The role of aggressive regional therapy for colorectal liver metastases

Surgical resection is the most effective treatment modality for liver metastases from colorectal cancer. However, most patients with liver metastases are not candidates for resection due to extensive intrahepatic disease. Approximately one-half of the patients who are able to undergo resection will eventually recur within the remnant liver. Hepatic arterial infusion (HAI) chemotherapy takes advantage of the arterial blood supply of colorectal liver metastases to increase tumor exposure to chemotherapy while minimizing systemic toxicity. HAI chemotherapy has been utilized in patients with unresectable disease in the neoadjuvant setting in an effort to convert them to resectability as well as in patients with resectable disease in the adjuvant setting in an effort to prevent recurrence. This article reviews the roles of HAI chemotherapy in an aggressive approach toward colorectal liver metastases.     

Outcome following repeat liver resection for colorectal liver metastases.

AIM: Our aim was to determine independent predictors of survival after second liver resection and to confirm whether the type of first resection influences survival after repeat resection. METHODS: Fifty-four patients who underwent a second liver resection for colorectal liver metastases were analyzed. To find independent predictors of survival, possible prognostic factors regarding the primary tumor, and the first and second resections were used in the Cox regression analysis. RESULTS: There were three postoperative deaths within 90 days of surgery. The 3- and 5-year overall survival rates were 53% and 46%, respectively. The size of the tumor (>50mm) (p=0.005), serum carcinoembryonic antigen level (>30microg/L) (p=0.002), and the presence of a positive surgical margin at the second resection (p=0.006) were independent predictors of poor survival following the second resection. The type of first resection was not associated with survival but was associated with the ability to achieve a histological negative surgical margin at the second liver resection (p=0.01). CONCLUSION: Three independent predictors of survival were identified. Major initial liver resection was associated with a reduced ability to achieve surgical clearance at the second resection. For colorectal liver metastases, major resection should only be performed if a negative margin cannot be achieved by minor resection.     

c-Met gene amplification is associated with advanced stage colorectal cancer and liver metastases

The c-Met proto-oncogene encodes a receptor tyrosine kinase (TK) that promotes invasive tumor growth and metastasis. Recent studies show that the presence of c-Met gene amplification is predictive for selective c-Met TK inhibitors in gastric cancer and lung cancer. In this study, we utilized a highly quantitative PCR/ligase detection reaction technique to quantify c-Met gene copy number in primary colorectal cancer (CRC) (N=247), liver metastases (N=147), and paired normal tissues. We identified no differences in c-Met gene copy number between normal colonic mucosa and liver tissue. However, mean c-Met gene copy number was significantly elevated in CRC compared with normal mucosa (P<0.001), and in liver metastases compared with normal liver (P<0.001). Furthermore, a significant increase in c-Met was seen in liver metastases compared with primary CRC (P<0.0001). c-Met gene amplification was observed in 2% (3/177) of localized cancers, 9% (6/70) of cancers with distant metastases (P<0.02), and 18% (25/147) of liver metastases (P<0.01). Among patients treated by liver resection, there was a trend toward poorer 3-year survival in association with c-Met gene amplification (P=0.07). Slight increases in c-Met copy number can be detected in localized CRCs, but gene amplification is largely restricted to Stage IV primary cancers and liver metastases. c-Met gene amplification is linked to metastatic progression, and is a viable target for a significant subset of advanced CRC.     

Synchronous resection for colorectal liver metastases: The future

Colorectal Cancer is a common malignancy. Many patients have metastatic disease at presentation and a significant proportion subsequently go onto develop metastatic disease, following surgery for the primary disease.     

