Liver resection for advanced or aggressive colorectal cancer metastases in the era of effective chemotherapy: a review

Liver surgery has been known to cure metastatic colorectal cancer in a small proportion of patients. However, advances in procedural technique and chemotherapy now allow more patients to have safe, potentially curative surgery. Here we review surgery for unresectable colorectal liver metastases using an expert multidisciplinary approach. With multidisciplinary management of patients with effective chemotherapy that can downstage metastases, more patients with previously inoperable disease can benefit from surgery. Portal vein embolization results in hypertrophy of the future liver remnant; on occasions, combining embolization with staged liver resection permits potentially curative surgery for patients previously unable to survive resection. However, increasing use of chemotherapy has raised awareness of potential hepatotoxicity and other deleterious effects of cytotoxic agents. Prolonged prehepatectomy chemotherapy therefore can reduce resectability even using a 2-stage procedure. Suitable timing of surgery for unresectable liver metastases during chemotherapy is critical. Because of advances in chemotherapy, colorectal cancer, like ovarian cancer, can now show survival benefit from maximum surgical debulking. Benefit from such maximum hepatic debulking surgery for metastatic colorectal disease is uncertain, but likely. Surgery in isolation may be approaching technical limits, but is now likely to help more patients because of the success of complementary strategies, particularly newer chemotherapy and targeted therapy. Expert individualized multidisciplinary treatment planning and problem-solving is essential.     

Liver-directed therapies in metastatic colorectal cancer

Colorectal cancer (CRC) is a major health concern in the United States (US) with over 140,000 new cases diagnosed in 2012. The most common site for CRC metastases is the liver. Hepatic resection is the treatment of choice for colorectal liver metastases (CLM), with a 5-year survival rate ranging from 35% to 58%. Unfortunately, only about 20% of patients are eligible for resection. There are a number of options for extending resection to more advanced patients including systemic chemotherapy, portal vein embolization (PVE), two stage hepatectomy, ablation and hepatic artery infusion (HAI). There are few phase III trials comparing these treatment modalities, and choosing the right treatment is patient dependent. Treating hepatic metastases requires a multidisciplinary approach and knowledge of all treatment options as there continues to be advances in management of CLM. If a patient can undergo a treatment modality in order to increase their potential for future resection this should be the primary goal. If the patient is still deemed unresectable then treatments that lengthen disease-free and overall-survival should be pursued. These include chemotherapy, ablation, HAI, chemoembolization, radioembolization (RE) and stereotactic radiotherapy.     

Lebermetastasen kolorektaler Karzinome

Radical resection of liver metastases (R0 resection) offers the chance to cure patients in the metastatic stage of colorectal cancer. The therapeutic algorithm is based on an assessment of operability and resectability and the K-RAS status as predictive biomarker. The number of metastases and their size is negligible for a technically possible resection, important is a sufficiently large future liver remnant (FLR). Generally, a distinction can be made between resectable and irresectable metastases and an ill-defined group of patients with potentially resectable metastases. In patients with potentially resectable metastases surgical procedures, such as two-stage liver resection, portal vein embolization, local ablation, such as radiofrequency ablation, neoadjuvant chemotherapy or a combination of these methods can be used. An R0-resection of all lesions is the most important factor for further prognosis.     

Portal vein embolization effect on colorectal cancer liver metastasis progression: Lessons learned

Colorectal liver metastasis (CRLM) is the major cause of death in patients diagnosed with colorectal cancer. The gold standard treatment of CRLM is surgical resection. Yet, in the past, more than half of these patients were deemed unresectable due to the inadequate future liver remnant (FLR). The introduction of efficient portal vein embolization (PVE) preoperatively allowed more resections of metastasis in CRLM patients by stimulating adequate liver hypertrophy. However, several experimental and clinical studies reported tumor progression after PVE which critically influences the subsequent management of these patients. The underlying pathophysiological mechanism of tumor progression post-PVE is still not fully understood. In spite of the adverse effects of PVE, it remains a potentially curative procedure in patients who would remain otherwise unresectable because of the insufficient FLR. Currently, the challenge is to halt tumor proliferation following PVE in patients who require this technique. This could potentially be achieved by either attempting to suppress the underlying oncologic stimulus or by inhibiting tumor growth once observed after PVE, without jeopardizing liver regeneration. More research is still required to better identify patients at risk of experiencing tumor growth post-PVE.     

