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.     

Metastatic colorectal cancer: recent advances in its clinical management

Colorectal cancer (CRC) is frequently complicated by metastatic disease, with the liver being the most common site of metastasis. Surgical resection is the only realistic cure for colorectal liver metastases; however only 10–25% of cases are initially resectable. The introduction of combination chemotherapy has improved survival rates by enabling 10–20% cases with previously unresectable hepatic metastases to become amenable to surgery. Recent results with the biologic agent bevacizumab, a chimeric human–mouse monoclonal antibody against VEGF, and cetuximab, a chimeric human–mouse monoclonal antibody against EGF receptor, have shown that they improve clinical surgical outcomes when added to current first-line regimens in patients with metastatic colorectal cancer. Dual biologic therapy in combination with chemotherapy has, however, yielded disappointing results. Identification of biological markers is expected to help determine which patients are most likely to respond to these newer agents and thus improve targeted therapy.     

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.     

Pathologic response to bevacizumab-containing chemotherapy in patients with colorectal liver metastases and its correlation with survival

For patients with colorectal liver metastases (CLM), hepatic resection currently offers the best chance for long-term survival. Preoperative chemotherapy is now integral to the management of these patients, conferring a disease-free survival advantage over surgery alone in patients with ‘upfront’ resectable disease and enabling some initially unresectable CLM to become resectable. However, although surgery may improve long-term survival, up to 65.0% of patients will experience disease recurrence at 5 years and reliable prognostic factors are needed to predict those patients who are more likely to experience recurrence after resection. Recently, pathologic tumor response, defined as the ‘objective measurement of residual cancer cells in resected tissue,’ has been identified as a reliable prognostic factor in patients with colorectal cancer (CRC) receiving preoperative chemotherapy and has been shown to correlate with improved survival after resection of CLM. Addition of the targeted biologic agent bevacizumab to preoperative chemotherapy is associated with an increase in pathologic response rate and an increase in survival compared with chemotherapy alone in patients undergoing hepatic resection. This review discusses the data in support of pathologic response rate as an important new outcome endpoint after hepatic resection of CLM and considers the evidence to date on pathologic response to bevacizumab-containing chemotherapy in metastatic CRC and its correlation with survival.     

Induction chemotherapy and surgery of colorectal liver metastases

Surgery is the only curative treatment for patients with colorectal liver metastases with recent reports documenting 5-year survival results of 40-50%. In unresectable patients, the use of more effective regimens of chemotherapy has contributed to improve the results of survival at short term and new onco-surgical strategies have emerged. By allowing resection of previously unresectable liver metastases, these onco-surgical strategies now offer 15-20% of patients a real potential of long-term remission (5-year survival 30-40%). Chemotherapy is also used in the adjuvant setting, to prevent post-operative recurrence. In resectable metastases, it may also be used as neo-adjuvant treatment to control tumor progression before surgery and to select the patients likely to really benefit from liver resection. The objective of this article is to describe this multidisciplinary approach of liver metastases and to report the results of these new strategies.     

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.     

Complete pathological response of colorectal liver metastases after chemotherapy and bevacizumab treatment: a case report

The vast majority of colorectal cancer patients who present with liver metastases are not initially candidates for hepatic resection. Although the combination of systemic chemotherapy and liver surgery can convert a significant proportion of patients from a palliative situation to a potentially curative situation, the majority of initially unresectable liver metastases do not respond sufficiently to initial chemotherapy to become resectable. More recently the addition of biologic agents (bevacizumab or cetuximab) to cytotoxic chemotherapy has increased the rate of tumor response, suggesting that the addition of these agents could improve resectability rate. Here we report the clinical case of a complete pathological response (pCR) in a 67-year-old male affected by metastatic colorectal cancer, with initially unresectable liver metastases, after treatment with chemotherapy and bevacizumab.     

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.     