结直肠癌同时性肝转移同期手术切除疗效分析

目的 分析结直肠癌同时性肝转移患者行同期手术切除原发灶和肝转移灶的近期及远期效果,探讨同期手术是否存在优势.方法 回顾性分析行手术治疗的53例结直肠癌同时性肝转移患者的临床资料,根据肝转移灶切除时间的不同,分为同期手术组(同期组)40例,分期手术组(分期组)13例,评价两组患者的手术效果.结果 同期组和分期组患者的手术时间分别为(212.9±72.3) min和(326.5±140.2)min,术中失血量分别为(337.5±298.0) ml和(594.6±430.5) ml,术后住院时间分别为(16.2±8.1)d和(25.8±8.5)d,差异均有统计学意义(均P＜0.05).同期组和分期组患者手术并发症的发生率分别为25.0％和53.8％ (P =0.053).两组均无手术死亡患者.同期组患者1、3、5年生存率分别为95.0％、57.0％和37.4％,中位生存时间为40.0个月,中位无病生存时间为14.0个月;分期组患者l、3、5年生存率分别为92.3％、58.7％和36.7％,中位生存时间为38.0个月,中位无病生存时间为13.0个月.两组患者生存时间差异无统计学意义(P＞0.05).结论 同期手术是治疗可切除的结直肠癌同时性肝转移患者安全、有效的措施,与分期手术比较,术中出血少,并发症发生率低,术后住院时间短.     

Microwave ablation with or without resection for colorectal liver metastases

Background

Ablation with or without resection for colorectal liver metastases has been suggested as a potential method of improving survival if complete surgical resection is not possible. This study assessed the safety and efficacy of surgical microwave ablation (MWA) with or without resection for colorectal liver metastases.

Methods

A retrospective case series was reviewed. Data was extracted for all patients treated with open MWA with or without resection for colorectal liver metastases. Endpoints included postoperative 30-day morbidity and mortality, local treatment failure, disease free survival and overall survival.

Results

A total of 43 patients with technically irresectable disease were treated with MWA; 28 underwent combined MWA and resection, whilst 15 underwent MWA as the sole treatment modality. Overall post-operative morbidity was 35%, 30-day postoperative mortality 2%. At a median follow-up of 15 months, local treatment failure was observed in 4% of ablated lesions. 3-year OS was 36% for MWA group, compared to 45% for the combined ablate/resect group with 3-year DFS of 32% and 8% respectively.

Conclusion

Microwave ablation with or without resection is a safe and effective method of achieving local disease control. Ablation with or without resection is associated with good long-term outcomes, and may be a suitable treatment option for small non-resectable colorectal liver metastases.     

Regional lymph node involvement in patients undergoing liver resection for colorectal cancer metastases

Background

While the indications for surgery among patients with colorectal cancer liver metastases (CRCLM) are expanding, the role of surgery in patients with hepatic lymph node involvement remains controversial. We report management and outcomes in a population-based cohort of patients undergoing hepatectomy with concomitant hepatic lymphadenectomy for CRCLM.

Selective resection of colorectal liver metastases.

AIMS: Safety of liver surgery for colorectal cancer liver metastases after neoadjuvant chemotherapy has to be re-evaluated. PATIENTS AND METHODS: Two hundred Patients were prospectively analyzed after surgery for colorectal cancer liver metastases between 2001 and 2004 at our institution. Special emphasis was given to perioperative morbidity and mortality under modern perioperative care. RESULTS: There was no in-hospital mortality and the perioperative morbidity was 10% (20/200). Four patients had to be reoperated due to bile leak or intraabdominal abscess. The remainder either had infectious complications or pleural effusion and/or ascites requiring tapping. Variables strongly associated with decreased survival were T, N, G and UICC (International Union against cancer) classification of the primary, hepatic lesions>5 cm and elevated tumour markers. Short disease free interval and neoadjuvant chemotherapy without response predicted impaired recurrence free survival (RFS). Multivariate analysis revealed lymph node status and differentiation of the primary, presence of extrahepatic tumour and gender as factors associated with decreased survival. Administration of neoadjuvant chemotherapy was not associated with higher postoperative morbidity or prolonged hospital stay. CONCLUSIONS: Modern dissection techniques and improved perioperative care contributed to a very low rate of surgery-related morbidity (10%) and a zero percent mortality which was also observed in patients pretreated with neoadjuvant chemotherapy prior to resection. Liver resection in experienced hands has become a safe part in the potentially curative attempt of treating patients with metastatic colorectal cancer.     

Effect of preoperative chemotherapy on liver resection for colorectal liver metastases

Aim

To compare the effects of preoperative chemotherapy on liver parenchyma morphology, as well as morbidity and mortality after liver resection for colorectal liver metastases.