The ALPPS Approach for the Management of Colorectal Carcinoma Liver Metastases

Liver resection is the treatment of choice for patients with colorectal liver metastases (CRLM). The possibility of achieving curative resection is limited by the future liver remnant (FLR), with posthepatectomy liver failure (PHLF) the most severe possible complication after major liver resection. Associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) has recently been introduced as a strategy for prevention of PHLF by inducing a rapid and large FLR hypertrophy not achieved by other methods. To date, most of the evidence regarding ALPPS is based on retrospective analysis of small series of patients or of case reports. The promising short-term results obtained are difficult to interpret oncologically, because of the heterogeneous groups of patients with different underlying pathology, variable chemotherapy use, and technical variations applied. Only increased experience and long-term outcomes will better define the utility of this novel method.     

Locoregional strategies for colorectal hepatic metastases

Hepatic colorectal metastases present a challenging problem in patients with recurrent colorectal cancer. Twenty percent of patients with recurrence will have liver metastases as a component of their disease, and only 10% of these patients will have isolated liver metastases that are resectable. Although systemic chemotherapy alone has not proven efficacious in the treatment of liver metastases, a number of options exist in managing these lesions. For those that are resectable, surgery remains the optimal treatment, with an expected 5-year survival rate of 33%-39% based on several large series. Hepatic artery chemotherapy is another adjunct treatment in patients undergoing resection and may further improve survival. This benefit may be even more pronounced when combined with systemic chemotherapy. Newer-generation agents are likely to further improve results. More recently, new therapeutic modalities have been used to treat unresectable lesions. These include hepatic artery chemotherapy and ablative techniques such as radiofrequency ablation and cryoablation. This article will highlight the data regarding hepatic resection for colorectal metastases, describe the rationale for and efficacy of hepatic arterial chemotherapy in the postoperative adjuvant setting and in unresectable liver disease, and review the current literature describing ablative techniques in the treatment of liver metastases.     

Dealing with insufficient liver remnant: Associating liver partition and portal vein ligation for staged hepatectomy

Liver resection for colorectal liver metastases has emerged to highly successful treatment in the last decades. Key to this success is complete hepatic tumor removal and systemic disease control by chemotherapy. Associating liver partition and portal vein ligation for staged hepatectomy is the most recent two-stage resection strategy for patients with very small future liver remnant making complete tumor removal possible within 1 to 2 weeks. Oncological outcome data are being collected at the moment and first results from small series reveal promising results.     

Modern multimodality approach to hepatic colorectal metastases: solutions and controversies

Hepatic resection for colorectal metastases, limited to the liver, has become the standard of care, and currently remains the only potentially curative therapy. Numerous single institutional reports have demonstrated long-term survival and there are no other treatment options that have shown a survival plateau. However, curative resection is possible in less than 25% of those patients with disease limited to the liver, which translates into only 5-10% of the original group developing colorectal cancer. To increase the number of patients who could benefit from hepatic resection, the last decade has seen considerable effort being directed towards novel approaches to permit curative hepatic resection such as: neoadjuvant systemic and regional chemotherapy, pre-operative portal vein embolization for hypertrophy of future liver remnant, staged hepatic resection and radio frequency ablation combined with resection for addressing multiple bilobar metastases. This article reviews development of these innovative multidisciplinary modalities and the aggressive surgical approach that has been adopted to extend the frontiers of surgical therapy for colorectal hepatic metastases.     

Updated Options for Liver-Limited Metastatic Colorectal Cancer

Liver metastases from colorectal cancer (CRC) are common in patients presenting with an initial diagnosis of metastatic disease or at the time of recurrence. Without treatment, patients with metastatic disease have a poor prognosis. Surgical resection of the metastases might provide long-term benefit.; however, the size, number, or location of the metastases can limit the ability to perform a resection. The use of chemotherapy, both systemic and via hepatic artery infusion, in patients undergoing surgery for liver metastases from CRC has augmented the long-term survival benefits and even the cure obtained in some patients with surgery. Chemotherapy might also convert a portion of patients with initially unresectable liver metastases to resectable. A growing body of literature is helping to define the role of chemotherapy for potentially resectable liver metastases and for initially unresectable liver metastases. The introduction of newer agents such as oxaliplatin and irinotecan, and targeted agents such as cetuximab and bevacizumab, has led to meaningful improvements in response rates and survival over those previously achieved with 5-fluorouracil. Further trials are needed to refine the use of chemotherapy and targeted agents in the management of patients with liver metastases.     

