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.     

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.     

Combination of surgery and chemotherapy and the role of targeted agents in the treatment of patients with colorectal liver metastases: recommendations from an expert panel

The past 5 years have seen the clear recognition that the administration of chemotherapy to patients with initially unresectable colorectal liver metastases can increase the number of patients who can undergo potentially curative secondary liver resection. Coupled with this, recent data have emerged that show that perioperative chemotherapy confers a disease-free survival advantage over surgery alone in colorectal cancer (CRC) patients with initially resectable liver disease. The purpose of this paper is to build on the existing knowledge and review the issues surrounding the use of chemotherapy ± targeted agents combined with surgery in the treatment of CRC patients with liver metastases, with a view to providing clinical recommendations. An international panel of 21 experts in colorectal oncology comprising liver surgeons and medical oncologists reviewed the available evidence. In a major change to clinical practice, the panel's recommendation was that the majority of patients with CRC liver metastases should be treated up front with chemotherapy, irrespective of the initial resectability status of their metastases.     

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.     

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.     

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.     

Conversion to Resection in Patients Receiving Systemic Chemotherapy for Unresectable and/or Metastatic Colorectal Cancer—Predictive Factors and Prognosis

Background

Systemic chemotherapy increases the possibility of resection in patients with initially unresectable colorectal cancer (CRC), especially patients with hepatic metastasis. However, the predictive factors and prognosis of conversion to resection after chemotherapy in patients with various organ metastases remain largely unknown.

The role of cetuximab in converting initially unresectable colorectal cancer liver metastases for resection

In patients with metastatic colorectal cancer (mCRC) predominantly confined to the liver, whether a patient undergoes potentially curative resection of the liver lesions is a well-established principal determinant of long-term survival. There are a number of different agents, both chemotherapeutic and targeted biologic agents, which can aid in shrinking liver tumors, which would have otherwise been unresectable, allowing for potentially curative resection. The aim of this review article is to summarize the available evidence regarding optimal therapeutic strategies for converting initially unresectable metastases for potentially curative resection; we do not discuss patients who present with initially resectable disease. We have taken the approach to review trials that included R0 resection rates as one of the principal study endpoints and specifically enrolled patients with liver-limited disease. Primary tumor location has recently emerged as a putative prognostic and predictive factor in patients with mCRC; however, presently, there is a lack of resectability outcomes differentiating tumor location–defined subgroups, and several ongoing trials and retrospective analyses are anticipated to guide insights in the future. In conclusion, in patients with RAS wild-type mCRC, the data support preferential use of the anti-epidermal growth factor receptor monoclonal antibody cetuximab when combined with standard-of-care infusional doublet chemotherapy regimens (FOLFOX or FOLFIRI) for the conversion of initially unresectable metastases for potentially curative resection. Furthermore, we discuss data involving intensified chemotherapy regimens (i.e., 3-drug backbones such as FOLFOXIRI with or without a targeted biologic agent) to promote the conversion of initially unresectable metastases for potentially curative resection.     

Pre-operative chemotherapy for colorectal cancer liver metastases: an update of recent clinical trials

The standard treatment of CRC patients with hepatic metastases is systemic chemotherapy; however, 5-year survival is disappointingly poor despite recent advances. On the other hand, in patients who undergo immediate radical surgical resection of hepatic metastases, 5-year survival reaches 30–40%. Unfortunately, only 15–20% of patients with hepatic metastases are initially eligible for a radical surgical approach. The majority of patients undergoing liver resection relapse after surgery. For this reason, new onco-surgery approaches have been investigated in recent years and the addition of biological agents to chemotherapy, such as bevacizumab and cetuximab, and the improvements of surgical techniques have opened a new scenario in the management of colorectal liver metastases. Recently, the EORTC trial has demonstrated that perioperative chemotherapy (Folfox regimen) is feasible and improves progression-free survival in patients with resectable liver metatsases. Chemotherapy and surgery can finally collaborate. In the unresectable setting, the association of chemotherapy with bevacizumab and cetuximab is particularly promising in improving resectability rate. In particular, K-RAS is a molecular response predictive factor that could be particularly useful in selecting the best treatment option in patients with unresectable liver disease.     

Curative strategies for liver metastases from colorectal cancer: a review

Colorectal cancer is a very common malignancy and frequently manifests with liver metastases, often without other systemic disease. Margin-negative (R0) resection of limited metastatic disease, in conjunction with systemic antineoplastic agents, is the primary treatment strategy, leading to long survival times for appropriately selected patients. There is debate over whether the primary tumor and secondaries should be removed at the same time or in a staged manner. Chemotherapy is effective in converting some unresectable liver metastases into resectable disease, with a correspondingly better survival outcome. However, the ideal chemotherapy with or without biological agents and when it should be administered in the course of treatment are uncertain. The role of neoadjuvant chemotherapy in initially resectable liver metastases is controversial. Local delivery of chemotherapy, with and without surgery, can lead to longer disease-free survival times, but it is not routinely used with curative intent. This review focuses on methods to maximize the disease-free survival interval using chemotherapy, surgery, and local methods.     