Methods

Prospectively collected data on 173 patients undergoing liver resection for CLM between 1/2003 and 9/2005 was analysed in three groups: A: preoperative oxaliplatin (Ox, n = 70); B: other chemotherapeutic agents (OC, n = 60); and C: surgery alone without chemotherapy (SA, n = 43). Blood transfusion, hospital stay, operative procedure, peak postoperative bilirubin levels, complications and histopathology of the resected liver were compared.

Results

Intra-operative blood transfusion requirement (34%) and biliary complications (16%) was higher in patients receiving oxaliplatin-based chemotherapy (p = 0.01 and p = 0.06, respectively). Oxaliplatin-based chemotherapy was also associated with sinusoidal dilatation of mild grade in 52.8% vs. 26.6% and 23.3% patients (p = 0.007 and p = 0.004) in other groups, respectively. Steatosis was similarly distributed across the study group. Postoperative mortality was 2, 1 and 4 patients, respectively (p = ns).

Conclusion

Oxaliplatin-based preoperative chemotherapy is associated with vascular alterations in the liver parenchyma without significantly increasing the risk of steatosis, or postoperative morbidity and mortality.     

Time-varying prognostic effects of primary tumor sidedness and grade after curative liver resection for colorectal liver metastases

BackgroundThe veracity of the proportional hazards (PH) requirement is rarely scrutinized in most areas of cancer research, although fulfilment of this assumption underpins widely-used Cox survival models. We sought to critically appraise the existence of prognostic factors with time-dependent effects and to characterize their impact on survival among CLM patients.MethodsConsecutive patients who underwent liver resection with curative intent for CLM at the Singapore General Hospital were identified from a prospectively-maintained database. We evaluated PH of 55 candidate variables, and parameters which departed significantly from proportionality were included in Cox models that incorporated an interaction term to account for time-dependent effects. As sensitivity analyses, we fitted Weibull mixture ‘cure’ models to handle long plateaus in the tails of survival curves, and also analyzed the restricted mean survival time.Results318 consecutive patients who underwent curative liver resection for CLM between Jan 2000 and Nov 2016 were included in this analysis. Hazard ratios for tumor grade (poorly-versus well- and moderately-differentiated) were found to decrease from 3.135 (95% CI: 1.637–6.003) at 12 months to 2.048 (95% CI: 1.038–4.042) after 24 months, and ceased to be significant at 26 months. Compared to left-sided tumors, a right-sided tumor location was found to portend worse prognosis for the first 10 months after resection but subsequently confer a survival benefit due to a crossing of survival curves. Corroborating this observation, long-term cure fractions were estimated to be 25.5% (95% CI: 17.4%–33.6%) and 34.2% (95% CI: 17.4%–50.9%) among patients with left-sided and right-sided primary disease respectively.ConclusionPrimary tumor sidedness and grade appear to exert time-varying prognostic effects in CLM patients undergoing curative liver resection.     

结直肠癌肝转移患者行全腹腔镜与腹腔镜辅助同期切除手术的疗效观察

目的 探讨结直肠癌肝转移(CRLM)患者采用全腹腔镜与腹腔镜辅助同期切除术治疗的临床疗效比较.方法 选取2010年2月至2015年4月间大连大学附属新华医院收治的68例CRLM同期切除患者,采用随机数表法分为辅助组和全镜组,每组34例.辅助组患者采用腹腔镜结直肠癌(CRC)根治术联合开腹CRLM切除术治疗,全镜组患者采...     

Stereotactic radiofrequency ablation (SRFA) for recurrent colorectal liver metastases after hepatic resection