结直肠癌肝转移外科治疗策略

目前手术切除是结直肠癌肝转移（CRLM）唯一具有治愈可能的治疗方式。近年来随着全身化疗及靶向药物的发展、肝动脉灌注化疗的应用,对于CRLM 治疗的有效率明显升高,通过手术获益的患者逐渐增多;而如射频消融、二步切除等外科技术的进步,也为更多CRLM 患者提供了治愈的机会。多学科诊疗模式（MDT ）也为更多CRLM 患者的个体化诊治创造了机会,使未来CRLM 的治疗向更加精准的方向发展。      

Colon Cancer Liver Metastasis: Addition of Antiangiogenesis or EGFR Inhibitors to Chemotherapy

For patients with unresectable colorectal liver metastases (CRLM), selection of adequate drug combinations, with or without biological agents, for immediate use is crucial for success of conversion to resectable CRLM with potentially curative results. This paper addresses the use of biological agents directed against the two main targets in colorectal cancer—vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). Addition of the anti-angiogenic monoclonal antibody (MAb) bevacizumab to chemotherapy may increase resection of CRLM for patients with KRAS mutated or for unselected patients. Caution must be exercised with wound healing complications when surgery is performed after bevacizumab use. Patients with KRAS wild-type should be considered for combination therapy with EGFR inhibitors, because this strategy has led to promising results with improved R0 resection.     

Métastases hépatiques des cancers colorectaux : intérêt du traitement d’induction dans l’optimisation des résections. À propos de neuf cas

Introduction

A multidisciplinary approach and advance in surgery and chemotherapy has been made to increase the number of patients who could be candidates for surgical resection. We try to assess the value of this treatment in strategies to treat primary unresectable liver metastases.

Materials and methods

From January 2005 to December 2008, we treated nine patients with primary unresectable liver metastases from colorectal cancer.

Results

There were 32 cases of liver metastases from colorectal carcinoma, 9 of them were primary unresectable liver metastases. After chemotherapy, radiofrequency and portal vein ligation, these metastases became eligible for curative resection: neoadjuvant chemotherapy (3 cases), chemotherapy + radiofrequency (3 cases), chemotherapy + portal vein ligation + two-stage hepatectomy (2 cases), chemotherapy + portal vein ligation (1 case). There were no surgical deaths. The postoperative death rate was 22.2% (15, 20 months).

Conclusion

To date, surgical resection remains the only treatment that can ensure long-term survival and cure in some patients; allowing treatment, with curative intent, of metastases initially considered as unresectable.     

Treatment of liver metastases, an update on the possibilities and results

Long-term results after liver resection for colorectal liver metastases show 5-year survival rates between 35 and 40%. However, only a limited number of patients appear to be candidates for resection, far more patients prove to have unresectable disease. Present challenges in liver surgery for colorectal metastases are to improve patient selection, to increase the resectability rate and to improve survival by multimodality treatment approaches. The variables most consistently associated with a poor prognosis and tumour recurrence are tumour-positive resection margins and the presence of extra-hepatic disease. Hence, patient selection and preoperative staging should concentrate on accurate imaging of the liver lesions and the detection of extrahepatic disease. For liver imaging, spiral computed tomography (CT) scan or magnetic resonance imaging (MRI), supplemented by intra-operative ultrasound, are currently regarded as the best methods for evaluating the anatomy and resectability of colorectal liver metastases. Extrahepatic disease should be investigated by spiral CT of the chest and abdomen and when possible by 2-fluouro-2-deoxy-D-glucose-positron emission tomography (FDG-PET). Resection remains the gold standard for the surgical treatment of colorectal liver metastases. In experienced centres, resection is a safe procedure and mortality rates are below 5%. The aim of resection should be to obtain tumour-negative resection margins. Edge cryosurgery should be considered in cases where very close resection margins are anticipated. The role of adjuvant chemotherapy after resection is still controversial, although two recent studies show a clear benefit. For the moment, local tumour ablative therapies such as cryotherapy and radiofrequency therapy should be considered as an adjunct to hepatic resection in those cases in which resection can not deal with all of the tumour lesions. In these cases, there seems a beneficial effect of a combined treatment consisting of resection and local tumour ablation. At this stage, there are no randomised data that local tumour ablation is as effective as resection. For a selected group of patients with unresectable liver metastases, there may be a chance to turn unresectable disease to resectable disease by aggressive neo-adjuvant chemotherapy or portal vein embolisation. For patients with unresectable disease, many different chemotherapy schedules may be used based on systemic drug administration. Regional chemotherapy and isolated liver perfusion should only be used within a study design.     