Curable metastatic colorectal cancer: Recommended paradigms

“Cure” for patients with stage IV colorectal cancer remains elusive, but for a growing subset of patients with colorectal liver metastases (CLMs), cure (ie, > 10-year survival without evidence of disease) is achieved in at least 17% of resected patients. Candidates for resection include those with limited and in some cases extensive hepatic disease, and in highly selected cases, patients with extrahepatic disease. Number, size, and bilaterality of CLMs no longer stand as absolute contraindications to surgery. Chemotherapy has further advanced the field of surgery for CLMs, enabling an additional group of patients who present with unresectable disease to undergo surgery after downsizing with chemotherapy. Modern surgical techniques and liver preparation allow resection after chemotherapy, with excellent results. This article summarizes the current multidisciplinary approach to treatment of CLMs. The definition of resectability, conversion of unresectable CLMs to resectable ones, advances in surgical techniques, advances in chemotherapy, and predictors of outcome are detailed     

The role of chemotherapy in the curative treatment of patients with liver metastases from colorectal cancer

As improved surgical techniques allow more patients with CRLM to be operated on with intent to cure, new systemic chemotherapy combinations and regional chemotherapy via the hepatic artery improve disease-free survival. Candidates for complete surgical resection with curative intent should proceed to surgery without neoadjuvant chemotherapy. Postoperative adjuvant therapy is appropriate for those remaining fit with potential for cure. Patients whose liver metastases cannot be resected safely who are otherwise fit for surgery should be treated aggressively with systemic or regional chemotherapy to sufficiently down stage the tumor for surgical resection. Correct timing of surgery, especially with bevacizumab use, has not been established. Without a multidisciplinary team, the potential to cure a select group of patients could be missed.     

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.     

Neoadjuvant chemotherapy before liver resection for patients with unresectable liver metastases from colorectal carcinoma.

Colorectal carcinoma is one of the most common cancers in the world, and more than 50% of these patients develop liver metastases. Despite recent advances, systemic chemotherapy for metastatic disease without the use of surgery is considered palliative, as there are rarely long-term survivors. However, patients who are candidates for surgical resection of their liver metastases can have a prolonged survival or possibly a cure. Consensus guidelines on criteria for resection and prognostic scores help facilitate patient selection, yet only 25% of patients with liver metastases are considered to have resectable metastases. Neoadjuvant chemotherapy has been explored in an attempt to render more patients candidates for resection. First reports using neoadjuvant systemic chemotherapy in patients with unresectable disease found that 13% to 16% of patients could be rendered resectable. Efforts to increase response rates using hepatic arterial infusion or biologic agents may increase resection rates. This review summarizes the current data on neoadjuvant chemotherapy, the rationale for this approach, potential complications, and future prospects.     

直肠癌姑息性切除联合肝动脉栓塞化疗治疗晚期直肠癌的临床研究

目的 探寻直肠癌伴不能手术切除的肝转移的有效治疗方法.方法 回顾性分析我院行直肠癌姑息性切除加肝动脉多次栓塞化疗的26例直肠癌同时伴不能手术切除的肝转移患者的临床资料.26例患者均于术前1月先行肝动脉栓塞化疗1次,1月后再行直肠癌姑息性切除,术后1月再行肝动脉栓塞化疗,以治疗后CT复查肝转移瘤全部碘化油沉积为标准,每...     

198例结直肠癌肝转移患者外科治疗的疗效分析

背景与目的:肝脏是结直肠癌常见的转移部位,35%的患者在确诊时已发生肝转移,肝转移患者的预后较差。尽管手术切除、化疗、射频消融术、介入治疗等手段应用于临床,但治疗效果不同。本研究探讨结直肠癌肝转移外科治疗的临床疗效。方法:对我院5年间经病理检查证实的198例结直肠癌肝转移患者的临床资料进行回顾性分析。根据治疗方法的不同进行分组:根治性切除组46例(23.2%)、姑息性切除组43例(21.7%)、手术探查组或最佳支持治疗组29例(14.6%)、肝动脉置泵化疗组41例(20.7%),全身化疗组39例(19.7%);对其生存期进行比较和统计学分析。结果:根治性切除组中位生存期37.1个月,5年生存率为31.2%;姑息性切除组的中位生存期14.3个月,5年生存率为0;肝动脉置泵化疗组的中位生存期21.3个月,5年生存期为7.5%;全身性化疗和探查组或最佳支持治疗组的中位生存期分别为18.7个月、6.3个月,均无5年生存者。根治性切除组与其他组比较,中位生存期有统计学意义(P<0.01)。结论:根治性切除是提高结直肠癌肝转移患者生存率的重要手段;姑息性切除治疗效果并不优于辅助性治疗,对于不能根治性切除的病例可采用肝动脉置泵化疗。     

