Redefining Unresectable Disease
Strategies for Treating Liver Metastases from Colorectal Cancer

by Sunni Hosemann

Certain cancers tend to spread to favorite sites. Breast cancer, for example, has a tendency to metastasize to the bone or lung, and lung cancer tends to metastasize to the brain. Colorectal cancer commonly metastasizes to the liver; the appearance of liver metastases has long been regarded as an ominous sign and is a leading cause of colorectal cancer–related morbidity and mortality.

In fully one-third of patients who die of colorectal cancer, metastatic disease is found only in the liver—meaning that effectively treating liver metastases could make a huge difference for many patients.

Patients who undergo surgical resection of liver metastases from colorectal cancer have a higher survival rate than those who undergo other treatments, and some are truly cured of cancer. Now, doctors are finding ways to make liver resection an option for more patients.

Moving hepatic resection forward

Eddie Abdalla, M.D., a hepatobiliary surgeon and assistant professor in the Department of Surgical Oncology at The University of Texas M. D. Anderson Cancer Center, is one of a group of physicians who treats and studies treatments for liver metastases from colorectal cancer. “Analysis of data for hepatic resection from 1992 to 2002 at multiple institutions,” he said, “revealed a dramatic difference in survival—an increase from 35% to 58%—between the pre- and post-1992 periods.”

Dr. Abdalla launched a study to look more closely at the relationship between rates of recurrence and survival in patients with colorectal cancer liver metastases and the aggressive treatments the patients received at M. D. Anderson Cancer Center (surgical resection, radiofrequency ablation, or chemotherapy).

Again, what Dr. Abdalla and his colleagues found was noteworthy: patients who underwent surgical resection as a primary treatment fared significantly better—in terms of both survival and recurrence—than those who received other primary treatments. Despite advances in chemotherapy, it alone was insufficient: few patients who received chemotherapy as their sole treatment reached the 5-year survival mark, even when metastatic disease was limited to the liver. Survival rates (less than 20% at 5 years) for patients who underwent radiofrequency ablation alone or a combination of radiofrequency ablation and resection paled in comparison with the 5-year survival rate of 58% for patients whose lesions were surgically resected.

Intrigued by the benefit of aggressive approaches to hepatic resection for colorectal metastases, Dr. Abdalla and his colleagues delved further, this time looking only at patients who had solitary liver tumors and who had been treated and undergone thorough radiologic follow-up at M. D. Anderson. Focusing the study on this population ensured the highest standard of documentation for procedures and recurrences. What the researchers found was astonishing: resection of solitary colorectal metastasis was associated with a 5-year survival rate of 71.5%.

“This survival rate for patients with stage IV colon cancer is remarkable,” Dr. Abdalla said. “Furthermore, those who remain disease free at 7 years frequently stay that way, and some may actually be cured.” In fact, the 5-year disease-free survival rate in this study was 50%. This improved outcome has encouraged the development of methods to further expand the limits of safe hepatic resection for more patients.

Making more patients candidates for surgery

Surgical resection is clearly the treatment associated with the best chance for long-term survival of patients with colorectal cancer liver metastases. There is one problem, however: most patients with colorectal cancer liver metastases present with “unresectable” disease and are thus not considered candidates for surgery.

“Now that we know resection can be curative for some patients, the goal is to expand the number of patients who can benefit,” said Robert A. Wolff, M.D., an associate professor in M. D. Anderson’s Department of Gastrointestinal Medical Oncology.

Dr. Abdalla said, “The key question is: what proportion of these patients can we convert into candidates for potentially curative surgery?” One of the latest efforts is a prospective trial underway for patients with extensive liver metastases; the study uses combination chemotherapy, staged hepatectomy, and portal vein embolization to make them eligible for complete resection.

The major limiting factor for hepatic resection has traditionally been the volume of metastatic disease in the liver. There is a limit to how much liver can be removed before liver function is too severely impaired. Multiple lesions, large lesions, and lesions affecting multiple lobes of the liver have long been considered to be unresectable. Dr. Abdalla and his colleagues have taken a different approach to determining the resectability of liver tumors: they have shifted away from the analysis of tumor size and number and now focus on how much of the liver will remain after surgery. This new way of thinking allows the doctors to explore different ways to shift a patient’s status from unresectable to resectable.

Preoperative chemotherapy

One critical tool in increasing the number of patients who can undergo surgery is chemotherapy, which can shrink lesions to a point where it is possible to surgically remove them with adequate disease-free margins. Tumor reduction in response to chemotherapy may be a good prognostic sign, because it suggests that any microscopic disease is also being affected. According to Dr. Wolff, new drugs and new strategies to optimize their use—for example, using cytotoxic agents in conjunction with biologic agents such as bevacizumab—have improved the response rate to over 50%. “That is a dramatic improvement in the last 10 years,” he said.

