Intraoperative ultrasound for the colorectal surgeon: current trends and barriers

Up to two thirds of patients diagnosed with colorectal cancer (CRC) develop colorectal liver metastases (CRLMs) and one quarter of patients present with synchronous metastases. Early detection of CRLM widens the scope of potential treatment. Surgery for CRLM offers the best chance of a cure. Current preoperative staging of CRC relies on computerized tomography and magnetic resonance imaging. Intraoperative ultrasound (IOUS) scans and contrast‐enhanced IOUS (CE‐IOUS) have been demonstrated to detect additional metastases not seen on routine preoperative imaging. IOUS is not widely used by colorectal surgeons during primary resection for CRC. Confident use of IOUS/CE‐IOUS during primary resection of CRC may improve decision‐making by providing the most sensitive form of liver staging even when compared with magnetic resonance imaging. This may be particularly important in the era of laparoscopic resections, where the colorectal surgeon loses the opportunity to palpate the liver. There are several implied barriers to the routine use of IOUS/CE‐IOUS by colorectal surgeons. These include time pressure, familiarity with techniques, a perceived learning curve, cost implications and limitation of the modality due to operator variations. Inclusion of IOUS in the training of colorectal surgeons and further investigation of potential benefits of IOUS/CE‐IOUS could potentially reduce these barriers, enabling usage during primary resection for CRC to become more widespread.     

Colorectal liver metastases: Resect,ablate, or embolize

The management of colorectal liver metastases (CRLM) is complex and should be individualized to each patient. Resectable CRLM benefit from surgical resection, preferably minimally invasive and parenchymal sparing, when feasible. Ablation is a viable alternative. Chemotherapy in this setting is potentially indicated in select patients, however, it has a clear role in unresectable CRLM. Newer locoregional therapies may benefit some unresectable CRLM with resistance to chemotherapy. Liver transplantation, a new therapy on the horizon for unresectable disease, has encouraging preliminary long-term survival outcomes for carefully selected patients.     

Liver transplantation for primary and metastatic liver cancers

Liver transplantation for hepatic malignancies has emerged as a well‐documented and proven treatment modality. However, early unsatisfactory results emphasized that only a highly selected patient population would benefit from transplantation. Currently, 15% of all liver transplants performed are for hepatocellular carcinoma (HCC). There is no controversy about the fact that liver transplantation for HCC in the adult population yields good results for patients whose tumour masses do not exceed the Milan criteria. It remains to be determined whether patients with more extensive tumours can be reliably selected to benefit from the procedure. In patients with small HCC at an early stage and preserved liver function, liver resection provides an alternative to transplant. Liver resection may offer similar survival results to orthotopic liver transplantation (OLT) in the short term, and does not carry the long‐term effects of immunosuppression; however, long‐term and disease‐free survival favours liver transplantation. Very promising results have been obtained for cholangiocarcinoma treated by aggressive combination therapies, including chemo‐ and radiotherapy followed by OLT. Survival rate in these selected patients can approach that of patients with cholestatic liver disease, and the role of transplantation now requires re‐evaluation. Similarly, hepatoblastoma is an excellent indication in paediatric patients with unresectable or recurrent tumours. Epithelioid hemangioendothelioma is also an appropriate indication for liver transplantation, even in the presence of extrahepatic metastases, unlike angiosarcoma which is associated with a very poor survival and considered as a contraindication. And finally for metastatic liver disease from neuroendocrine tumours, liver transplantation can result in long‐term survival and even cure in well selected patients. Conversely, the value of transplantation for colorectal liver metastases (currently a contraindication) requires further evaluation by well‐designed trials.     

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??Risk and prognostic factors of colorectal liver metastases LIANG Li, LIU Tian-shu. Department of Medical Oncology??Zhongshan Hospital, Fudan University??Shanghai 200032, China
Corresponding author: LIU Tian-shu, E-mail: liu.tianshu@
zs-hospital.sh.cn
Abstract Liver is the most common metastasis site of colorectal cancer, and the prognosis of colorectal liver metastases (CRLM)is poor. CRLM are divided into synchronous metastasis and metachronous metastasis. Single factor and multiple factor regression analyses show that the risk factors of CRLM include the depth of invasion, lymph node metastasis, tumor node, differentiation degree, tumor antigen and carbohydrate antigen. The factors influencing the prognosis of CRLM include the size and quantity of liver metastases, primary resection, surgical resection of liver metastases, systemic drug therapy and so on. Therefore, the surgical resection of liver metastases as well as drug therapy to get the opportunity of resection can maximize the survival of patients with CRLM. For a combination of a number of factors, the scoring system can better predict the prognosis of CRLM.     