Advances in neoadjuvant therapy for colorectal cancer with liver metastases

Metastatic colorectal cancer (CRC) is most frequently seen in the liver. Resection of metastases remains the treatment of choice; however, the majority of patients are ineligible for surgery due to unfavorable location, size, or number of metastases; insufficient liver reserve; or extrahepatic disease. The activity of irinotecan- and oxaliplatin-based regimens as first-line therapy has prompted the investigation of these agents as neoadjuvant therapy in patients with resectable and unresectable disease. Although studies suggest considerable promise for a neoadjuvant strategy in patients with unresectable liver metastases, the heterogeneity, small size, and retrospective nature of many of these studies precludes drawing firm clinical conclusions at this time, especially in patients with resectable disease. Therefore large, prospective trials that examine the impact of preoperative chemotherapy in patients with initially unresectable or resectable liver metastases are needed. These trials must include well-defined criteria for resectability and clear reporting of the extent of resection.     

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.     

Liver-directed therapies in colorectal cancer

The liver is the most common site of metastatic colorectal cancer (CRC) and the status of this organ is an important determinant of overall survival in patients with advanced disease. Complete resection of hepatic CRC metastases can provide a long-term cure for some patients, but the majority of liver metastases are not amenable to such surgery. Furthermore, most patients after curative resection ultimately suffer from recurrence, and the majority of such failures occur in the liver. Various ablative techniques can achieve local control of tumor after incomplete resection or for palliation. Tumor ablation currently has a secondary therapeutic role, as there is no evidence that it can achieve long-term survival comparable to surgical resection. Regional chemotherapy delivers tumoricidal agents in a selective fashion, minimizing systemic toxicity and damage to normal liver cells. Chemotherapy agents delivered through the hepatic artery can extend time to liver recurrence after curative resection and may prolong survival both in the adjuvant setting and when given to patients with unresectable disease. Molecular-based therapies, such as gene delivery and oncolytic viruses, provide promise for curative outcomes in patients with advanced disease.     

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.     

Successful treatment with cetuximab combination chemotherapy in a case of FOLFOX-refractory rectal cancer with previously unresectable multiple liver metastases leading to complete resection

Most colorectal cancer patients with liver metastases are not resectable upon initial diagnosis. Recently, chemotherapy improves overall survival of initially unresectable patients by allowing tumor downstaging and complete resection. We report a FOLFOX-refractory rectal cancer patient with unresectable multiple liver metastases, whose tumors could be downstaged and completely resected after initiation of FOLFIRI with cetuximab. Case: A 41-year-old male demonstrated rectal cancer with unresectable multiple liver metastases. He was treated by FOLFOX4 therapy as first-line chemotherapy. After initiating 14 courses, he was treated by FOLFIRI with cetuximab because of disease progression. After initiation of chemotherapy, radiographic examination demonstrated remarkable reduction of primary rectal tumor and metastatic liver tumors. He underwent complete rectal tumor resection after 13 courses of chemotherapy, and metastatic liver tumor resection after 18 courses of chemotherapy.     

Use of neoadjuvant and postoperative chemotherapy with surgical resection of colorectal cancer hepatic metastases

Hepatic metastases from colorectal cancer are common in patients presenting with an initial diagnosis of metastatic disease or at the time of recurrence. For many patients, the liver may be the only site of metastatic disease. Surgical resection of the metastases may provide long-term benefit, but their size, number, or location may limit the possibility of a resection. A growing body of literature from both retrospective patient series and prospective clinical trials suggests that preoperative therapy may enhance the chance for resection and improve outcome for initially unresectable or not optimally resectable metastases. In selected situations, neoadjuvant chemotherapy also may be beneficial for patients with potentially resectable metastases. Further trials are needed to refine the guidelines for preoperative and perioperative chemotherapy.     

The Oncosurgery Approach to Managing Liver Metastases from Colorectal Cancer: A Multidisciplinary International Consensus

An international panel of multidisciplinary experts convened to develop recommendations for the management of patients with liver metastases from colorectal cancer (CRC). The aim was to address the main issues facing the CRC hepatobiliary multidisciplinary team (MDT) when managing such patients and to standardize the treatment patients receive in different centers. Based on current evidence, the group agreed on a number of issues including the following: (a) the primary aim of treatment is achieving a long disease‐free survival (DFS) interval following resection; (b) assessment of resectability should be performed with high‐quality cross‐sectional imaging, staging the liver with magnetic resonance imaging and/or abdominal computed tomography (CT), depending on local expertise, staging extrahepatic disease with thoracic and pelvic CT, and, in selected cases, fluorodeoxyglucose positron emission tomography with ultrasound (preferably contrast‐enhanced ultrasound) for intraoperative staging; (c) optimal first‐line chemotherapy—doublet or triplet chemotherapy regimens combined with targeted therapy—is advisable in potentially resectable patients; (d) in this situation, at least four courses of first‐line chemotherapy should be given, with assessment of tumor response every 2 months; (e) response assessed by the Response Evaluation Criteria in Solid Tumors (conventional chemotherapy) or nonsize‐based morphological changes (antiangiogenic agents) is clearly correlated with outcome; no imaging technique is currently able to accurately diagnose complete pathological response but high‐quality imaging is crucial for patient management; (f) the duration of chemotherapy should be as short as possible and resection achieved as soon as technically possible in the absence of tumor progression; (g) the number of metastases or patient age should not be an absolute contraindication to surgery combined with chemotherapy; (h) for synchronous metastases, it is not advisable to undertake major hepatic surgery during surgery for removal of the primary CRC; the reverse surgical approach (liver first) produces as good an outcome as the conventional approach in selected cases; (i) for patients with resectable liver metastases from CRC, perioperative chemotherapy may be associated with a modestly better DFS outcome; and (j) whether initially resectable or unresectable, cure or at least a long survival duration is possible after complete resection of the metastases, and MDT treatment is essential for improving clinical and survival outcomes. The group proposed a new system to classify initial unresectability based on technical and oncological contraindications.     

