overall median survival was 32 months (range 1–124 months), with 1-, 3- and 5-year survival values of 85%, 45% and 29%, respectively. The overall recurrence rates were 66% and 78% for resection and resection/cryotherapy groups, respectively. For the resection group, the median survival was 34 months, with 1-, 3- and 5- year survival values of 88%, 47% and 32%, respectively. The median survival for the resection/cryotherapy group was 29 months, with 1-, 3- and 5-year survival values of 84%, 43% and 24%, respectively (P = 0.206). Five factors were independently associated with an improved survival: absence of extrahepatic disease at diagnosis, well- or moderately-differentiated colorectal cancer, largest lesion size being 4 cm or less, a postoperative CEA of 5 ng/ml or less and absence of liver recurrence. Conclusions Long-term survival results of resection combined with cryotherapy for multiple bilobar CRLM are comparable to that of resection alone in selected patients.     

Regulatory T Cell Infiltration Predicts Outcome Following Resection of Colorectal Cancer Liver Metastases

Background

Tumor-infiltrating lymphocyte (TIL) counts in colorectal cancer liver metastases (CRCLM) predict survival following resection. While CD4 and CD8 T cells have been correlated with outcome following CRCLM resection, the role of regulatory T cells (Treg) is not well defined.

Methods

TIL in 188 patients who underwent CRCLM resection between 1998 and 2000 were analyzed by immunohistochemistry using tissue microarrays. Correlation between TIL composition and outcome was determined while controlling for established prognostic factors. Total T cells (CD3), helper T cells (CD4), cytotoxic T cells (CD8), and Treg (FoxP3) were analyzed.

Results

Median follow-up time was 40 months for all patients and 95 months for survivors. Overall survival (OS) at 5 and 10 years was 40 and 25 %, respectively. The CD4 T cell count correlated with OS (p = .02) and recurrence-free survival (p = .04). A high number of CD8 T cells relative to total T cells (CD8:CD3 ratio) predicted longer OS times (p = .05). Analysis of Treg revealed that high FoxP3:CD4 (p = .03) and FoxP3:CD8 (p = .05) ratios were independent predictors of shorter OS. Patients with a high clinical risk score (CRS) were more likely to have a high number of intratumoral Treg, and patients ≥65 years old had a less robust CRCLM T cell infiltration.

Conclusions

A high number of Treg relative to CD4 or CD8 T cells predicted poor outcome, suggesting an immunosuppressive role for FoxP3 + TIL. The intratumoral immune response was an independent predictor of outcome in patients with colorectal liver metastases.     

Outcome after Resection of Hepatic and Pulmonary Metastases of Colorectal Cancer

Introduction  

Multimodal therapies (especially surgery of metastases and “aggressive” chemotherapy) in patients with metastases of colorectal cancers (CRC) are increasingly performed and may provide long-term survival in selected patients with more than one location of metastases. In the current literature, there are only few studies with relatively low patient numbers reporting on the outcome after resection of both hepatic and pulmonary metastases of CRC. We therefore evaluated survival of patients who underwent sequential resection of hepatic and pulmonary metastases under potentially curative intention.     

Favorable Outcome After Repeat Resection for Colorectal Liver Metastases

Background

The rate of recurrence after liver resection for colorectal liver metastases (CLM) is high, and repeat resection (RR) is reserved with curative intent in selected patients. This study evaluated the benefit of RR for recurrence after liver resection for CLM.

Methods

Data were collected on 287 consecutive patients who underwent primary curative hepatectomy between January 1999 and October 2008 for CLM at our institution.

Results

After median follow-up of 63 months, 211 patients (73 %) developed recurrence and RR was conducted in 102 (48 %) patients. Five-year overall survival (OS) was significantly higher in the RR group than in those patients not selected for RR (70 vs. 45 %, P = 0.002). On multivariate analyses, RR was identified as an independent factor for good prognosis. According to the first recurrence sites, 5-year OS after recurrence was significantly better in patients with liver or lung only recurrence (55, 51 %, respectively) than in locoregional/lymph node metastases and other/multiple sites recurrence (33, 9.0 %, respectively). In patients with liver- or lung-only recurrence, 5-year OS after recurrence was significantly higher in RR patients than in those without RR (liver; 67 and 0 %, lung; 88 and 24 %, respectively; P < 0.001).

Conclusion

Given similar indication criteria as the primary CLM, nearly half of all recurrence cases after liver resection for CLM could be salvaged by RR. In patients with liver-or lung-only recurrence, RR warrants a favorable outcome.     