Intraoperative interstitial radiation therapy for hepatic metastases from colorectal carcinomas

Liver metastases from colorectal carcinomas occur frequently. While surgical resection offers the only hope for long-term cure, unsuspected bilobar metastases or extrahepatic metastatic disease may be found at laparotomy, precluding hepatic resection for cure. In this setting intraoperative interstitial hepatic irradiation using the Gamma Med II (Mick Radio-Nuclear Instruments, Bronx, New York) remote afterloading irradiator and an Iridium-192 source permits delivery of a tumoricidal dose to liver tumor(s) with a limited radiation dose to adjacent normal liver. Six patients underwent laparotomy for potential resection of hepatic metastases in a shielded operating room equipped with remote anesthesia monitoring capability and were found to be unresectable. An upper hand retractor facilitated liver exposure during the exploratory and subsequent radiation phases of the procedure. Intraoperative interstitial radiation therapy was performed in each patient. No significant complications occurred on follow-up from 2 to 9 months. Hepatic tumor regression or stabilization occurred on sonography and/or CT scan in each case with a median follow-up of 5 months. The technique offers the potential to ablate discrete tumor nodules within the liver. Ongoing clinical trials will determine the role of intraoperative interstitial radiation in the treatment of hepatic metastases.     

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结直肠癌肝转移发生率高,且临床就诊者大多数肝转移灶为不可切除。尽管关于不可切除结直肠癌肝转移病人原发灶的处理尚有一定争议,但随着结直肠癌原发灶处理经验的积累,多学科综合治疗团队(MDT)模式的开展,转化性治疗思维的应用,"个体化治疗"原则的实施,针对不可切除结直肠癌肝转移病人原发灶的处理逐步形成包括手术切除原发灶在内较合理的综合治疗体系。手术切除、新辅助治疗与姑息治疗的合理选择是改善不可切除结直肠癌肝转移病人生存质量及提高生存期,获得最佳治疗效果的关键。     

Perihepatic Lymph Node Micrometastases Impact Outcome after Partial Hepatectomy for Colorectal Metastases

Background Hepatectomy for resectable colorectal liver metastases provides a survival advantage but is usually reserved for patients without extrahepatic disease. Metastases to perihepatic lymph nodes (LN) occur with controversial significance. This study uses standard pathologic analysis and immunohistochemistry (IHC) to determine the impact of occult metastatic disease to perihepatic LN in patients with colorectal cancer undergoing hepatectomy. Methods Fifty-nine patients with liver metastases from colon or rectal primary cancer were studied prospectively. Perihepatic LN were sampled from the portocaval, pancreaticoduodenal, and common hepatic artery regions. All LN were analyzed using hematoxylin and eosin (H&E), and those negative by H&E were analyzed using IHC for cytokeratin. Recurrence and survival were compared amongst LN groups. Results Median follow-up was 42 months for survivors. There were eight patients with metastatic disease to at least one perihepatic LN identified by H&E and fourteen patients with metastases identified by IHC only. Forty-one patients (70%) recurred after resection, and patients with LN metastases, regardless of detection method, had a shorter recurrence-free survival compared to node negative patients. However, patterns of recurrence differed by LN group. Compared to H&E-positive patients, IHC-positive patients had a better overall survival and were more likely to recur at a single site amenable to salvage resection. Conclusions In patients with hepatic colorectal metastases, IHC analysis of perihepatic LN adds prognostic value regarding the timing and burden of recurrence after resection. Routine IHC assessment of perihepatic LN is reasonable since the information garnered would potentially influence postresection chemotherapy recommendations.     