Diagnosis and treatment of metastatic disease to the liver

A number of cancers present with synchronous or metachronous hepatic metastases. Historically, many of these patients were considered unresectable and were treated with either systemic chemotherapy or supportive care. Today, a variety of options exist for the management of hepatic metastases. Newer agents for systemic therapy continue to be introduced and are providing improved progression-free and overall survival and increased resectability of liver metastases. However, complete surgical resection of isolated hepatic metastases remains the optimal management for these patients. Surgical interventions can be offered to patients with hepatic-only metastases. Hepatic artery chemotherapy represents an adjunct for those patients undergoing resection and can improve survival. This benefit may be even more pronounced when combined with systemic chemotherapy. Newer generation biologic agents can improve results. New therapeutic modalities to treat lesions that are unresectable include ablative techniques such as radiofrequency ablation (RFA) and cryoablation. This article will examine modalities of diagnosis of hepatic metastases and highlight the data regarding hepatic resection for metastases of several types of primary cancers, the rationale for, and efficacy of, hepatic arterial chemotherapy, in both the postoperative adjuvant setting and in unresectable liver disease, and review the current literature for ablative techniques in the treatment of liver metastases.     

The Role of Neoadjuvant Chemotherapy in Patients With Resectable Colorectal Metastases: Where Are We Now?

Approximately 25 % of patients with colorectal cancer (CRC) have colorectal liver metastases (CRLMs) at the time of diagnosis, and up to 60 % of CRC patients will develop CRLM during the course of their disease. Complete surgical resection of CRLM affords patients the possibility of long-term cure. With modern chemotherapy, shrinkage in the size of unresectable CRLM may allow patients to undergo surgery. However, the role of chemotherapy given prior to surgery for patients with already-resectable CRLM at the time of presentation is unclear. Currently, the use of neoadjuvant chemotherapy (NAC) is an area of controversy in which few randomized prospective data exist to guide its use. In this review, we examine the literature and data for neoadjuvant chemotherapy for resectable CRLM. We review advantages and disadvantages of NAC and discuss rational indications for NAC use in resectable CRLM.     

Neoadjuvant chemotherapy for colorectal liver metastases: A contemporary review of the literature

Colorectal carcinoma (CRC) is one of the leading causes of cancer-related deaths worldwide, and up to 50% of patients with CRC develop colorectal liver metastases (CRLM). For these patients, surgical resection remains the only opportunity for cure and long-term survival. Over the past few decades, outcomes of patients with metastatic CRC have improved significantly due to advances in systemic therapy, as well as improvements in operative technique and perioperative care. Chemotherapy in the modern era of oxaliplatin- and irinotecan-containing regimens has been augmented by the introduction of targeted biologics and immunotherapeutic agents. The increasing efficacy of contemporary systemic therapies has led to an expansion in the proportion of patients eligible for curative-intent surgery. Consequently, the use of neoadjuvant strategies is becoming progressively more established. For patients with CRLM, the primary advantage of neoadjuvant chemotherapy (NCT) is the potential to down-stage metastatic disease in order to facilitate hepatic resection. On the other hand, the routine use of NCT for patients with resectable metastases remains controversial, especially given the potential risk of inducing chemotherapy-associated liver injury prior to hepatectomy. Current guidelines recommend upfront surgery in patients with initially resectable disease and low operative risk, reserving NCT for patients with borderline resectable or unresectable disease and high operative risk. Patients undergoing NCT require close monitoring for tumor response and conversion of CRLM to resectability. In light of the growing number of treatment options available to patients with metastatic CRC, it is generally agreed that these patients are best served at tertiary centers with an expert multidisciplinary team.     