Hepatic Pedicle Clamping During Hepatic Resection for Colorectal Liver Metastases: No Impact on Survival or Hepatic Recurrence

Background

Hepatic pedicle clamping is often used during liver resection. While its use reduces blood loss and transfusion requirements, the long-term effect on survival and recurrence has been debated. This study evaluates the effect of hepatic pedicle clamping [i.e., Pringle maneuver (PM)] on survival and recurrence following hepatic resection for colorectal liver metastasis (CRLM).

Methods

Patients who underwent R0 resection for CRLM from 1991 to 2004 were identified from a prospectively maintained database. Operative, perioperative, and clinicopathological variables were analyzed. The primary outcomes were disease-free survival (DFS) and liver recurrence (LR). Disease extent was categorized using a well-defined clinical risk score (CRS). Subgroup analysis was performed for patients given preoperative systemic chemotherapy and postoperative pump chemotherapy.

Results

This study included 928 consecutive patients with median follow-up of 8.9 years. PM was utilized in 874 (94 %) patients, with median time of 35 min (range 1–181 min). On univariate analysis, only resection type (p < 0.001) and tumor number (p = 0.002) were associated with use of PM. Younger age (p = 0.006), longer operative time (p < 0.001), and multiple tumors (p = 0.006) were associated with prolonged PM (>60 min). There was no association between DFS, overall survival (OS) or LR and Pringle time. Neither the CRS nor use of neoadjuvant therapy stratified disease-related outcome with respect to use of PM.

Conclusions

PM was used in most patients undergoing resection for CRLM and did not adversely influence intrahepatic recurrence, DFS, or OS.     

Extending the Limits of Resection for Colorectal Liver Metastases: Positive Resection Margin and Outcome After Resection of Colorectal Cancer Liver Metastases

Journal of Gastrointestinal Surgery -     

Mode of Infiltrative Growth of Colorectal Liver Metastases Is a Useful Predictor of Recurrence after Hepatic Resection

Many studies have been conducted to determine prognosis on the basis of the characteristics of metastatic liver tumor from colorectal cancer. The present study was carried out to determine whether the pathological mode of infiltrative growth (INF) of a metastatic liver nodule is useful in predicting recurrence in the remnant liver after hepatic resection. A total of 42 curative hepatic resections were performed for 37 patients with isolated liver metastases from colorectal cancer. Multivariate analysis (n = 42) showed that number, INF type, and size of liver metastases were statistically significant as independent risk factors. Of these, 28 resected liver metastases (smaller than 6 cm in size or containing fewer than 4 nodules) were classified pathologically into INF alpha or beta types (INF a b; n = 14) and gamma type (INFg; n = 14). Disease-free survival at 5 years was 64% for patients with INF a b type, and 14% for those with the INF g type of liver metastases. Of these, recurrent disease of the liver after hepatic resection was found in 2 (14%) and 11 (79%) patients with INF a b and INF g types, respectively. From these observations, we concluded that pathological infiltrative growth of liver metastases is an informative predictor of disease-free survival and especially of recurrence in the remnant liver.     

Preoperative Chemotherapy and the Outcome of Liver Resection for Colorectal Metastases

Background Neoadjuvant systemic chemotherapy is being increasingly used prior to liver resection for colorectal metastases. Oxaliplatin has been implicated in causing structural changes to the liver parenchyma, and such changes may increase the morbidity and mortality of surgery. Patients and Methods A retrospective study was undertaken of 101 consecutive patients who had undergone liver resection for colorectal metastases in two HPB centers. Preoperative demographic and premorbid data were gathered along with liver function tests and tumor markers. A subjective assessment of the surgical procedure was noted, and in-hospital morbidity and mortality were calculated. The effect of preoperative chemotherapy on short-term and long-term outcome was analyzed, and actuarial 1 and 3 year survival was determined. Results Patients who received neoadjuvant chemotherapy had a higher number of metastases (median 2, range 1–8 versus median 1, range 1–5; P = 0.019) and more had synchronous tumors (24 patients versus 8; P < 0.001). Overall morbidity was 37% and hospital mortality was 3.9%. Operative and in-hospital outcome was not influenced by chemotherapy. Long-term survival was worse in patients who had received preoperative chemotherapy (actuarial 3-year survival 62% versus 80%; P = 0.04). Conclusions This study shows no evidence that neoadjuvant chemotherapy, and in particular oxaliplatin, increases the risk associated with liver resection for colorectal metastases. Long-term outcome is reduced in patients receiving preoperative chemotherapy, although they have more advanced disease.     

Recurrence Location After Resection of Colorectal Liver Metastases Influences Prognosis

Aim

To assess the impact of first recurrence location on survival following surgery of colorectal liver metastases.

Methods

A total of 265 consecutive patients with colorectal liver metastases undergoing liver surgery (2000–2011) were categorized according to first site of tumor recurrence. Time to recurrence (TTR) and overall survival (OS) were determined. Uni- and multivariate analysis were performed to identify factors associated with TTR and OS.