Even in patients who do not become clear candidates for surgical resection, there can be sufficient tumor reduction to dramatically improve the patient’s overall condition, said Dr. Wolff. In these cases, additional tools are needed to render hepatic metastases resectable. To that end, two important surgical approaches are being brought to bear.

Portal vein embolization

The first approach is portal vein embolization (PVE), a strategy that addresses the problem of unresectable disease in a different way. Unlike chemotherapy, PVE does not reduce the tumor burden but rather induces an increase in the volume and function of the liver that will remain after resection. This procedure grew out of the observation that when the portal vein on one side of the liver was occluded, the ipsilateral lobe of the liver atrophied, but the contralateral lobe grew.

When the portal vein is occluded, diversion of blood flow to the opposite side of the liver triggers hypertrophy. Hepatocyte regeneration begins within hours throughout the nonembolized liver, while apoptosis leads to atrophy of the embolized lobe. Regeneration rates are fastest in patients with healthy livers and slower in patients with cirrhosis or diabetes (insulin plays a physiologic role). In a patient with metastases in an otherwise healthy liver, adequate hypertrophy to enable surgery can be achieved within 2 to 4 weeks. In patients with diabetes or cirrhosis, this typically takes longer—6 to 8 weeks—and the volume increase may be smaller.

PVE-induced liver hypertrophy helps to make unresectable disease resectable and directly improves patient care. First, PVE increases the volume and function of the liver remnant. Second, it allows the future liver remnant to adjust to portal pressure changes several weeks before surgery in order to minimize tissue damage to the liver remnant. Dr. Abdalla and his colleagues have used this understanding of liver regeneration, refined the indications and technique for PVE, and used PVE and liver volume analysis to increase the number of patients who can safely undergo extensive hepatic resection. Finally, according to Dr. Abdalla, PVE does not preclude any other treatment. “It closes no doors,” he said. Patients can safely receive chemotherapy while their liver is growing.

Staged resection

Staged resection is another strategy that has made a dramatic impact on the treatment of patients with extensive colorectal cancer liver metastases. For example, patients with bilateral liver tumors typically receive preoperative chemotherapy and then undergo first-stage surgery to resect the tumors but preserve most of the liver parenchyma on one side of the liver. This side will be the future disease-free liver, but because it is small, PVE is performed to induce hypertrophy. After sufficient liver growth, the tumor-bearing liver on the opposite side is resected to completely remove all remaining disease. Dr. Abdalla cites a 5-year survival rate of 40% for this procedure—a rate that is striking when compared with the near-zero survival rate in patients with otherwise unresectable disease.

According to Dr. Abdalla, these advances have shattered previous notions of what is “unresectable” and the idea that stage IV colon cancer is always incurable. “Tumor burden used to define resectability. Now, we can look at ways of not only reducing tumor burden but also maximizing the amount of liver that will remain after treatment,” he said.

Liver volume after resection

How much of the liver must remain to support life and avoid complications? Dr. Abdalla and his colleagues conducted a study that showed that in a healthy liver, it is safe to remove 80% of the liver and that the complication rate is low.

Accurate measurement of liver volume is critical to ensure safe resection and is made possible by three-dimensional computed tomographic volumetry. A formula for total liver volume that is based on body surface area is used to standardize the measured liver remnant size to a patient’s size—smaller patients need smaller liver remnants, while larger patients need larger remnants. An M. D. Anderson study showed that when this approach, plus PVE when indicated, is used, extended hepatectomy has an operative mortality rate of only 0.8%, much lower than any previously reported rate.

Sorting through the variables

In addition to the advances in chemotherapy and surgery, Dr. Abdalla cites “better anesthesia, better postoperative care, and better imaging” as critical contributors to the goal of offering potentially curative treatments to more patients. The key is to use all of the tools strategically. Because patients present in various degrees of health, with various degrees of tumor burden, Dr. Wolff noted that “deciding which tools to use is best done by a multidisciplinary team that can evaluate all of the factors and tailor a treatment to the individual patient.”

For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.

Other articles in OncoLog, April 2006 issue:

• Cancer Screening Guidelines Revised: One on One with Dr. Therese Bevers
• M. D. Anderson’s Cancer Screening Guidelines
• In Brief: Research News from the Laboratories and Clinics of M. D. Anderson
• House Call: What Is “Breast Self-Awareness”?
• DiaLog: The Revolutionary Cervical Cancer Vaccine

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