BackgroundTo evaluate the efficacy, safety and overall clinical outcome of multiprobe SRFA as a treatment for recurrent colorectal liver metastases after hepatic resection (HR).MethodsA retrospective, single center study carried out between 2006 and 2018. 64 consecutive patients with recurrent or new CRLM after previous HR were treated by SRFA for 217 lesions (median size 2.7 cm, 1–7.5) in 103 ablation sessions. Endpoints consisted of i) technical efficacy ii) complication and mortality rates iii) local and distant recurrence, iv) disease free survival (DFS), and v) overall survival (OS).Results213/217 tumors were successfully ablated at initial SRFA (97.7% primary technical efficacy rate). Four tumors required repeat ablation, resulting in a secondary technical efficacy rate of 99.5% (216/217). Local recurrence developed in 25/217 lesions (11.5%). Major complication rate was 5.8% (6/103 sessions) and mortality rate was 1.0% (1/103 ablation sessions), respectively.1-, 3-, and 5- year OS rates from date of first SRFA were 90.1%, 46.2%, and 34.8% (median 33.1 months). DFS rates were 54.2%, 17.2%, and 17.2%, at 1-, 3- and 5- years, respectively (median 13.3 months).ConclusionSRFA is a safe, feasible and effective option for CRLM after HR with low morbidity levels and favorable clinical outcome.     

Systemic chemotherapy and its implications for resection of colorectal liver metastasis

Background

Liver resection remains the only chance of cure for patients with colorectal liver metastasis. Modern chemotherapy can play a role in the management of these patients but is not without risk.

Methods

The online databases Medline and Pubmed were searched to identify relevant articles. Keywords used in these searches were “colorectal cancer”, “liver metastasis”, “chemotherapy”, “liver resection”, “monoclonal antibody”, “steatohepatitis”, “sinusoidal obstruction” and “liver regeneration”. Databases were searched for the period January 1970 to September 2009 inclusively. In addition hand referencing of retrieved articles was performed.

Results

Modern chemotherapy regimens can effectively downstage initially unresectable disease such that surgical resection can be performed with the prospect of long term cure. There is insufficient evidence however to recommend its use in either the neoadjuvant or adjuvant setting in those with resectable disease from the outset.

Conclusion

Chemotherapy can be associated with significant changes to the hepatic parenchyma with subsequent increased risk of morbidity and mortality in the perioperative period. Much work needs to be done to understand the molecular mechanisms underlying these changes to make extended resections safer in patients who are at risk.     

Prognostic models for outcome following liver resection for colorectal cancer metastases: A systematic review

Background

Liver resection provides the best chance for cure in colorectal cancer (CRC) liver metastases. A variety of factors that might influence survival and recurrence have been identified. Predictive models can help in risk stratification, to determine multidisciplinary treatment and follow-up for individual patients.

Aims

To systematically review available prognostic models described for outcome following resection of CRC liver metastases and to assess their differences and applicability.

Methods

The Pubmed, Embase and Cochrane Library databases were searched for articles proposing a prognostic model or risk stratification system for resection of CRC liver metastases. Search terms included ‘colorectal’, ‘liver’, ‘metastasis’, ‘resection’, ‘prognosis’ and ‘prediction’. The articles were systematically reviewed.

Results

Fifteen prognostic systems were identified, published between 1996 and 2009. The median study population was 305 patients and the median follow-up was 32 months. All studies used Cox proportional hazards for multi-variable analysis. No prognostic factor was common in all models, though there was a tendency towards the number of metastases, CRC spread to lymph nodes, maximum size of metastases, preoperative CEA level and extrahepatic spread as representing independent risk factors. Seven models assigned more weight to selected factors considered of higher predictive value.

Conclusion

The existing predictive models are diverse and their prognostic factors are often not weighed according to their impact. For the development of future predictive models, the complex relations within datasets and differences in relevance of individual factors should be taken into account, for example by using artificial neural networks.     

Preoperative ultrasonography screening for liver metastases of patients with colorectal cancer

The clinical value of preoperative ultrasonography in screening for synchronous liver metastases was prospectively evaluated in 338 patients with colorectal cancer. Synchronous liver metastases were observed at laparotomy in 11.5% (39/338) of the patients. The liver metastases had been found by preoperative ultrasonography in 30 patients and missed in nine. The overall accuracy rate, sensitivity and specificity, and the positive and negative predictive values of this modality were 0.970, 0.769, 0.997, 0.968 and 0.971, respectively. In detecting liver metastases, the results were superior to those of biochemical blood tests and measurements of carcinoembryonic antigen serum levels. The accuracy of the ultrasonography was also superior to that of these other tests combined. The results indicate ultrasonography to be an indispensable preoperative examination for patients with colorectal cancer.     

