Chance of Cure Following Liver Resection for Initially Unresectable Colorectal Metastases: Analysis of Actual 5-Year Survival

Background

Survival with long-term follow-up following liver resection for unresectable colorectal liver metastases (CRLM) downsized by chemotherapy has rarely been reported. The aim of this study was to determine the chance of cure following liver resection for initially unresectable CRLM.

Methods

Between January 2000 and December 2009, 61 patients underwent hepatectomy for unresectable liver-only CRLM downsized after chemotherapy. Cure was defined as a recurrence-free interval of at least 5 years after primary hepatectomy.

Results

Resectability of CRLM was achieved after a mean number of 11 courses, and 42.6 % of patients underwent liver resection after ≥10 courses. Postoperative mortality was nil, and morbidity rate was 19.7 %. The 5- and 10-year actuarial overall survival rates were 42.6 and 16.0 %. Of 30 patients with a follow-up ≥5 years, 11 were alive, yielding a 5-year actual overall survival rate of 36.7 %, and 7 (23.3 %) were considered cured because they are alive without recurrence. On multivariate analysis, response to chemotherapy was the only independent predictor of both overall and disease-free survival.

Conclusions

Cure can be achieved in about 23 % of patients resected for initially unresectable CRLM downsized by chemotherapy. Liver resection can be safely performed in selected patients even after multiple courses of chemotherapy.     

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.     

Repeat Hepatectomy for Recurrent Liver Metastasis From Gastric Carcinoma

Background

The efficacy of repeat hepatectomy for recurrent hepatocellular carcinoma and colorectal liver metastases is widely accepted. However, the benefits of such treatment for intrahepatic recurrence of gastric cancer liver metastasis remain unknown. This study sought to clarify the survival benefit for patients undergoing repeat hepatectomy for gastric cancer liver metastasis.

Methods

A total of 73 patients underwent hepatectomy for gastric cancer liver metastasis from January 1993 to January 2011. Macroscopically curative surgery was performed in 64 patients. Among them, repeat hepatectomy was performed in 14 of the 37 patients with intrahepatic recurrence. Among these 14 patients, clinicopathologic factors were evaluated by univariate and multivariate analysis to identify the factors affecting survival.

Results

The overall 1-, 3-, and 5-year survival rates after a second hepatectomy were 71, 47, and 47 %, respectively. The median survival was 31 months. Operative morbidity and mortality rates of repeat hepatectomy were 29 and 0 %, respectively. Multivariate analysis identified the duration of the disease-free interval as the only independent significant factor predicting better survival.

Conclusions

In selected patients, repeat hepatectomy for recurrent gastric cancer liver metastasis may offer the same chance of cure as the primary hepatectomy. Disease-free intervals exceeding 12 months predict good patient survival after repeat hepatectomy.     

Reconsideration of the Indications for Adjuvant Chemotherapy for Liver Metastases from Colorectal Cancer After Initial Hepatectomy

Background

The effectiveness of perioperative adjuvant chemotherapy for colorectal cancer liver metastasis (CRLM) remains a matter of debate. Despite the lack of clear evidence supporting its effectiveness after curative hepatectomy, adjuvant chemotherapy has been widely used clinically. The purpose of this study was to clarify the indications for adjuvant chemotherapy in order to develop an appropriate treatment strategy for CRLM.

Methods

The clinicopathological factors of 110 patients who underwent initial hepatectomy for CRLM between April 2000 and March 2010 were retrospectively analyzed. The prognostic factors of CRLM were identified and then CRLM was stratified according to the number of prognostic factors into the high-score group (H-group: score 2 or 3) and the low-score group (L-group: score 0 or 1), and the effectiveness of adjuvant chemotherapy was analyzed in each group.

