ABSTRACT: Significant advances have been made in the treatment of metastatic colorectal cancer (mCRC). Development of the targeted biologic agents and their integration with cytotoxic chemotherapy regimens has led to improvements in clinical efficacy. Despite these gains, the overall impact of these combination regimens in mCRC therapy has been relatively modest. While 2-year survival has improved, substantive gains have yet to be made in 5-year survival. However, a small subset of patients can be cured of their metastatic disease, with prolonged 5- and 10-year overall survival. This select group of patients includes those with metastatic disease limited to the liver or other organ-specific sites, as these patients are able to undergo surgical resection at the time of diagnosis or following conversion therapy with the appropriate integration of chemotherapy. A multimodality team-based approach involving medical oncologists, surgical oncologists, radiologists, and other healthcare providers is absolutely critical for the success of this therapeutic approach. This article reviews the main issues that must be considered from the surgical oncology and medical oncology perspectives, respectively.
In 2012, colorectal cancer (CRC) continues to be a major public health problem. In the United States this year, there will be an estimated 147,000 new cases diagnosed and nearly 50,000 deaths resulting from this disease. Worldwide, approximately 1 million new cases of CRC are diagnosed each year, with nearly 500,000 deaths attributed to this disease annually. About 25% of patients present with metastatic disease, and of this group, 50% to 75% will have disease confined to the liver.[2-4] In patients who present initially with early-stage disease, up to 50% will eventually develop metastatic disease, with the liver being the most common site. Another 10% to 20% of patients will present with disease involving the lung and other less common sites of metastatic involvement, including the peritoneum, ovaries, adrenal glands, bone, and brain.[5,6]
When metastatic disease is limited to an organ-specific site, an important consideration is whether the disease is resectable at the time of initial diagnosis or whether it is initially deemed to be unresectable but may become resectable with the up-front use of chemotherapy. With the integration of chemotherapy and surgical resection, overall 5-year survival rates on the order of 30% to 40% can now be achieved. A multidisciplinary, team-based approach involving surgeons, medical oncologists, radiologists, and other healthcare professionals is required to determine the optimal timing and sequence of surgery and chemotherapy.
This article reviews the multidisciplinary approach to patients who have organ-limited metastatic CRC (mCRC), with the main focus being on liver- limited disease. In particular, the surgical and chemotherapy aspects of disease management will be discussed.
Surgical Considerations for Patients With Metastatic Disease
Historically, the setting of liver-limited metastases from CRC has been one of the few examples of curative metastasectomy in oncology. Even before the development of effective chemotherapy agents, surgical resection of limited hepatic metastases was associated with prolonged survival and cures. Several important prognostic factors, such as disease-free interval, number and size of metastases, presence of extrahepatic disease, and stage of the primary cancer, have all helped to define the expected cure rate for hepatic metastasectomy. For patients with metastases defined by the most favorable prognostic categories, cure rates of 24% have been achieved with surgery alone. The indications for surgical metastasectomy were for patients with disease limited to the liver, a total of four or fewer metastases, unilobar involvement, tumors of less than 5 cm in their greatest diameter, and a disease-free interval of at least 6 months.[9-12] It is, therefore, not surprising that the development of more effective chemotherapy has led to a significant improvement in overall survival and cure rates, as well as an expansion of the indication for metastasectomy. This indication has evolved into resection of any disease that allows for adequate hepatic residual volume for liver regeneration and survival, assuming there has been a response to neoadjuvant chemotherapy. In the past, surgeons were appropriately concerned that resection of visible disease would be followed by rapid recurrence from microscopic metastases in the residual liver. However, incorporation of effective neoadjuvant and/or conversion chemotherapy, as will be discussed in this article, provides greater confidence that micrometastatic disease can be eliminated and that removal of gross disease can lead to long-term cure. In addition, as hepatic surgery has become safer and easier for the patient, there is now wider acceptance of incorporating hepatic resection into a multimodality strategy to prolong survival.