结直肠癌肝转移危险及预后因素分析

肝脏是结直肠癌最常见的远处转移器官,结直肠癌病人出现肝转移一般预后较差。结直肠癌肝转移分为同时性肝转移和异时性肝转移,对众多的临床以及病理学特征进行的单因素和多因素回归分析提示,影响结直肠癌发生肝转移的危险因素有：浸润深度、淋巴结转移、癌结节、分化程度、癌胚抗原和糖类抗原等。影响结直肠癌肝转移病人预后的因素有：肝转移灶大小及数目、肝外器官转移、原发灶手术切除、肝转移灶手术切除、全身药物治疗等。因此,手术切除肝转移灶、药物治疗获得手术切除机会等治疗模式能够最大程度地提高结直肠癌肝转移病人的存活率。由众多因素组合起来的评分系统,能够较好地预测结直肠癌肝转移病人的预后。     

RAS基因突变对结直肠癌肝转移患者肝切除术后预后的影响

目的分析RAS基因突变对结直肠癌肝转移行肝切除患者预后的影响。方法回顾分析北京大学肿瘤医院肝胆胰外一科2008年1月1日至2016年12月31日连续收治的545例结直肠癌肝转移行肝切除的患者资料,依据纳入和排除标准最终纳入356例,男性232例,女性124例,年龄21〜83岁。比较RAS基因野生型和突变型患者的临床和随访资料。采用Kaplan-M eier法进行生存分析,比较采用log-rank检验。单因素和多因素Cox回归分析患者生存的影响因素。结果RAS基因野生型和突变型患者分别为247例和109例。RAS基因野生型患者中位生存期为74个月,突变型为30个月。RAS基因野生型患者累积生存率和累积无病生存率均优于突变型,差异有统计学意义(均P<0.05)。多因素Cox回归分析,肝转移出现间隔≤12个月(HR=1.673,95%CI:1.016~2.637)、肝转移瘤最大直径>5cm(HR=1.717,95%(CI:1.102〜2.637)、RAS基因突变型(HR=1.836,95%CI:1.322〜2.550)是结直肠癌肝转移患者手术切除后生存的独立危险因素。结论RAS基因突变是结直肠癌肝转移患者肝切除术后生存的危险因素,RAS基因突变型患者预后更差。     

THE AETIOLOGY AND MANAGEMENT OF HEPATIC METASTASES

Hepatic metastases are a common event in the metastatic spread of primary tumours and indicate advanced disease. However, the presence of hepatic metastases does not necessarily imply incurability; in selected patients resection of hepatic metastases may result in 5-year survival rates of 25–35%, usually in patients with colorectal liver metastases in whom solitary metastases are more frequent than with other primary tumours. However, hepatic metastases from Wilm's tumours, adrenal tumours, renal cell carcinoma, and neuroendocrine tumours may also be resected with similar success rates. A poor prognosis after resection of hepatic metastases is likely when there are more than three metastatic deposits, involved resection margins (often as a result of ‘wedge’ resections), when there is extrahepatic disease, or nodal involvement at the primary tumour site. Cyto-reductive procedures may provide excellent palliation and possibly long-term survival in selected patients with hepatic metastases unsuitable for resection. However, further study is required to establish the appropriate role for these treatments.     

Liver resection for colorectal metastases

BACKGROUND: Colorectal cancer is the second commonest malignancy in the UK. Metastases to the liver occur in greater than 50% of patients and remain the biggest determinant of outcome in these patients. Liver resection is a safe procedure that achieves good long-term survival, but surgery has traditionally been limited to select groups of patients. The improved outcome suggests that more patients could benefit from resection if more was known of what criteria are predictive of a good outcome. PATIENTS AND METHODS: A retrospective analysis was performed on all patients undergoing surgical resection of the liver for colorectal metastases between March 1989 and March 2001 in the Birmingham Liver Unit. RESULTS: During this period, 212 liver resections for colorectal cancer metastases were performed in 82 females and 130 males. The median follow-up was 16 months with an overall actuarial survival of 86% at 1 year, 54% at 3 years, and 28% at 5 years. The peri-operative mortality was 2.8%. The number and timing (metachronous or synchronous) of metastatic lesions, the gender of the patient, pathological staging of the primary lesion or surgical resection margins had no significant influence on survival. Patients with lesions less than 5 cm in size had a significantly prolonged survival compared with patients with lesions greater than 5 cm in size (P < 0.004). CONCLUSIONS: Liver resection is the only curative treatment for patients with colorectal metastases. The long-term survival reported in patients with resected colorectal metastases confined to the liver is comparable to primary surgery for solid gastrointestinal tumours. Every attempt must be made to increase the availability of liver resection to patients with hepatic metastases from colorectal cancer.     