Results

Median TTR was 1.16 years following liver resection, and 0.56 years following radiofrequency ablation (RFA). Intrahepatic recurrence following liver resection resulted in a significantly shorter median TTR compared to extrahepatic recurrence. Intrapulmonary recurrence was associated with superior survival compared to other recurrence locations. Such patterns were not observed in the RFA-treated group. Multivariate analysis identified the type of surgical treatment and extra-hepatic first-site recurrence (other than lung) as independent predictors for OS. Pre-operative chemotherapy and simultaneous intrahepatic and extrahepatic recurrence were independent predictors for both TTR and OS.

Conclusions

Patients with intrahepatic recurrence following liver resection have a significantly shorter TTR and OS when compared to patients developing extrahepatic recurrence. Pulmonary recurrence following resection is associated with longer survival. Simultaneous intra- and extrahepatic recurrence is an independent prognostic factor for TTR and OS.     

Effect on Outcome of Recurrence Patterns After Hepatectomy for Colorectal Metastases

Background

Despite improvements in surgery and chemotherapy, most patients develop recurrence after hepatectomy for metastatic colorectal cancer. Data are lacking on the effect of these patterns on outcome.

Methods

A retrospective review of a prospectively maintained hepatobiliary database was performed. Pattern and timing of recurrence and outcome after recurrence were analyzed. Univariate and multivariate analyses of factors associated with outcome after recurrence were carried out.

Results

From January 1997 through May 2003, a total of 733 patients underwent hepatectomy for colorectal metastases. Of these, 637 patients (87%) were included in the analysis, and in 393 patients (62%), recurrence was documented at the time of last follow-up. Initial recurrence patterns included the following: liver only in 120 patients (31%), lung only in 107 (27%), other single sites in 49 (12%), and multiple sites in 117 (30%). Recurrence occurred within 2 years of hepatectomy in 75% of patients and after 3 years in 11%. Margins at hepatectomy, recurrence pattern, resected recurrence, and disease-free interval from time of colectomy to hepatic metastasis and from time of hepatectomy to recurrence were independently associated with survival as measured from the time of recurrence. Recurrence in the lung, resected recurrence, and time to recurrence after hepatectomy were associated with prolonged survival as measured from the time of hepatectomy and the time of recurrence.

Conclusions

The timing and pattern of recurrence after hepatic resection for metastatic colorectal cancer are important predictors of long-term survival.     

Patterns of Recurrence After Liver Transplantation for Nonresectable Liver Metastases from Colorectal Cancer

Background

Surgical resection is the only curative modality for colorectal liver metastases (CLM), and the pattern of recurrences after resection affects survival. In a prospective study of liver transplantation (Lt) for nonresectable CLM we have shown a 5-year overall survival rate of 60 %, but 19 of 21 experienced recurrence. This study reports the pattern of recurrences after Lt for CLM and the effect on survival.

Methods

Characterization of metastatic lesions in a prospective study for Lt for nonresectable CLM was performed (n = 21). The study included reexamination of chest computed tomographic scans taken before Lt.

Results

At the time of first recurrence, 16 were a single site, and three were multiple sites. Thirteen of the single sites were pulmonary recurrences. The pulmonary recurrences appeared early and were slow growing, and several were accessible to surgical treatment. When chest computed tomographic scans were reexamined, seven patients had pulmonary nodules at the time of Lt without an effect on survival. There was no first single-site hepatic recurrence. Six of the seven patients who developed metastases to the transplanted liver died from metastatic disease.

Conclusions

The pulmonary recurrences after Lt for CLM were of an indolent character, even those that were present at the time of Lt. This contrasts with the finding of metastases to the transplanted liver, which was prognostically adverse. The lack of single hepatic first-site recurrences and hepatic metastases only as part of disseminated disease is different from the pattern of recurrence after liver resection. This suggests two distinct mechanisms for hepatic recurrences after resection for CLM.     

Resection of Colorectal Liver Metastases

Introduction  

The gold-standard treatment for colorectal liver metastases (CLM) is liver resection. Advances in staging, surgical technique, perioperative care and systemic chemotherapy have contributed to steady improvement in oncologic outcomes for patients following surgery in this subset of patients with stage IV colorectal cancer. The limits of resection continue to expand to include patients with more, larger and bilateral CLM, yet outcomes continue to improve with 5-year overall survival exceeding 50% following resection. Chemotherapy is an important element of treatment for patients with CLM, and chemotherapy can be combined safely with surgery to improve outcomes further.     

Patterns of Recurrence After Ablation of Colorectal Cancer Liver Metastases

Purpose  

To determine the local recurrence rate and factors associated with recurrence after intraoperative ablation of colorectal cancer liver metastases.