Results

Multivariate analysis identified pT4 (p = 0.0047), lymph node metastasis in colorectal cancer (CRC) (p = 0.0165), and H2-classification (p = 0.0051) as factors related to a poor prognosis. The overall 5-year survival rate was markedly higher in the L-group (68 %) than in the H-group (26 %, p < 0.0001). Moreover, in the L-group, patients who did not receive adjuvant chemotherapy had the same prognosis as those who received adjuvant chemotherapy. As for recurrence, tumor relapse more often was treated by resection in the L-group than in the H-group (p = 0.0339).

Conclusions

Adjuvant chemotherapy did not improve overall survival and disease-free survival in patients with no more than two factors of the H2-classification, invasion depth pT4, and lymph node metastasis in CRC.     

Feasibility of the liver-first approach for patients with initially unresectable and not optimally resectable synchronous colorectal liver metastases

Purpose

To investigate the outcomes of patients with colorectal cancer and initially unresectable or not optimally resectable liver metastases, who were treated using the liver-first approach in the era of modern chemotherapy in Japan.

Methods

We analyzed and compared data retrospectively on patients with asymptomatic resectable colorectal cancer and initially unresectable or not optimally resectable liver metastases, who were treated either using the liver-first approach (n = 12, LF group) or the primary-first approach (n = 13, PF group).

Results

Both groups of patients completed their therapeutic plan and there was no mortality. Postoperative morbidity rates after primary resection and hepatectomy, and post-hepatectomy liver failure rate were comparable between the groups (p = 1.00, p = 0.91, and p = 0.55, respectively). Recurrence rates, median recurrence-free survival since the last operation, and 3-year overall survival rates from diagnosis were also comparable between the LF and PF groups (58.3 vs. 61.5 %, p = 0.87; 10.5 vs. 18.6 months, p = 0.57; and 87.5 vs. 82.5 %, p = 0.46, respectively).

Conclusions

The liver-first approach may be an appropriate treatment sequence without adversely affecting perioperative or survival outcomes for selected patients.

     

Does “Conversion Chemotherapy” Really Improve Survival in Metastatic Colorectal Cancer Patients with Liver-Limited Disease?

Background

The clinical benefits of conversion chemotherapy followed by liver resection for initially unresectable colorectal liver metastases are still controversial. The criteria for unresectability vary from one team to another. To clarify this issue, we retrospectively assessed the survival and characteristics of metastatic colorectal cancer (mCRC) patients with liver-limited disease (LLD) who underwent conversion therapy.

Method

Our criteria for resectability depended on the size of the remnant liver volume (>30 %) and expected function after removal of all metastases. Between December 2007 and September 2011, a total of 115 patients were diagnosed as having mCRC with LLD and received chemotherapy. Among them, 47 had tumors that were initially diagnosed as resectable. They underwent hepatic resection after chemotherapy (resected group). Of the 67 tumors were initially diagnosed as unresectable, 12 became resectable after chemotherapy (conversion group), leaving 55 tumors that remained unresectable after chemotherapy (unresected group).

Results

The median follow-up was 25.2 months. Hepatic resection was more invasive in the conversion group than in the resected group. Median disease-free survival was significantly higher in the resected group than in the conversion group (p = 0.013). Overall survival (OS) was also higher in the resected group, but the difference was not significant (p = 0.36). However, OS was significantly higher in the conversion group than in the unresected group (p = 0.034). Multivariate analysis of the resected and conversion groups showed that OS was significantly negatively influenced by abnormal carcinoembryonic antigen levels at surgery (p = 0.037) and a hospital stay >30 days (p = 0.009).

Conclusions

Our results showed that conversion chemotherapy could contribute to longer OS in mCRC patients with LLD.     

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.     

A Meta-Analysis to Determine the Effect of Primary Tumor Resection for Stage IV Colorectal Cancer with Unresectable Metastases on Patient Survival

Background

Approximately 20 % of patients diagnosed with colorectal cancer will have distant metastases at first presentation (stage IV disease). The effect of removing the primary tumor on survival for patients with stage IV disease with unresectable metastases remains unclear. To address this a meta-analysis of all studies comparing primary tumor resection with chemotherapy alone in cases of stage IV colorectal cancer with unresectable metastases was performed.

