Recurrence After Partial Hepatectomy for Metastatic Colorectal Cancer: Potentially Curative Role of Salvage Repeat Resection

Annals of Surgical Oncology - Patients with recurrence after complete resection of colorectal liver metastases (CLM) are considered for repeat resection as a potential salvage therapy (PST)....     

Long-Term Survival and Disease Recurrence Following Portal Vein Embolisation Prior to Major Hepatectomy for Colorectal Metastases

Background  Portal vein embolisation (PVE) can be used to increase the remnant liver parenchyma volume before major hepatectomy but may stimulate tumour growth. The pattern of disease recurrence and long-term survival has not been adequately addressed. Methods  Over a period of 7 years 36 patients underwent preoperative PVE before resection of four or more liver segments for colorectal cancer (CRC) liver metastases. PVE was performed when the future liver remnant (FLR) assessed by magnetic resonance imaging (MRI) scan volumetry was less than 30%. Disease-free and overall survival was compared with a control group (65 patients) undergoing extended right/right hepatectomy for CRC metastases without PVE during the same time period. Results  PVE was successful in all patients. PVE increased the median FLR volume by 37% [295 ml (22%) to 404 ml (32%), p < 0.0001]. 61% of patients undergoing PVE proceeded to liver resection (n = 22). Twelve patients (33%) developed disease progression following PVE. The 5-year survival after liver resection with PVE was 25%, compared with 50% without PVE. The 5-year disease-free survival was 30% post PVE and 50% without PVE. Conclusion  We conclude that PVE significantly increases the future liver remnant. Only two-thirds of patients proceed to resection because of disease progression. Long-term survival is less than in patients who do not require PVE. The effect of PVE on tumour growth requires investigation. Presented at the 8th World Congress of the International Hepato-Pancreato-Biliary Association, February 2008 Mumbai, India, in Award Oral Paper Session.     

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.     

T Cell Infiltrate Predicts Long-Term Survival Following Resection of Colorectal Cancer Liver Metastases

Background  While tumor infiltrating lymphocytes (TIL) have been shown to independently predict survival in primary colorectal cancer, the prognostic implications of TIL in resectable colorectal cancer liver metastases (CRCLM) have not been previously defined. This study examines the correlation between TIL numbers and survival following hepatic resection. Methods  We studied patients who survived ≤2 or ≥10 years following CRCLM resection. Immunohistochemistry was performed on tissue microarrays (TMAs) to determine the number of T cells within CRCLM. Correlation between TIL frequency and ≤2 or ≥10 year survival was determined while controlling for established prognostic factors. Results  Of 162 patients, 104 survived ≤2 years and 58 survived ≥10 years. Independent correlates of 10-year survival following CRCLM resection included a high number of CD8 T cells, a low number of CD4 T cells, and a clinical risk score of ≤2 (P < 0.001). Among 10-year survivors, 31% of patients had a high number of CD8 T cells compared with 8% for ≤2 year survivors (P < 0.01). Surprisingly, only 22% of 10-year survivors had a high number of CD4 T cells, in contrast to 69% of those who died within 2 years (P < 0.001). The combination of CD8 and CD4 T cell counts was a more powerful predictor of survival than either marker alone. Conclusions  CRCLM T cell number is an independent correlate of long-term survival following liver resection. We conclude that CRCLM TIL analysis represents a potentially powerful prognostic tool which will require further validation prior to broad application.     

Repeat Hepatectomy for Metastatic Colorectal Cancer Is Safe but Marginally Effective

Background

Although hepatectomy for metastatic colorectal cancer (mCRC) offers prolonged survival in up to 40% of people, recurrence rates are high, approaching 70%. Many patients experience recurrent disease in the liver after initial hepatectomy. We examined our experience with repeat hepatectomy for mCRC.

Methods

After Institutional Review Board approval, we reviewed the records of all patients at a single institution who underwent hepatectomy for mCRC. Repeat hepatectomy was defined as partial liver resection any time after the initial hepatectomy for recurrent mCRC. We estimated time to recurrence and survival by using the Kaplan?CMeier method and compared outcomes between groups by using the log-rank test.