Current Management of Liver Metastasis From Colorectal Cancer

Purpose of Review

To describe the main components of modern treatment for colorectal cancer (CRC) metastatic to the liver.

Recent Findings

Liver metastasis occurs in 50–60% of patients with CRC, and surgery is the only potentially curative treatment. Surgery should be performed where a complete (R0) resection of all radiologically visible metastases is possible. The presence of extra-hepatic disease no longer precludes liver metastectomy, and combined metastectomy in the liver and the extra-hepatic site can result in acceptable long-term survival. Peri-operative chemotherapy significantly improves PFS and DFS, but not OS. Modern cytotoxic regimens can convert a significant percentage of unresectable patients to resectable status, and the addition of biologic agents can increase the rate of conversion. Several local treatment modalities serve as alternatives, or sometimes as adjuncts, to resection of CRC liver metastasis and systemic chemotherapy.

Summary

The modern approach to CRC with liver metastasis combines surgery, modern cytotoxic and biologic agents, and modern technologies in the field of ablation, radiation, and endovascular access. The result is that long-term survival, and even cure, is now possible.

     

A case report of conversion therapy for initially unresectable colorectal cancer liver metastases after cetuximab as third-line treatment

The introduction of monoclonal antibodies into the treatment protocols for metastatic colorectal cancer(mCRC)has significantly improved outcomes. There are some patients with mCRC, initially judged unresectable, who become resectable after chemotherapy. For patients with isolated liver metastases, surgical resection is recommended when feasible. We experienced a case in which an initially unresectable mCRC liver metastases converted into a resectable one after cetuximab monotherapy as third-line treatment. The sample from hepatectomy was a pathologically complete response; no remnants were detected. The management of liver metastases contributes to improvements in the clinical setting. For conducting a multimodal treatment of mCRC, the participation of various specialists such as medical oncologists, colorectal/hepaticsurgeons and diagnostic/therapeutic radiologists is indispensable. Furthermore, it is necessary to construct an evidence-based consensus on potentially resectable CRC liver metastases in each hospital.     

Multidisciplinary approach of colorectal liver metastases

Colorectal cancer (CRC) is the second most common cause of cancer death in Spain. Fifty percent of patients will develop colorectal liver metastases (CLM) during the course of the disease. Less than 20% of patients with CLM are initially resectable and for them 5-year disease-free survival (DFS) is about 20-25%, with a high recurrence rate. CLM is a heterogeneous disease. From a clinical point of view, four main groups can be differentiated: initially resectable, not optimally resectable, unresectable that could be resectable and unresectable that never will be likely to be resected. Treatment of CLM must be established, always, in a multidisciplinary team discussion with an analysis of prognostic factors and resectability. For patients with resectable CLM, the EORTC trial 364 demonstrated that chemotherapy plus surgery is better than surgery alone. Consequently most patients should be treated with perioperative chemotherapy based on oxaliplatin, and if resection has been done without chemotherapy, they should receive adjuvant chemotherapy after R0 resection. Based on oncological factors, the 5-year survival rate after resection of CLM ranges from 60% to only 14% with a poor score. If a patient has more than one of the poor prognostic factors he should probably be referred for preoperative (induction) chemotherapy. Only a minority of patients with CLM are amenable to surgery; therefore, efforts have been made to increase the percentage of patients who could be candidates for resection. Studies, mostly retrospective, have confirmed the ability of neoadjuvant chemotherapy (conversion chemotherapy) to render some metastases resectable. The regimens we must use depend on the KRAS mutational status and the toxicity profiles of drugs in the context of each patient. In k-ras mutated tumours we can use bevacizumab combined with standard chemotherapy or concomitant administration of the three active agents (FOLFOXIRI) in suitable patients. In k-ras wild-type patients, the combination of cetuximab and FOLFIRI-FOLFOX improved response rates and resection rate in phase III-II trials. With a lower level of evidence, panitumumab is an alternative combined with FOLFOX. Bevacizumab is also an alternative as it does not depend on KRAS status. Radiotherapy is becoming an alternative in selected patients, where surgery is not an alternative. For the majority of patients, who will never be resectable, the continuum of care with chemotherapy will be the paradigm for their management.