Methods

A comprehensive search for published studies examining the effect of primary tumor resection in the setting of colorectal cancer with unresectable metastases was performed. Each study was reviewed and data extracted. Random-effects methods were used to combine data.

Results

There were 21 studies including a total of 44,226 patients that met the inclusion criteria. Resection of the primary tumor in patients with unresectable metastases compared with chemotherapy alone was associated with a lower mortality risk (OR 0.28; 95 % CI 0.165–0.474; P < 0.001), translating into a difference in mean survival of 6.4 months in favor of resection (95 % CI 5.025–7.858, P < 0.001). Patients who underwent resection of the primary tumor were more likely to have liver metastasis only (OR 1.551; 95 % CI 1.247–1.929; P < 0.001), were less likely to have ≥2 metastasis (OR 0.653; 95 % CI 0.508–0.839; P = 0.001), and were less likely to have rectal cancer (OR 0.495; 95 % CI 0.390–0.629; P < 0.001). There was significant cross-study heterogeneity.

Conclusions

Resection of the primary tumor may confer a survival advantage in stage IV colorectal cancer with unresectable metastases but significant selection bias exists in current studies. Randomized controlled trials are essential to validate these findings.     

A Systematic Review of Repeat Hepatectomy for Recurrent Colorectal Liver Metastases

Background

Selected patients with recurrent colorectal liver metastases (CLM) may be resectable by repeat hepatectomy approach. In this review, we aim to collate and evaluate the published evidence for repeat hepatectomy in patients with recurrent CLM.

Methods

Searches of the Medline and Embase databases were undertaken to identify studies of repeat hepatectomy in patients with recurrent CLM focusing on the perioperative treatment regimen, operative strategy, morbidity, technical success and survival outcomes.

Results

Twenty-two observational studies were reviewed. A total of 1,610 patients underwent second hepatectomy for recurrent CLM. The median percentage of extra-hepatic disease was 15 % (range, 0–39 %). Preoperative chemotherapy was reported in 5/22 studies. Major liver resection was undertaken in 25 % (range, 9–59 %) of patients and the R0 resection rate was 90 % (range, 77–96 %). Postoperative morbidity and mortality after the second hepatectomy were 23 % and 1.2 %, respectively. Recurrence rate after second hepatectomy was 63.9 % (range, 42–91 %) with a median follow-up period of 32 months (range, 19–59 months). Median overall survival was 35 months (range, 19–56 months). The 3-year and 5-year overall survival rates were 55 % (range, 11–82 %) and 42 % (range, 31–73 %), respectively.

Conclusion

Second hepatectomy is safe and feasible in selected patients with recurrent CLM and is associated with acceptable perioperative and survival outcomes. Future prospective studies are required to further define the patient selection criteria for repeat hepatectomy and the exact role of perioperative chemotherapy.     

Usefulness of Contrast-Enhanced Intraoperative Ultrasonography (CE-IOUS) in Patients with Colorectal Liver Metastases after Preoperative Chemotherapy

Aims

The aim of this study was to evaluate the ability of contrast-enhanced intraoperative ultrasonography to detect colorectal liver metastases after preoperative chemotherapy compared with intraoperative ultrasound and preoperative imaging techniques.

Methods

From January 2010 to December 2011, 28 patients with colorectal liver metastases underwent intraoperative ultrasonography and contrast-enhanced intraoperative ultrasonography during hepatectomy following preoperative chemotherapy. The findings were compared to preoperative imaging using contrast-enhanced ultrasonography, computed tomography, magnetic resonance imaging, and/or fluorodeoxyglucose positron emission tomography.

Results

Preoperative imaging techniques detected 58 metastatic lesions in 28 patients. In 32 % of patients (n?=?9), intraoperative ultrasound detected 24 missed hepatic nodules. In 14 % of patients (n?=?4), contrast-enhanced intraoperative ultrasonography detected an additional six nodules and change in operative management occurred in 18 % of patients. Using univariate analysis, we found three factors significantly related to detection of additional metastases with contrast-enhanced intraoperative ultrasonography: three or more metastases before chemotherapy (p?=?0.047), resolution of at least one metastasis (p?=?0.011), and small liver metastases (largest lesion size ≤20 mm) after chemotherapy (p?=?0.007).