Liver resection is justified for patients with bilateral multiple colorectal liver metastases: A propensity-score-matched analysis

Background

Increasingly, patients with multiple colorectal liver metastases (CLM) are surgically treated. Some studies have shown that patients with bilobar and unilobar multiple CLM have similar outcomes, but other have shown that patients with bilobar CLM have worse outcomes after resection. We aimed to compare clinical outcomes of surgical treatment of bilobar and unilobar CLM using propensity score matching.

Primary tumor resection in colorectal cancer with unresectable synchronous metastases: A review

At the time of diagnosis, 25% of patients with colorectal cancer (CRC) present with synchronous metastases, which are unresectable in the majority of patients. Whether primary tumor resection (PTR) followed by chemotherapy or immediate chemotherapy without PTR is the best therapeutic option in patients with asymptomatic CRC and unresectable metastases is a major issue, although unanswered to date. The aim of this study was to review all published data on whether PTR should be performed in patients with CRC and unresectable synchronous metastases. All aspects of the management of CRC were taken into account, especially prognostic factors in patients with CRC and unresectable metastases. The impact of PTR on survival and quality of life were reviewed, in addition to the characteristics of patients that could benefit from PTR and the possible underlying mechanisms. The risks of both approaches are reported. As no randomized study has been performed to date, we finally discussed how a therapeutic strategy’s trial should be designed to provide answer to this issue.     

‘Close Shave’ in liver resection for colorectal liver metastases

Introduction

The optimal size of clear liver resection margin width in patients with colorectal liver metastases (CRLM) remains controversial. The aim of this study was to investigate the effects of margin width on long-term survival after liver resection for CRLM with a policy of standard neo-adjuvant chemotherapy.

Methods

Consecutive patients (n = 238) who underwent liver resection for CRLM were included over a ten-year period. All patients with synchronous or early (<2 years) metachronous tumours were treated with neo-adjuvant chemotherapy. Data were recorded prospectively.

Results

Overall survival of the cohort at 1, 3 and 5 years were 90.3%, 68.1% and 56.1% respectively. The incidence of cancer involved resection margins (CIRM) was 5.8%. Patients with macroscopically involved resection margins had a poorer overall survival than those with microscopically involved margins (p = 0.04). Involved resection margins had a poorer overall survival (p = 0.002) than patients with clear margins. Width of clear resection margin did not affect long-term survival.

Conclusion

CIRM independently predicts poor outcome in patients with CRLM. Clear margin width does not affect survival. A standard policy of neo-adjuvant chemotherapy may be associated with a low incidence of CIRM and improved long-term outcome of sub-centimetre margin widths, resembling those with >1 cm resection margins.     

A comparison of right and extended right hepatectomy with all other hepatic resections for colorectal liver metastases: A ten-year study

Aims

Colorectal liver metastases are treated by a combination of adjuvant chemotherapy followed by liver resection. In this study we compared all major right-sided resections with left or parenchymal sparing resections.

Methods

Consecutive patients (n = 283) who had successful hepatic resections for colorectal metastases from September 1996 to November 2006 were prospectively studied. Early and late outcomes of those who had right and extended right hepatectomies (RH) were compared with those who had all other types of liver resection (AOLR). Adjuvant therapy and pre-operative assessment were standardised for all.

Results

The 1-, 3- and 5-year overall survival rates in the RH group were 84.1%, 54.3% and 38.9%, respectively. The 1-, 3- and 5-year overall survival rates in the AOLR group were 95.4%, 65.9% and 53.3%, respectively. The difference was statistically significant (p = 0.03). The 1-, 3- and 5-year disease-free survival rates in the RH group were 69.5%, 34.4% and 25.5%, respectively and 68.4%, 34.91% and 34.91%, respectively in the AOLR group (p = 0.46). Operative mortality was 3.9% in the RH group and 0.7% in the AOLR group (p = 0.04). Morbidity was 31.3% in the RH group and 18% in the AOLR group.

Conclusion

Patients undergoing right and extended right hepatectomies for colorectal metastases have a greater operative morbidity and mortality and have a significantly worse overall survival compared to all other liver resections for the same disease.