The options for local and regional treatment of hepatic metastases have become broad, and include surgical resection, local ablation therapy, hepatic arterial infusion therapy, transarterial chemoembolization, radiomicrosphere therapy, and isolated hepatic perfusion.[14,15] Each of these approaches has been associated with long-term cures, although surgical resection and local ablation strategies have been the most effective. The goal for surgical resection is to achieve a negative microscopic margin. Given the concern about microscopic extension beyond the visible tumor, a 1-cm margin around the tumor is ideal. Numerous coagulation devices exist to enhance the safety of parenchymal transection by limiting blood loss. Minimally invasive approaches, such as laparoscopic and robotic assistance, have become commonplace, and they are associated with reduced blood loss, shortened hospital stay, and decreased narcotic usage postoperatively.[16,17] For patients undergoing multimodality therapies, minimally invasive surgery may also improve quality of life during treatment and decrease the recovery time necessary before adjuvant chemotherapy is administered. The options for resection include extended lobectomy, lobectomy, segmentectomies, and nonanatomic wedge resections. Many surgeons remove the least amount of liver tissue feasible to preserve the anatomy for future resections, if necessary, while others prefer formal anatomic resections in order to provide the best chance of a negative margin. These two approaches have not been directly compared in a randomized trial; however, retrospective data suggest that the ability to achieve a negative margin, as opposed to the specific type of resection, determines long-term prognosis.
Local ablative approaches have provided an alternative to surgical resection for patients with mCRC. These approaches include radiofrequency ablation (RFA), microwave ablation, cryotherapy, and focused radiotherapy (eg, using the CyberKnife). RFA is a reliable technique to ablate metastases up to 5 cm in size. However, it has limited efficacy in centrally located tumors in which proximity to the main portal triads or hepatic veins may cause bile duct injury, extensive hepatic necrosis, or inadequate tumor cell death adjacent to the vessels. The potential advantages of these local strategies over surgical resection include enhanced safety, outpatient percutaneous treatment options, and the ability to preserve hepatic parenchyma. The local recurrence rate after local ablative procedures is clearly higher than with surgical resection, with rates as high as 34% having been reported. The local recurrence rate at the site of ablation is influenced by the size and location of the metastatic lesions, as well as the use of percutaneous vs laparoscopic approaches. Although local recurrence can often be salvaged with repeat ablation or resection, for patients with limited comorbidities in whom the goal is curative intent, surgical resection is the preferred and most reliable method for actual cure. A meta-analysis of nonrandomized studies comparing RFA with surgical resection demonstrated an improvement in 5-year survival for patients treated with hepatic resection.
The curative potential of surgical resection for hepatic metastases from CRC varies depending on a number of important prognostic factors (Table 1). Nomograms for predicting cancer-related survival have been developed, and may be helpful when considering the utility of resection. A patient’s risk for morbidity and mortality also plays a significant role in defining the eventual treatment strategy. Surgical resection is still associated with a defined mortality rate of 2.8% (0 to 6.6%), which is influenced, in large part, by the health of the background liver.[22,23] Liver failure is the most common cause of death after hepatectomy, and as discussed below, this complication is influenced by the specific type and cumulative dose of chemotherapy received. The indications for surgical resection are currently based on feasibility and safety in patients who have responded to chemotherapy. It is critically important for the surgical resection to leave 20% to 25% of functioning liver volume (future liver remnant [FLR]) in patients with a normal background liver, and 40% of liver volume in patients whose background liver is diseased from previous chemotherapy. Preoperative planning CT scans, including residual volume calculations, are essential when planning an extended or bilobar resection.
To date, more than 750 series of hepatic metastasectomy for metastatic CRC have been reported in the literature. The actuarial 5-year survival rate for patients who underwent R0 resections (negative margins) was 30% when combining 16 well-reported series of more than 100 patients with follow-up greater than 2 years (15% to 67%). While 5-year survival was historically considered a cure for this disease, because of advances in systemic chemotherapy an increasing number of patients are now living with their disease beyond 5 years. A single-institution study of 455 patients revealed a median overall survival of 33 months, with 5- and 10-year actuarial survival rates of 34% and 25%, respectively. In that study, 124 patients were identified as actual 5-year survivors (27%), and of this group 59 were found to be 10-year survivors. This finding suggests ongoing disease-related mortality beyond the 5-year time-frame, with actual cure rates of 10% to 15%. Randomized clinical data suggest an improvement in disease-free survival when systemic chemotherapy is incorporated as part of a combined neoadjuvant and postoperative adjuvant approach, as will be discussed in detail in this article.
With the extended indications for hepatic metastasectomy in the presence of active systemic chemotherapy, larger resections can now be safely and effectively performed. Commonly used techniques include staged resections for bilobar disease and preoperative portal vein occlusion to achieve compensatory hypertrophy and safer extended resections.[27,28] While there appear to be impressive actuarial 5-year survival rates in these series of extensive surgical resections, it is expected that the true cure rate will be much lower. When looking at patients with initially unresectable colorectal liver metastases who were treated with chemotherapy and then resected, 16% of this group were considered cured, with a disease-free interval of more than 5 years after metastasectomy. On multivariate analysis, the main predictors of cure included maximum size less than 3 cm, no more than three metastatic lesions, and complete pathologic response.