Conclusion

In patients undergoing surgery for colorectal liver metastases after chemotherapy, contrast-enhanced intraoperative ultrasonography improved both the sensitivity of intraoperative ultrasonography to detect liver metastases and the R0 hepatic resection rate.     

Comparison Between Perioperative and Postoperative Chemotherapy After Potentially Curative Hepatic Resection for Metastatic Colorectal Cancer

Background

Additional chemotherapy in patients with resectable colorectal liver metastases (CRLM) likely improves outcomes. Whether to administer chemotherapy as perioperative or adjuvant therapy remains controversial. We analyzed outcomes between these two treatment strategies.

Methods

Patients were identified from a prospective CRLM database and studied retrospectively. Patients with extrahepatic disease or initially unresectable CRLM were excluded. Only patients receiving oxaliplatin- and/or irinotecan-containing chemotherapy regimens were included. Univariate and Cox regression models were developed for recurrence and death.

Results

Between 1998 and 2007, 236 patients (57.4 %) in the adjuvant group and 175 patients (42.6 %) in the perioperative group were compared. The perioperative group was younger and had more tumors, shorter disease-free intervals, and higher clinical risk scores (CRS), but had smaller tumors. The overall survival was similar between the groups (perioperative 72.9 months vs. adjuvant 71.5 months; p = 0.48). When the comparison was adjusted for other clinicopathologic factors and CRS, the differences remained insignificant. On univariate analysis, there was a significant difference in recurrence-free survival between the groups (perioperative 17.2 months vs. adjuvant 27.4 months, p = 0.036). However, when the recurrence-free survival was adjusted for other clinicopathologic factors and the CRS, differences were not significant.

Conclusions

The timing of additional chemotherapy for resectable CRLM is not associated with outcomes. Trials comparing adjuvant and perioperative chemotherapy would have to be powered for small differences in outcome.     

Timing of Two-stage Liver Resection during Chemotherapy for Otherwise Unresectable Colorectal Metastases

Background

Tumor downsizing by effective chemotherapy while increasing remnant liver volume by two-stage hepatectomy can expand eligibility for resection of otherwise unresectable liver metastases. However, optimal timing of two-stage hepatectomy with respect to chemotherapy is undetermined.

Methods

We retrospectively analyzed the effect of timing of two-stage hepatectomy and chemotherapy using data from 95 patients whose colorectal liver metastases initially were considered unresectable.

Results

In 21 of 22 (95?%) patients whose first liver resection preceded chemotherapy (Hx-CTx group) and in 39 of 73 (53?%) patients whose chemotherapy preceded surgery (CTx-Hx group), macroscopic complete resection ultimately was achieved (P?P?P?=?0.12 and P?=?0.24, respectively), although poor response to chemotherapy was more frequent in the Hx-CTx group.

Conclusions

Optimal timing of hepatectomy and chemotherapy is difficult to specify, but performing the initial resection in a two-stage hepatectomy before chemotherapy may increase likelihood of macroscopic complete resection, even in patients with a poor response to chemotherapy or with limited courses of chemotherapy.     

Unresectable Colorectal Liver Metastases: The Safety and Efficacy of Conversion Therapy Using Hepatic Arterial Infusion Immunochemotherapy with 5-Fluorouracil and Polyethylene Glycol-Interferon α-2a

Background

Hepatic arterial infusion (HAI) or systemic chemotherapy has been used to treat unresectable colorectal liver metastases. The prognosis of the disease in recent years has been improved because chemotherapy is performed before hepatectomy to reduce tumor size (conversion therapy). The purpose of this study was to investigate the safety and efficacy of conversion therapy following HAI immunochemotherapy.