Results

From 1998 to 2008, 405 patients underwent hepatectomy for mCRC, and 215 (53%) experienced disease recurrence at a median of 13?months. Of 150 patients with liver-only or liver-predominant recurrence, 52 (35%) underwent repeat hepatectomy. The median time to recurrence after repeat hepatectomy was 10?months, and median overall survival was 19?months. There was one (1.9%) perioperative death, and there were 14 (27%) major complications. The median overall survival in the repeat hepatectomy group from the time of recurrence after initial hepatectomy was 22?months, compared with 15?months in the 98 patients with liver recurrence who were not selected for repeat hepatectomy (P?=?0.02).

Conclusions

Repeat hepatectomy for mCRC is feasible in highly selected patients, with acceptable perioperative morbidity and mortality. Although repeat hepatectomy should be considered, recurrence rates are high. Although the initial hepatectomy for mCRC is potentially curative, recurrence of metastatic disease in the liver is unlikely to be cured.     

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.     

Aggressive Multimodal Treatment and Metastatic Colorectal Cancer Survival

1. Download : Download high-res image (265KB)
2. Download : Download full-size image

     

Impact of Simultaneous Diaphragm Resection During Hepatectomy for Treatment of Metastatic Colorectal Cancer

Introduction

For colorectal cancer patients with liver metastases involving the hepatic dome or invading the diaphragm, a concomitant diaphragm resection is often required to achieve negative surgical margins. The purpose of this study is to determine whether diaphragm resection during partial hepatectomy for metastatic colorectal cancer influences short-term perioperative outcomes and overall survival.

Methods

Demographics, treatments, and outcomes of 442 patients who underwent hepatic resection for metastatic colorectal cancer from 1996 to 2010 at a high-volume center were reviewed. Recurrence and survival were measured from the date of metastectomy. Actuarial curves were generated using the Kaplan?CMeier method and compared using log?Cranks testing. Multivariate predictors of worse survival were compared using a Cox-proportional hazards model.

Results

A total of 442 patients underwent hepatectomy for metastatic colorectal cancer. Of these, 34 required simultaneous diaphragm resection (DR) and 408 did not (LR). No significant differences existed in patient demographics or comorbidities. The DR group had longer median operative times (336 vs. 267?min, p?=?0.0008) but had comparable rates of perioperative morbidity and mortality. Median overall survival was shorter in the DR group compared to the LR group (18.8 vs. 36?months, p?=?0.0017). When controlling for potential cofounders, liver metastases size?>?5?cm (HR 1.45 95?% CI (1.08?C1.99), p?=?0.015) and diaphragm resection (HR?=?1.72 95?% CI (1.03?C2.86), p?=?0.038) predicted worse survival.

Conclusions

Simultaneous diaphragm resection during partial hepatectomy does not significantly influence perioperative morbidity or mortality despite longer operative times. However, patients who require diaphragm resection have less favorable survival rates as compared to those who do not.     

Determinants of Survival following Hepatic Resection for Metastatic Colorectal Cancer

p = 0.0001), resected versus nonresected ( p < 0.0001), and tumor-free surgical margins versus positive margins ( p = 0.001). Surprisingly, the disease-free interval and the original stage of the primary tumor did not predict survival ( p = not significant). Other factors that had no influence on survival were type of resection, size and number of liver metastases, ABO blood group, and the number of perioperative blood transfusions. For those patients who underwent resection of unilobar metastases with tumor-free margins, the 5-year survival rate was 29% with a median survival of 35 months and eight survivors > 7 years. In addition, one patient with bilobar disease had survival > 7 years and five patients who had resection of hepatic metastases and extrahepatic cancer simultaneously had survival > 3 years. Our data support the concept that patients with unilobar metastatic disease who undergo surgical resection with tumor-free surgical margins can be afforded a significant opportunity at long-term survival with acceptable morbidity, mortality, and hospital stay. Also, certain patients with bilobar or extrahepatic disease (or both) who undergo complete resection can enjoy a long-term survival. In these subgroups of patients resection should be considered on an individual basis.     