Regional hepatic therapies: an important component in the management of colorectal cancer liver metastases

The treatment of colorectal cancer liver metastases (CRLM) has evolved significantly in the last 15 years. Currently, complete surgical resection remains the only potentially curative option; unfortunately, approximately 80% of patients with CRLM are not candidates for complete tumor resection. For patients with unresectable CRLM the available treatment options were historically limited; however, the development of regional hepatic therapies (RHT) and improvement of systemic chemotherapeutic regimens have emerged as viable options to improve overall survival and quality of life for this group of patients. The selection, sequence and integration of interventions into a multi-modal approach is a complex and evolving discipline. In this article, the currently available RHT modalities for CRLM are presented as a guide to the options for clinical treatment decisions.Key Words: Colorectal, liver metastases, tumor ablation     

p53, DCC and thymidylate synthase as predictors of survival after resection of hepatic metastases from colorectal cancer

BACKGROUND: Hepatic metastasis from colorectal cancer is a common problem. Hepatic resection offers the only chance of cure. Prognosis of patients following hepatic resection is currently based on clinicopathological factors (of both the primary cancer and the hepatic metastasis), which do not accurately predict the subsequent behaviour of the tumour. The aim of this study was to evaluate three molecular genetic markers - p53, DCC (deleted in colonic cancer) and thymidylate synthase - in both the primary colorectal tumour and the resected hepatic metastases, and to determine their correlation, if any, with survival in patients with resected hepatic metastases from colorectal cancer. METHODS: Sixty-three patients with hepatic metastases and 40 corresponding colorectal primary tumours were studied using immunohistochemical staining for p53, DCC and thymidylate synthase, as well as p53 gene mutations using polymerase chain reaction-single-stranded conformational polymorphism (PCR-SSCP) analysis. The results were correlated with survival. RESULTS: There was no correlation between p53, DCC or thymidylate synthase immunohistochemical staining, or between p53 PCR-SSCP analysis, and survival for either hepatic metastases or the colorectal primary tumour. CONCLUSION: Prediction of prognosis in patients having resection of hepatic metastases from colorectal cancer continues to be problematic. Other genetic markers or combination of markers need to be evaluated.     

Kurative und diagnostische Resektionen an der Leber

BACKGROUND: Data from the Brandenburg Tumor Documentation Center (TDCB) in Germany were analyzed for an overview of the current treatment standards of liver surgery in that state. MATERIAL AND METHODS: The analysis was based on prospective data from a total of 37,165 patients diagnosed with malignant tumors between 1 January 1999 and 31 December 2004. Of these patients, 3,986 were diagnosed with liver metastases and 554 had primary tumors of the liver or bile duct. Liver metastases of colorectal carcinoma were reported in 1,299. RESULTS: Analysis confirmed that resection of colorectal metastases (51%) and primary liver or bile duct tumors (23.1%) is by far the most frequent indication for liver surgery. Liver metastasis was developed by 29.2% (n=1299) of patients with colorectal carcinoma. Of the patient total, 71.5% showed evidence of liver metastasis already present when colorectal carcinoma was diagnosed. Of 248 patients who had received liver surgery after diagnosis of liver metastases of a colorectal carcinoma, 114 (46%) underwent hepatic segment resection, which was thus performed in only 8.8% (n=114) of patients with liver metastases after colorectal carcinoma (n=1299). CONCLUSIONS: Since only 8.8% of those with liver metastases underwent curative hepatic segment resection, we can conclude that if patients and doctors were provided with adequate information on the curative potential of this surgical method along with regular consultations with surgeons experienced in liver surgery, the result on resection rates would be positive. Data from tumor documentation centers enable selective analysis of the oncological situation of specific diseases.     