Methods

Hepatic arterial infusion of 5-fluorouracil (5-FU)/polyethylene glycol (PEG)-IFNα-2a was performed in 21 patients. The primary endpoint was the safety of HAI and hepatectomy. The secondary endpoints were response rate, rate of conversion to hepatectomy, survival rate, and prognostic factors.

Results

With regard to side effects, drugs were discontinued temporarily in one patient because of a decrease in white blood cell count; however, other patients continued chemotherapy. The response rate with HAI was 61.9 %, and the conversion rate was 38.1 %. Hepatectomy was completed successfully without mortality. Median progression-free survival (PFS) was 11.5 months (with and without conversion, 16.7 and 4.8 months, respectively; p = 0.021). Median overall survival was 34.6 months (with and without conversion, 48.4 and 26.6 months, respectively; p = 0.003). Prognosis was poor when the number of metastatic tumors was ≥10 [PFS: hazard ratio (HR) 32.21, p = 0.003; overall survival (OS): HR 9.13, p = 0.07], but prognosis improved after hepatectomy (OS: HR 0.08, p = 0.09).

Conclusions

Hepatic arterial infusion immunochemotherapy with 5-FU/PEG-IFNα-2a was performed safely without major side effects. Prognosis is expected to improve after successful conversion to hepatectomy.     

Evaluation of Chemotherapy-Associated Liver Injury in Patients with Colorectal Cancer Liver Metastases Using Indocyanine Green Clearance Testing

Background

Systemic chemotherapy may render initially unresectable colorectal cancer liver metastases resectable. Histopathologic examinations of resected nontumoral liver tissue revealed chemotherapy-associated liver injuries, which was recognized to impair the function of the remnant liver. We therefore evaluated whether indocyanine green (ICG) plasma clearance helps to assess chemotherapy-induced liver damage.

Methods

Data of 101 liver resections performed between 2006 and 2008 for colorectal liver metastases were analyzed for this study. Eighteen patients had liver resection without preoperative treatment, whereas 83 patients underwent neoadjuvant chemotherapy before surgery. ICG clearance was assessed by pulse densitometry before surgery.

Results

Comparison of ICG retention clearances demonstrated that patients pretreated with systemic chemotherapy had a significantly lower plasma disappearance rate (ICG-PDR; 19.3 ± 5.9 vs. 23.1 ± 3.8%/min; P = 0.002) and a significantly elevated ICG retention rate at 15 min (7.9 ± 6.6 vs. 3.8 ± 1.9%; P < 0.001). The percentage of subjects with an abnormal ICG-PDR (≤18%/min) was significantly higher in the pretreated group (48.2% vs. 5.6%; P = 0.001). Patients with an ICG-PDR of ≤18 had a prolonged postoperative hospital stay and experienced four times more complications in their postoperative course.

Conclusions

ICG clearance helps to identify patients with impaired liver function after neoadjuvant chemotherapy and aids in the estimation of the postoperative risk of morbidity after liver resection for colorectal liver metastases.     

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.     

The feasibility and potential benefit of preoperative chemotherapy for colorectal liver metastasis (CLM): a single-centered retrospective study

Purposes

The benefit of neo-adjuvant chemotherapy for liver-limited metastatic colorectal cancer is still controversial. This study defined the resectability regardless of the size and number of liver metastases, and attempted curative hepatic resection in all cases.

Methods

Sixty-four patients that tolerated chemotherapy were diagnosed with CLM (colorectal liver metastases) without extrahepatic metastase from January 2007 to November 2010, and received an oxaliplatin-based regimen. This study assessed the resectability after chemotherapy, and the patients were divided in two groups; the resected and unresected group. Sixteen patients underwent hepatic resection without chemotherapy.

Results

Thirty-five patients underwent surgical resection (resected group) and twenty-nine patients were considered unresectable (unresected group). All 35 patients in the resected group safely received oxaliplatin-based chemotherapy safely without serious adverse effects. No serious postoperative complications were observed. The median overall survival (MST) was significantly higher in the resected than in the unresected group (56.93 [95 % CI 38.13–75.73] and 25.07 months [95 % CI 17.87–32.26], respectively; P < 0.001). The median disease-free survival was 20.2 [95 % CI 8.82–31.65] months in the resected group.