Two-stage hepatectomy for colorectal cancer hepatic metastases

Colorectal cancer is the third most common cancer in the United States. Roughly one half of patients with primary colorectal cancer will develop liver metastases. When feasible, the combination of hepatic resection and chemotherapy can achieve 5-year survival rates in the range of 50% to 58%. Patients with extensive bilateral hepatic disease are often deemed not to be operative candidates because complete curative resection may not be possible while maintaining an adequate future liver remnant. More recently, a two-stage approach has been advocated as a means to achieve complete surgical extirpation of all metastatic disease. The two-stage approach usually involves an initial partial resection followed by some time to allow interval hepatic hypertrophy. Often portal vein ligation or embolization is used to augment hepatic hypertrophy. At the second operation, complete removal of all remaining hepatic metastases is achieved. In well-selected patients, two-stage hepatectomy is feasible, safe, and efficacious, with reported 3-year survival rates ranging from 35% to 86% in patients with metastases that otherwise would have been considered 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.     

Surgical treatment for colorectal liver metastases--results of multi-institute study for effects of radical hepatectomy

Four hundred and ten patients with colorectal liver metastases underwent radical liver resection from 1992 to 1996 at 15 institutes were reviewed retrospectively. Survival rates were calculated for more than 5 years after hepatic resection and timing of surgery and recurrences, maximum diameter and number of liver metastases, and intrahepatic recurrence were examined. There was no significant difference in survival rates for the type of liver resection (partial or anatomical) or preoperative serum CEA levels. As for the number of metastases, the 5-year survival rate was lower for patients with over 4 metastases than those with 1, 2, and 3 metastases (p < 0.034). A significant difference in survival rates was recognized for size of liver metastases (p = 0.0309) as follows: 54.6% 5-year survival rate for smaller than 4 cm and 43.8% for over 4 cm. Overall 5-year survival rate for the 410 patients was 50.1% after radical hepatectomy. Of the 410 patients, the 153 (37.3%) patients with intrahepatic recurrence had a 5-year survival rate of 27.3%. The 5-year survival rates for patients with a metastasis smaller than 4 cm, considered to reduce the influence in the difference between surgical procedure or indication for surgery, were verified to be from 88.2% to 11.9% in each institute. This suggests that there could be a difference in diagnostic accuracy, surgical indication or timing of surgery for synchronous liver metastases in each institute.     

新辅助化疗在结直肠癌肝转移治疗中的作用

目的 探讨新辅助化疗在结直肠癌肝转移治疗中的作用。方法 选取76例接受新辅助化疗的结直肠癌肝转移患者,观察新辅助化疗前后原发灶及肝转移灶大小、血清CEA水平变化情况,分析其根治性手术切除率、化疗不良反应、手术并发症以及根治性手术切除患者及其他治疗方式患者的2年生存情况。结果 新辅助化疗后,大部分患者原发灶、肝转移灶体积明显缩小,血清CEA水平明显下降,与接受新辅助化疗前相比,差异有统计学意义（P＜0.05）。其中肝转移灶获CR 0 例,PR 51 例, SD 24 例, PD 1例, 有效率为66.11%（51/76）;原发灶获CR 0 例,PR 44 例, SD 30例, PD 2例, 有效率为57.89% （44/76）。新辅助化疗不良反应以周围神经炎、消化道反应、骨髓抑制等为主,多为Ⅰ～Ⅱ级,未出现Ⅳ级不良反应。根治性手术切除率为30.26%（23/76）,手术并发症发生率为3.95%（3/23）。Kaplan-Meier生存分析显示,行根治性手术切除的结直肠癌肝转移患者2年生存情况显著优于其他治疗方法的患者（P＜0.05）。结论 新辅助化疗应用于肝转移灶潜在可切除的结直肠癌肝转移患者,使部分患者肝转移灶缩小,提高根治性手术切除率,改善预后,不良反应可耐受,是一种安全、有效的治疗方法。     

Neoadjuvant Chemotherapy Prior to Resection of Colorectal Liver Metastases

Surgery is the reference treatment of resectable colorectal liver metastases (CLM) as it is associated with 5-year survival rate as high as 50?% in selected patients. Unfortunately, most patients have too advanced metastatic disease to undergo liver resection with curative intent and are therefore treated by systemic chemotherapy. In patients undergoing resection of CLM, disease recurrence can occur in up to 70?% and consequently, adjuvant treatment to surgery have been tested to improve oncologic outcome. In patients with unresectable CLM, chemotherapy is initially the sole treatment option. The considerable improvement of the efficacy of anticancer agents has contributed to increase the response rate in patients with advanced colorectal cancer. In case of major response to chemotherapy, surgery with curative intent can be offered to patients with initially unresectable liver metastases.     

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.