Key points

Introduction

The management of colorectal cancer has continued to evolve over approximately 1 century. The most effective strategy to combat this disease is prevention. Prevention involves the identification of high-risk groups, dietary changes, and possible dietary supplements. The next most effective management strategy is screening for disease to confirm a diagnosis in its early stages. The use of the hemoccult test on a regular basis has been proved effective. Better yet for screening is complete colonoscopy. In symptomatic patients, the management strategies have been well defined for both colon cancer and rectal cancer. The surgery must provide a complete clearance of the primary cancer and its lymph node groups at risk for metastatic disease. The resection must be accomplished with perfect containment of the process. A patient may enter the operating room with a contained process and leave with disseminated disease. This situation results from trauma to the surgical specimen so that cancer cells are lost from the specimen into the resection site or free peritoneal cavity. This loss can occur with open colorectal surgery or with laparoscopic resection.

This article is not a commentary on the 70% of patients who have an uncomplicated colorectal cancer resection and a favorable prognosis. It concerns the approximately 30% of patients who have advanced disease at the time of presentation and the 50% of patients who months or years after resection fail treatment of primary disease. The focus is on local recurrence and metastases from colon and rectal cancer.

Introduction

The management of colorectal cancer has continued to evolve over approximately 1 century. The most effective strategy to combat this disease is prevention. Prevention involves the identification of high-risk groups, dietary changes, and possible dietary supplements. The next most effective management strategy is screening for disease to confirm a diagnosis in its early stages. The use of the hemoccult test on a regular basis has been proved effective. Better yet for screening is complete colonoscopy. In symptomatic patients, the management strategies have been well defined for both colon cancer and rectal cancer. The surgery must provide a complete clearance of the primary cancer and its lymph node groups at risk for metastatic disease. The resection must be accomplished with perfect containment of the process. A patient may enter the operating room with a contained process and leave with disseminated disease. This situation results from trauma to the surgical specimen so that cancer cells are lost from the specimen into the resection site or free peritoneal cavity. This loss can occur with open colorectal surgery or with laparoscopic resection.

This article is not a commentary on the 70% of patients who have an uncomplicated colorectal cancer resection and a favorable prognosis. It concerns the approximately 30% of patients who have advanced disease at the time of presentation and the 50% of patients who months or years after resection fail treatment of primary disease. The focus is on local recurrence and metastases from colon and rectal cancer.

Lymph nodal metastases from colorectal cancer

In the past, extensive lymphadenectomy as part of a colorectal cancer resection was believed to be unnecessary. The rationale was that patients with metastases to the intermediate or para-aortic nodes could not survive, even if these nodes were resected as part of the primary colorectal surgical intervention. Recent data suggest that this retreat to a conservative resection is not indicated; rather, a wide resection should be performed of lymph nodes to the superior mesenteric vessels on the right and left to the origin of the inferior mesenteric artery on the left. Swanson and colleagues reported on the survival of 35,787 prospectively collected cases of T3N0 colon cancers that were surgically treated and pathologically reported from 1985 to 1991. T3 cancers are expected to be at a higher risk for lymph nodal metastases compared with T1 or T2 lesions and, therefore, adequate lymphadenectomy is of greater benefit in this subgroup of patients. The 5-year survival of patients with T3N0M0 colon cancer varied from 64% if 1 or 2 lymph nodes were examined to 86% if more than 25 lymph nodes were examined. Three strata of lymph nodes (1–7, 8–12, and >13) distinguished significantly different observed 5-year survival rates. These investigators concluded that the prognosis of patients with T3N0 colon cancer is dependent on the number of lymph nodes examined and suggest a minimum of 13 lymph nodes to be resected.

Le Voyer and colleagues reported on survival from an intergroup trial, INT-0089. In 3411 assessable patients, 648 had no evidence of lymph node metastases. Multivariate analyses were performed on both the node-positive and node-negative groups separately to ascertain the effect of extent of lymph node resection on survival. Survival decreased with increasing number of lymph nodes involved ( P = .0001), as might be expected. After controlling for the number of nodes involved, survival increased as more nodes were analyzed ( P = .0001). Even when no nodes were involved, overall survival and cause-specific survival improved as more nodes were analyzed ( P = .0005 and P = .007, respectively). These investigators concluded that the number of lymph nodes resected and available for analysis for staging colon cancer is a prognostic variable on outcome.

West and colleagues looked at the plane of surgical resection of colonic cancer. The complete mesocolic excision with central vascular ligation produced a survival of greater than 89%. There was a greater yield of lymph nodes in 49 specimens from Erlangen, Germany compared with 40 standard specimens from Leeds, United Kingdom; a lymph node yield of 30 in Erlangen was compared with 18 in Leeds ( P <.0001). These investigators concluded that the plane of colon cancer resection and the extent of lymphadenectomy are important in optimal surgical technique. A mesocolic resection contained along with the associated greater lymph node yield was suggested as the explanation for increased survival rates reported in Erlangen.

Hepatic metastases from colorectal cancer

As a result of the pioneering efforts of Wilson and Adson, Foster and Berman, and Hughes and colleagues, the benefits that occur with the resection of liver metastases from metastatic colorectal cancer have been established as a standard of practice. Nevertheless, there has been no verification of the evidence in terms of a phase 3 randomized controlled study. Overall, the 5-year survival after hepatic resection is 30% to 50%. There may be some improvement in this statistic as a result of repeat hepatic resections that have been shown to be successful. In some patients with liver metastases that are unresectable because of a large extent of disease, systemic chemotherapy can downsize the liver metastases so that an R-0 resection is possible. The survival of this group of patients receiving neoadjuvant chemotherapy is nearly identical to patients having surgery as an initial treatment.