Conclusion

Preoperative chemotherapy for CLM is well tolerated and does not increase postoperative complications. Curative surgery with preoperative chemotherapy has the potential to improve the overall survival in patients with CLM.     

Recurrence Following Hepatectomy for Metastatic Colorectal Cancer: Development of a Model that Predicts Patterns of Recurrence and Survival

Background

While several prognostic models have been developed to predict survival of patients who undergo hepatectomy for metastatic colorectal cancer (mCRC), few data exist to predict survival after recurrence. We sought to develop a model that predicts survival for patients who have developed recurrence following hepatectomy for mCRC.

Methods

A retrospective analysis was performed on data from consecutive patients that underwent hepatectomy for mCRC. Clinicopathologic data, recurrence patterns, and outcomes were analyzed. Kaplan–Meier survival analysis and univariate and multivariate analyses were performed. An integer-based model was created to predict the patterns of recurrence and survival after recurrence.

Results

This analysis included 280 patients with a median follow-up of 50.1 months. Of these, 53% underwent major hepatectomy and 87% had negative margins. Recurrent disease developed in 63% of patients. After hepatectomy, factors associated with short disease-free interval (DFI) and overall survival (OS) included CEA > 200 ng/ml (P < 0.0005), >1 metastasis (P < 0.0005), and a high Fong score (P < 0.0005). After recurrence, the pattern of recurrence was a strong predictor of OS (P < 0.0005). Independent predictors of the pattern of recurrence on multivariate analysis include CEA > 200 ng/ml, tumor size >5 cm, and >1 liver metastasis. A simple predictive scoring system was developed from the beta coefficients of this analysis that correlated with recurrence pattern (P < 0.0005).

Conclusions

After hepatectomy, survival of patients with recurrent mCRC is strongly predicted by the patterns of recurrence, and the recurrence pattern can be predicted with a simple model. This can also be extended to create a scoring system that estimates expected survival.

     

Prognostic Impact of Positive Surgical Margins After Resection of Colorectal Cancer Liver Metastases: Reappraisal in the Era of Modern Chemotherapy

Background

The purpose of the present study was to assess the prognostic impact of positive surgical margins (R1) after liver resection (LR) of colorectal liver metastases (CRLM) in the era of modern chemotherapy regimens. R1 resection is a negative prognostic factor after LR of CRLM. The significance of R1 margins in the era of effective chemotherapy is unknown.

Methods

From January 2000 to December 2009, 215 patients (177 men: 62 %; median age 60 years; range 30–84 years) underwent LR of CRLM. The LR was considered R1 (margin <1 mm) in 49 patients (23 %) and R0 in 166 patients (77 %). Overall, 108 (50 %) patients received preoperative chemotherapy and 156 (72 %) patients received postoperative chemotherapy.

Results

With a median follow-up of 36 months (range 1–141 months), the 5-year overall survival (OS) rate (47 vs 40 %; p = 0.05) and the disease-free survival (DFS) rate (36 vs 23 %; p = 0.006) were significantly lower in the R1 group. Recurrence developed in 152 patients (71 %) and the rate of recurrence was significantly higher (84 vs 67 %; p = 0.02) in the R1 group. On multivariate analysis, N+ status of the colorectal primary tumor (p = 0.008), presence of radiologically occult disease (p = 0.04), and R1 resection (p = 0.03) were independent adverse predictors of OS. The N+ status of the primary tumor (p = 0.003) and R1 resection (p = 0.02) were independent adverse predictors of DFS. On multivariate analysis use of postoperative chemotherapy was the only independent predictor of improved DFS (p = 0.02) in the R1 group.

Conclusions

A positive resection margin remains a significant poor prognostic factor after LR of CRLM in the era of modern chemotherapy. Postoperative chemotherapy reduces recurrence rates after R1 resection of CRLM.     