The developing clinical problem of chemotherapy-induced hepatic injury

Chemotherapy is being administered to an increasing number of patients with colorectal liver metastases (CRLM), whether they have resectable disease or not. Although this may be appropriate to downstage patients with unresectable disease, and offers theoretical advantages to those who have resectable disease, there is a price to be paid in the development of chemotherapy-induced hepatic injuries (CIHI). These include chemotherapy-associated fatty liver diseases and sinusoidal injuries. The main chemotherapeutic agents currently used in the adjuvant setting for colorectal carcinoma, and the neoadjuvant treatment of CRLM include 5-flurouracil, oxaliplatin and irinotecan, and while there are non-specific and overlapping injury profiles, oxaliplatin does appear to be primarily associated with sinusoidal injury and irinotecan with steatohepatitis. In this review, the rationale for administering chemotherapy to patients with CRLM is presented, and the problems this brings are outlined. The specific injury patterns will be detailed, as well as the data correlating specific chemotherapy regimens to these injury patterns. Finally, the clinical outcomes of patients with CRLM who undergo neoadjuvant chemotherapy followed by hepatic resection will be considered. The need for methods to identify patients at risk of CIHI and to recognize established CIHI prior to surgery will be emphasized.     

Liver resection and transplantation — Therapeutic concepts in surgical treatment of hepatic metastases

Summary Background: Surgical procedures such as liver resection or liver transplantation are the only treatment modalities that provide a chance of cure for patients with liver metastases. Methods: This report reviews results of liver resection and liver transplantation for liver metastases from colorectal cancer and neuroendocrine tumors as compared to the natural course. Results: Overall 5 year survival after curative liver resection for colorectal metastases ranges between 25 and 48%. The operative mortality is between 0 and 5%. Risk factors for tumor recurrence are more or less defined. Reresections of metastases can be performed with comparable mortality rates and results. Liver transplantation for unresectable colorectal metastases offers a median survival of 28 months, but the chance of cure only for individual patients. Exclusion of patients with positive lymph nodes of the primary tumor improves median survival. As there are alternative treatment options for neuroendocrine metastases, indication for liver resection or transplantation is not clearly defined, but the chance of cure by means of surgical treatment should not be missed. Curative resections of neuroendocrine liver metastases can achieve 5-year survival rates of more than 80%. Conclusions: Radical surgical removal of liver metastases from colorectal and neuroendocrine cancer can improve the prognosis for selected patients. Further improval is expected from a multimodal approach.      

Survival after liver resection for secondary tumors

The results achieved by liver resection for metastatic cancer in more than 400 patients have been studied in a collected review. Certain conclusions seem justified: The liver is no longer the surgeon's "no-man's-land," and local excision of metastatic tumor can achieve clinical cure in some patients. The risk-benefit ratio for hepatic resection for secondaries seems to be shifting in favor of benefit for selected patients with primary colorectal tumors. At present liver resection for tumors metastatic from pancreas, breast, lung, stomach, kidney, reproductive organs, and skin (melanoma) cannot be recommended. Liver resection may play an important part in the multi-modal therapy of children with extensive malignant disease.     

Interval Period Tumor Progression: Does Delayed Hepatectomy Detect Occult Metastases in Synchronous Colorectal Liver Metastases?

Background  Rapid remnant liver recurrence in patients with synchronous colorectal liver metastases (CRLM) is occasionally experienced after simultaneous colorectal and liver resection. We evaluated the tumor progression during interval periods to determine whether delayed hepatic resection detects occult metastases. Methods  One hundred thirty-seven patients underwent hepatectomy for synchronous CRLM. Up to 2003, 116 patients underwent simultaneous colorectal and hepatic resection. From 2004 onward, we identified 21 patients undergoing delayed hepatectomy for synchronous CRLM. The tumor progression during interval was determined by a dynamic computed tomography scan. Results  Median/mean interval between the two evaluations prior to the first and second surgery was 2/2.4 months. The median/mean number of metastases detected at each evaluation was 2/3.3 and 3/4.6, respectively. Nine of the 21 (43%) patients had new detectable metastatic lesions after reevaluation. For 11 of the 21 patients, it was necessary to reconsider planned surgical procedure which was determined prior to colorectal surgery. Hepatic disease-free survival was significantly different between patients undergoing delayed and simultaneous hepatectomy. Multivariate analysis showed that the delayed hepatectomy was a significant independent prognostic factor in hepatic disease-free survival. Conclusion  Tumor progression was recognized and occult metastases were detected after the interval reevaluation. Delayed hepatectomy may be a useful approach to reduce rapid remnant liver recurrence in synchronous CRLM.     