Long-Term Survival and Recurrence Outcomes Following Surgery for Distal Rectal Cancer

Background

Treatment of distal rectal cancer remains clinically challenging and includes proctectomy and coloanal anastomosis (CAA) or abdominoperineal resection (APR). The purpose of this study is to evaluate operative and pathologic factors associated with long-term survival and local recurrence outcomes in patients treated for distal rectal cancer.

Methods

A retrospective consecutive cohort study of 304 patients treated for distal rectal cancer with radical resection from 1993 to 2003 was performed. Patients were grouped by procedure (CAA or APR). Demographic, pathologic, recurrence, and survival data were analyzed utilizing chi-square analysis for comparison of proportions. Survival analysis was performed using Kaplan–Meier method and log-rank test for univariate and Cox regression for multivariate comparison.

Results

The median tumor distance from the anal verge was 2 cm [interquartile range (IQR) 0.5–4 cm]. Margins were negative in all but four patients (one distal, 0.3%; three radial, 1%). The 5-year overall survival rate was 82% (88.6% stage pI, 80.5% stage pII, 67.9% stage pIII). Older age, advanced pathologic stage, presence of lymphovascular or perineural invasion, earlier treatment period, and APR surgery type were associated with worse survival on multivariate analysis. The 5-year local recurrence rate was 5.3% after CAA and 7.9% after APR (p = 0.33).

Conclusions

Low rates of local recurrence and good overall survival can be achieved after treatment of distal rectal cancer with stage-appropriate chemoradiation and proctectomy with CAA or APR. Sphincter preservation can be achieved even with distal margins less than 2 cm.     

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.

     

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.     

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.

     

Up-front Hepatic Resection for Metastatic Colorectal Cancer Results in Favorable Long-term Survival

Background

Hepatic metastasis from colorectal cancer (CRC) is best managed with a multimodal approach; however, the optimal timing of liver resection in relation to administration of perioperative chemotherapy remains unclear. Our strategy has been to offer up-front liver resection for patients with resectable hepatic metastases, followed by post–liver resection chemotherapy. We report the outcomes of patients based on this surgical approach.

Methods

A retrospective review of all patients undergoing liver resection for CRC metastases over a 5-year period (2002–2007) was performed. Associations between clinicopathologic factors and survival were evaluated by the Cox proportional hazard method.

Results

A total of 320 patients underwent 336 liver resections. Median follow-up was 40 (range 8–80) months. The majority (n = 195, 60.9 %) had metachronous disease, and most patients (n = 286, 85 %) had a major hepatectomy (>3 segments). Thirty-six patients (11 %) received preoperative chemotherapy, predominantly for downstaging unresectable disease. Ninety-day mortality was 2.1 %, and perioperative morbidity occurred in 68 patients (20.2 %). Actual disease-free survival at 3 and 5 years was 46.2 % and 42 %, respectively. Actual overall survival (OS) at 3 and 5 years was 63.7 % and 55 %, respectively. Multivariate analysis identified four factors that were independently associated with differences in OS (hazard ratio; 95 % confidence interval): size of metastasis >6 cm (2.2; 1.3–3.5), positive lymph node status of the primary CRC (N1 (2.0; 1.0–3.8), N2 (2.4; 1.2–4.9)), synchronous disease (2.1; 1.3–3.5), and treatment with chemotherapy after liver resection (0.42; 0.23–0.75).

Conclusions

Up-front surgery for patients with resectable CRC liver metastases, followed by chemotherapy, can lead to favorable OS.     