Role of liver transplantation in the management of colorectal liver metastases: Challenges and opportunities

The liver is the most common site of colorectal cancer metastasis. Complete resection of the metastatic tumor is currently the only treatment modality available with a potential for cure. However, only 20% of colorectal liver metastases (CRLM) are considered resectable at the time of presentation. Liver transplantation (LT) has been proposed as an alternative oncologic treatment for patients with unresectable CRLM. This review summarizes the published experiences of LT in the setting of unresectable CRLM from the previous decades and discusses the challenges and future horizons in the field. Contemporary experiences that come mostly from countries with broader access to liver grafts are also explored and their promising findings in terms of overall survival (OS) and disease-free survival (DFS) are outlined along with their study design and methods. The rationale of establishing specific patient selection criteria and the dilemmas around immunosuppressive regimens in patients undergoing LT for CRLM are also highlighted. Additionally, this review describes the findings of studies comparing LT vs chemotherapy alone and LT vs portal vein embolization plus resection for CRLM in terms of OS and DFS. Last but not least, we present current perspectives and ongoing prospective trials that try to elucidate the role of LT for CRLM.     

Management of liver metastases from colorectal cancer

The liver is a frequent site of metastatic colorectal disease. Over the past 20 years, improvements in systemic chemotherapy and surgical techniques have improved the survival of patients with hepatic metastases. For 4 decades, fluorouracil and leucovorin were the only drugs available to treat metastatic colorectal cancer, but several new drugs and a variety of novel regimens are now available. Further improvements in results have been seen with the delivery of chemotherapy via the hepatic artery. Surgical resection of liver metastases has been encouraged when possible, and recent advances in surgery such as portal vein embolization, have made liver resection a possibility for more patients. This review considers the timing and sequence of chemotherapy and surgery in this setting, as well as the roles of cryoablation, radiofrequency ablation, and radiation therapy.     

Two-stage hepatectomy combined with converting chemotherapy achieved a successful treatment for initially unresectable multiple bilobar colorectal liver metastases

A 60-year-old man having metachronous multiple bilobar colorectal liver metastases was referred to our institution. The lesions were diagnosed unresectable due to a lack of the estimated future remnant liver volume. He underwent 13 courses of mFOLFOX6 + bevacizumab as down-staging chemotherapy. The periodic abdominal CT scans revealed metastatic lesions to become PR. We had decided to perform two-stage hepatectomy to preserve a hepatic functional reserve. After the rest of chemotherapy for 4 weeks, four tumors were resected and right branch of the portal vein embolization was performed at the first operation. Right hemihepatectomy was performed 5 weeks after the first operation to achieve curative resection. Postoperative course was uneventful and the patient was discharged at 17 days after the operation. He has no signs of tumor recurrence during the follow-up. The combination of two-stage hepatectomy and neoadjuvant systemic chemotherapy may contribute to improve prognoses of initially unresectable multiple bilobar colorectal liver metastases, leading to prolonged survival.     

Do we need biologic agents in preoperative systemic therapy of liver metastases?

Liver metastases from colorectal cancer are common in patients who present with an initial diagnosis of metastatic disease or in those with recurrence. Without treatment, patients with metastatic disease have a poor prognosis. However, with surgical resection of the metastases, many patients may have the opportunity for long-term survival. The use of chemotherapy in patients undergoing surgery has augmented the long-term survival benefits that are gained with surgery. The use of preoperative chemotherapy may convert a portion of initially unresectable liver metastases to resectable ones. A growing body of literature is helping to define the role of chemotherapy in this setting. The introduction of newer biologic agents (eg, cetuximab and bevacizumab) has led to meaningful improvements in response rates and survival for metastatic colorectal cancer patients. However, further trials are required to better determine the benefits of chemotherapy and biologic agents in the management of patients with liver metastases.