Interstitial laser thermotherapy for liver tumours

BACKGROUND: Primary hepatocellular carcinoma (HCC) and metastases from colorectal cancer are the most common malignant liver tumours. Surgical resection is the optimum treatment in suitable patients. Interstitial laser thermotherapy (ILT) is gaining acceptance for the treatment of irresectable liver tumours and as a potential alternative to surgery. An understanding of the principles of therapy and review of clinical outcomes may allow better use of this technology. METHOD: An electronic search using the Medline database was performed for studies on the treatment of hepatic malignancy published between January 1983 and February 2003. RESULTS: Current information on the efficacy of ILT is based on prospective studies. ILT appears to be a safe and minimally invasive technique that consistently achieves tumour destruction. The extent of destruction depends on the fibre design, delivery system, tumour size and tumour biology. Real-time magnetic resonance imaging provides the most accurate assessment of laser-induced tumour necrosis. In selected patients with HCC and colorectal cancer liver metastases, ILT achieves complete tumour necrosis, provides long-term local control, and improves survival, compared with the natural history of the disease. In addition, ILT has survival benefits for patients with other tumour types, especially those with isolated liver metastases from a breast cancer primary. CONCLUSION: ILT improves overall survival in specific patients with liver tumours. Advances in laser technology and refinements in technique, and a better understanding of the processes involved in laser-induced tissue injury, may allow ILT to replace surgery as the procedure of choice in selected patients with liver malignancies.     

Liver resection for metastatic colorectal cancer: assessing the risk of occult irresectable disease

Background: Liver resection is standard therapy for selected patients with metastatic colorectal cancer. Extrahepatic metastases and inability to remove all hepatic disease usually preclude curative resection and are the most common contraindications. This study analyzes irresectability in patients considered to have resectable disease taken to operation for potentially curative hepatic resection. We describe preoperative factors associated with irresectability and propose a preoperative scoring system that identifies patients at particularly high risk for occult irresectable disease.Study Design: Patients considered to have resectable hepatic colorectal metastases were identified from a prospective database. Intraoperative findings that precluded liver resection were recorded. Demographic data, characteristics of the primary tumor, and characteristics of the hepatic metastases were recorded and analyzed.Results: From April 1992 through July 1997, 416 patients were explored with the intention of performing a potentially curative liver resection; 329 (79%) were resected. Eighty-seven patients (21%) had apparently resectable tumors on preoperative imaging but irresectable disease at laparotomy. Forty-four patients (51%) had irresectable disease limited to the liver; 32 had extensive bilobar disease not appreciated before surgery, and 12 were not resected for technical or other reasons unrelated to disease extent. Forty-three patients (49%) had extrahepatic disease, 31 of whom had resectable hepatic tumors. Of the several preoperative factors analyzed, only the estimated number of hepatic tumors was an independent predictor of irresectable findings at operation. This held true for patients with extrahepatic metastases and those with extensive hepatic disease. From these data, we devised a preoperative scoring system that estimates the probability of finding occult irresectable disease. Resectability ranged from 95% in patients with a score of 0 (solitary, unilobar) to 62% in those with a score of 3 (multiple, bilobar; p = 0.0001). The predictive value of this scoring system was then validated by applying it prospectively to an additional group of 118 patients taken to surgery for resection; the results were similar.Conclusions: Standard preoperative investigations predicted resectability in 79% of patients with hepatic colorectal metastases. Unresectable disease limited to the liver and extrahepatic disease were seen with nearly equal frequency. The majority of patients with extrahepatic metastases had resectable hepatic disease (31 of 43, 72%). A preoperative scoring system is proposed that identifies patients at high risk for unrecognized irresectable disease and may help focus the use of additional diagnostic modalities such as laparoscopy and positron emission tomography (PET).