Phase II Trial of Adjuvant Chemotherapy with S-1 for Colorectal Liver Metastasis

Background

This phase II trial was designed to evaluate the safety and efficacy of adjuvant chemotherapy with S-1 in patients with curatively resected liver metastasis from colorectal cancer. Results of an interim analysis of safety and short-term outcomes are reported.

Methods

Patients who underwent curative resection of liver metastasis from colorectal cancer received S-1 monotherapy (on days 1–28, followed by 14 days’ rest, 8 cycles) as adjuvant chemotherapy.

Results

Among 62 patients enrolled between October 2008 and August 2010, a total of 60 patients were eligible for analysis. The most frequent grade 3 or higher hematologic toxicity involved neutropenia in three patients (5.0 %). Nonhematologic toxicities of grade 3 or higher were fatigue in 6.7 % of patients. Grade 4 enteritis occurred in one patient, but resolved promptly after withdrawal of S-1 therapy. The completion rate of the eight scheduled cycles of chemotherapy was 58.3 %. The most common reasons for withdrawal of treatment was the detection of early relapse in 16 patients (64 %). When the 16 patients who had recurrence during adjuvant treatment were excluded from analysis, 79.5 % of the remaining 44 patients completed the scheduled treatment. Early recurrence within 1 year after curative liver resection occurred in 21 patients (35 %). The most common site was the remnant liver in 14 patients.

Conclusions

Orally administered S-1 after curative liver resection has an acceptable toxicity profile and a high rate of completion of the therapy. S-1 can be safely used and might be a viable treatment option in an adjuvant setting.     

A Randomized Phase II Trial of Three Intensified Chemotherapy Regimens in First-Line Treatment of Colorectal Cancer Patients with Initially Unresectable or Not Optimally Resectable Liver Metastases. The METHEP Trial

Purpose

This study was designed to evaluate neoadjuvant intensified chemotherapy in potentially resectable or unresectable liver metastases (LM) from colorectal cancer (CRC).

Methods

Criteria for potentially resectable LM were complex hepatectomy and/or risky procedure, close contact with major vascular structures, and for unresectable LM, a future liver remnant predicted to be less than 25–30 % of total liver volume. Between October 2004 and August 2007, 125 patients were randomized to either standard (FOLFIRI/FOLFOX4) or intensified chemotherapy (FOLFIRI-HD/FOLFOX7/FOLFIRINOX). Primary endpoint was objective response rate (ORR) after 4 cycles of chemotherapy. Secondary endpoints included safety, R0 surgical resection, best ORR, progression-free survival (PFS), and overall survival (OS).

Results

A total of 122 patients were treated; 45 % of patients had less than 30 % of remaining liver tissue, 20 % had major vascular contact, and 35 % were potentially resectable. Grade 3/4 toxicities were neutropenia (24, 19, 10, 23 %) diarrhoea (0, 6, 3, 23 %), mucositis (0, 3, 0, 7 %), vomiting (7, 9, 0, 3 %), and neurotoxicity (0, 0, 10, 3 %) in arms (FOLFIRI + FOLFOX4)/FOLFIRI-HD/FOLFOX7/FOLFIRINOX, respectively. ORR was 33, 47, 43, and 57 % after the first 4 cycles in arms (FOLFIRI + FOLFOX4)/FOLFIRI-HD/FOLFOX7/FOLFIRINOX, respectively. FOLFIRINOX offered the best conversion rate to resectability (67 %). Disease-free status after chemotherapy and surgery (R0, R1, Rx) was achieved in 54 of 64 operated patients. Median PFS was 9.2 months in control arms versus 11.9 months in experimental arms (hazards ratio [HR] = 0.76, p = 0.115), and the median OS was 17.7 versus 33.4 months (HR = 0.73, p = 0.297), respectively.

Conclusions

FOLFIRINOX showed promising activity in CRC patients with LM compared with standard or intensified bi-chemotherapy regimens.