Patient-related factors associated with poor outcome include increase in serum carcinoembryonic antigen (CEA), positive lymph node status of the primary tumor, lymph nodes present in the regional periportal lymph nodes, and disease-free interval of less than 1 year. Factors in respect to liver metastases that carry a poor prognosis are increasing number of lesions, increasing size of the largest lesion, bilobar distribution, and percentage of hepatic replacement by cancer. Also, technical factors such as a positive or close margins of resection carry a reduced prognosis.

The technology used to destroy the liver metastases may vary greatly from institution to institution. Also, the anatomic location, size, and number of metastases may favor 1 method of ablation over another. With multiple metastases limited to either the right or left lobe, a right or left hepatectomy is indicated. Also, a lesion greater than 5 cm usually requires hemihepatectomy. However, segmental resection with clear margins may be indicated if an R-0 resection is possible. Radiofrequency ablation is an option if metastases are less than 5 cm and are not immediately adjacent to a major bile duct or major vascular structure. Indications for a cryogenic ablation are similar to those for radiofrequency ablation. A frequent indication for an ablative procedure in combination with resection is 1 or 2 metastases deep in the residual liver after a hemihepatectomy.

Recently, percutaneous ablation procedures have been reported. Results in properly selected patients seem to be acceptable. Also, laparoscopic liver resection has been reported and associated with a reduced hospital stay.

Multiple sites of colorectal metastases

Management of peritoneal metastases

Survival benefits for peritoneal metastases from colon and rectal cancer using cytoreductive surgery and perioperative chemotherapy began to appear in publications in the 1990s. In 1995, Sugarbaker and Jablonski showed a 3-year survival of 35% in patients with peritoneal metastases from colon cancer treated with cytoreductive surgery plus intraperitoneal mitomycin C and fluorouracil. In 2003, Verwaal and colleagues from Amsterdam published a 3-year projected survival of 38% in 54 patients treated by cytoreductive surgery and hyperthermic intraperitoneal mitomycin C with adjuvant systemic 5-fluorouracil. Shen and colleagues accumulated patients between 1991 and 2002. Seventy-seven patients with nonappendiceal colorectal cancer underwent the combined treatment. These investigators concluded that one-third of patients with complete resection have long-term survival and that systemic chemotherapy did not contribute to the control of peritoneal metastases. These studies performed in the absence of modern colorectal cancer chemotherapy (oxaliplatin and irinotecan) document the efficacy of cytoreductive surgery and perioperative chemotherapy to rescue approximately one-third of patients with peritoneal metastases.

Since that time, multiple publications confirming the efficacy of the combination of cytoreductive surgery and perioperative chemotherapy to benefit patients with colorectal metastases have been published. Glehen and colleagues, in a multi-institutional retrospective study of 506 patients from 28 institutions, reported an overall median survival of 19.2 months in patients with peritoneal metastases from colorectal cancer treated with the combined approach. Patients in whom the cytoreductive surgery was complete had a median survival of 32.4 months compared with 8.4 months in patients in whom cytoreduction was not completed ( P <.001). The morbidity was 22.9% and mortality 4%. These investigators concluded that the therapeutic approach of combining cytoreductive surgery with perioperative intraperitoneal chemotherapy achieved long-term survival in a selected group of patients with peritoneal metastases of colorectal origin with acceptable morbidity and mortality. The complete cytoreduction was the most important prognostic indicator.

Elias and colleagues reported on colorectal peritoneal metastases in a retrospective analysis of 523 patients from 23 French-speaking centers. The overall median survival was 30.1 months and the 5-year overall survival was 27%. Eighty-four percent of the patients had a complete cytoreduction, with a median survival of 33 months. These investigators concluded that cytoreductive surgery and perioperative chemotherapy is now considered the gold standard in the French guidelines for management of peritoneal metastases. Similarly, Verwaal reported a long-term Dutch multicenter data analysis. The survival of 562 patients at 10 years was 37%.

At the top of the list regarding evidence-based medicine for this treatment strategy is the phase 3 study reported by Verwaal and colleagues in 2003. This landmark study compared 105 patients with colorectal peritoneal metastases who were randomly assigned to receive either standard treatment with systemic 5-fluorouracil and leucovorin compared with an aggressive cytoreductive surgery with perioperative chemotherapy using hyperthermic mitomycin C. The patients in the experimental therapy arm also had systemic 5-fluorouracil chemotherapy. After a median follow-up of 21.6 months, the median survival was 12.6 months with systemic chemotherapy and 22.3 months with cytoreduction and perioperative chemotherapy ( P = .032). These investigators reported that a complete cytoreduction and a limited extent of disease were important determinants of benefit. The durability of the benefit of cytoreductive surgery and perioperative chemotherapy was confirmed in a follow-up article in 2008.

Recently, these benefits have been called into question by Ryan. He has questioned the relevance of cytoreductive surgery and perioperative chemotherapy now that oxaliplatin, irinotecan, and molecular agents are available. He contends that the benefits of systemic chemotherapy alone are so great that cytoreduction plus perioperative chemotherapy is no longer indicated. However, current data confirm that for a limited extent of peritoneal metastases, a multidisciplinary approach using the best surgical and best chemotherapy treatments is preferable. Franko and colleagues presented data to show that these 2 options work best when used together. They showed that the median survival was longer in patients treated by modern systemic chemotherapy when cytoreductive surgery and hyperthermic intraperitoneal chemotherapy were added to the clinical pathway. Currently, standard of care, until more data become available, indicates that patients with peritoneal metastases from colorectal cancer have the right to be informed of a possible curative treatment option. It is the oncologist’s obligation to provide the relevant information in a timely fashion.