Impact of Blood Transfusions on Survival and Recurrence in Colorectal Cancer Surgery

The aim of our study was to evaluate the prognostic significance of blood transfusion on recurrence and survival in patients undergoing curative resections for colorectal cancer. Retrospective analysis of prospectively collected data of patients after elective resections for colorectal cancer between January 2001 and December 2009 was undertaken. The main endpoint was overall survival, disease-free survival, and recurrence rate. These data were evaluated in relation to blood transfusion (group A, no blood transfusion; group B, one to two blood transfusions; group C, three and more blood transfusions). A total of 583 patients met the criteria for inclusion in the study. Of these, 132 (22.6 %) patients received blood transfusion in the perioperative period. There were 83 (14.2 %) patients who received one or two blood transfusions and 49 (8.4 %) patients who required three or more transfusions. Patients with three or more transfusions had a significantly worse 5-year overall survival, disease-free survival, and increased incidence of distant recurrences in comparison with the group without transfusion or the group with one or two transfusions. Multivariate analysis showed that the application of three or more blood transfusions is an independent risk factor for overall survival (P?=?0.001; HR 2.158; 95 % CI 1.370–3.398), disease-free survival (P?<?0.001; HR 2.514; 95 % CI 1.648–3.836), and the incidence of distant recurrence (P?<?0.001; HR 2.902; 95 % CI 1.616–5.212). Application of three or more blood transfusions in patients operated for colorectal carcinoma is an adverse prognostic factor. Indications for blood transfusion should be carefully considered not only with regard to the risk of early complications, but also because of the possibility of compromising long-term results.     

Postoperative Detection of Circulating Tumor Cells Predicts Tumor Recurrence in Colorectal Cancer Patients

Introduction

Circulating tumor cells are thought to play a crucial role in the development of distant metastases. Their detection in the blood of colorectal cancer patients may be linked to poor outcome, but current evidence is controversial.

Materials and Methods

Pre- and postoperative flow cytometric analysis of blood samples was carried out in 76 colorectal cancer patients undergoing surgical resection. The EpCAM/CD326 epithelial surface antigen was used to identify circulating tumor cells.

Results

Fifty-four (71 %) patients showed circulating tumor cells preoperatively, and all metastatic patients showed high levels of circulating tumor cells. Surgical resection resulted in a significant decrease in the levels of circulating tumor cells. Among 69 patients undergoing radical surgery, 16 had high postoperative levels of circulating tumor cells, and 12 (75 %) experienced tumor recurrence. High postoperative level of circulating tumor cells was the only independent variable related to cancer relapse. In patients without circulating tumor cells, the progression-free survival rate increased from 16 to 86 %, with a reduction in the risk of tumor relapse greater than 90 %.

Conclusions

High postoperative levels of circulating tumor cells accurately predicted tumor recurrence, suggesting that assessment of circulating tumor cells could optimize tailored management of colorectal cancer patients.     

Up-regulation of Neutrophil Gelatinase-Associated Lipocalin in Colorectal Cancer Predicts Poor Patient Survival

Background

Lipocalin-2 (Lcn-2) is expressed in human neutrophils and epithelial cells, particularly in the presence of inflammation or cancer. It was shown to be highly expressed in various human cancers. Increased protein levels were associated with decreased survival of patients with breast or gastric cancer. The main focus of this work was to analyze the implication of Lcn-2 up-regulation in the genesis of colon cancer.

Methods

Expression of Lcn-2 was analyzed in colorectal carcinoma cell lines, paired colorectal carcinoma tissues, and regular mucosa by Western blot analysis. Lcn-2 immunohistochemical staining was performed in 192 colorectal carcinoma resection specimens and correlated with clinicopathologic parameters.

Results

Western blot analysis of colorectal carcinoma tissues demonstrated Lcn-2 overexpression in carcinomas as compared with regular mucosa. Immunohistochemical staining revealed Lcn-2 expression in 179 (93.2 %) colorectal carcinoma tissues. Intense immunoreactivity was significantly correlated with metastasis (p = 0.042) and UICC stage (p = 0.027). Survival analysis according to the Kaplan–Meier method revealed a significant association between Lcn-2 overexpressing tumors and overall survival (p < 0.001) and disease-free survival (p < 0.001).

Conclusions

Our data provide evidence that Lcn-2 expression is up-regulated with tumor progression and was found to be a predictor of overall survival.