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From OncoLog, April-May 2011, Vol. 56, No. 4-5

Two-Stage Resection and Improved Chemotherapy Regimens Lengthen Survival for Patients with Liver Metastases from Colorectal Cancer

By Bryan Tutt

New surgical techniques and new chemotherapy drugs have pushed up the median survival times for patients with liver metastases from colorectal cancer since the 1990s.

Patients with colorectal cancer metastases involving both lobes of the liver were once considered poor candidates for surgery because removing all the metastases in a single hepatectomy would not leave enough healthy liver tissue for the patient to survive. Two-stage liver resection—in which a limited liver resection is performed to remove some metastases and to help physicians determine whether a second, more extensive resection would benefit the patient—was widely adopted in the late 1990s, making surgery possible for more patients.

Because the surgery is usually done only in patients who have responded to chemotherapy—and because several new and potent chemotherapy drugs were approved for the treatment of colorectal cancer in the 1990s and early 2000s—some physicians have questioned whether the survival benefits of two-stage resection are the result of selection bias.

Advances in chemotherapy

Patients with colorectal cancer—with or without metastatic disease—typically are treated by resection of the primary colorectal tumor followed by chemotherapy. The chemotherapy regimen for these patients has evolved rapidly in recent years. Most patients with colorectal cancer were treated with 5-fluorouracil and levamisole until 1994, when irinotecan was approved by the U.S. Food and Drug Administration and added to the regimen. In 1998, leucovorin replaced levamisole in the regimen, and in 2004 oxaliplatin replaced irinotecan to create the FOLFOX regimen that is now the standard chemo therapy for patients with colorectal cancer. Since 2004, monoclonal antibodies such as bevacizumab, cetuximab, or panitumumab have been added to the regimen for many patients with colorectal cancer. The addition of these monoclonal antibodies to the regimen has been shown to prolong survival in patients with colorectal cancer liver metastases and to reduce the size of the metastases.

“Because response to chemotherapy is the best predictor of outcome in patients with colorectal liver metastases, it is logical to consider response to treatment when selecting candidates for surgery,” said Jean-Nicolas Vauthey, M.D., a professor in the Department of Surgical Oncology at The University of Texas MD Anderson Cancer Center.

Selecting patients for surgery

During their course of chemotherapy, patients with colorectal cancer liver metastases who are candidates for two-stage liver resection are regularly evaluated by computed tomography (CT) to assess the response of the metastases to treatment. Because chemotherapy can cause liver damage, surgeons and medical oncologists consider it preferable to begin the two-stage resection after 2–3 months of treatment; 6 months of chemotherapy can potentially cause enough liver damage to preclude surgery. Chemotherapy is resumed after the patient has recovered from surgery.

“We’re continually adjusting our practices to optimize outcomes for these patients,” said Scott Kopetz, M.D., an assistant professor in the Department of Gastrointestinal Medical Oncology. “We want to administer just the right regimen of chemotherapy for just the right duration to shrink the tumors enough to make surgery feasible without causing toxicity to the liver.”

In addition to shrinking the tumors, which for some patients is necessary before two-stage resection is possible, chemotherapy helps physicians determine whether a patient will benefit from the surgery. “We know that patients whose disease progresses during chemotherapy will have bad outcomes,” Dr. Vauthey said. “For these patients, resection of the metastases is not worth the morbidity of surgery.”

Patients are selected for the first stage of surgery on the basis of the response of their metastases to chemotherapy as indicated by CT. Signs of a response include shrinkage of the metastases and changes in the tumors’ appearance. Dr. Vauthey said that a homogenous, cyst-like appearance on CT can indicate a response to chemotherapy even if the size of a metastasis has not changed. Patients considered to have stable disease or a response to therapy are likely to be a good candidates for resection of their liver metastases.

Surgeons used to consider patients with more than four metastases in the liver to be poor candidates for resection, but Dr. Vauthey said the number of metastases to be resected is now considered less important than the response to chemotherapy and the amount of cancer-free liver that can be preserved. Patients are likely to be selected to undergo two-stage resection if their metastases are located such that 20% or more of the liver will be preserved after the second stage. Metastases in other sites do not necessarily preclude the resection of liver metastases.

According to Dr. Kopetz, about 1 in 5 patients with colorectal cancer liver metastases could be candidates for either a one-stage or two-stage resection, but only 1 in 20 actually undergoes a resection. To ensure that surgery is available to all patients who might benefit from it, surgeons at MD Anderson are typically consulted before patients with colorectal cancer liver metastases begin chemotherapy. “Surgery and chemotherapy are two modalities in which we’ve seen fairly significant advances independently, but the best outcomes occur when these two are integrated,” Dr. Kopetz said.

Two-stage resection

The first stage of surgery for colorectal cancer liver metastases is a limited resection of the metastases in the less affected side of the liver (usually the left side). Following this relatively minor procedure, a multidisciplinary team of physicians evaluate several criteria to determine whether they should attempt the second stage of surgery, an extended resection of the more involved side of the liver.

The most important of these criteria is the resected tumors’ response to chemotherapy, which is determined by a pathological examination. Patients whose metastases do not show substantial response based on a decrease of viable cancer cells are unlikely to benefit from further surgery.

Another important consideration is whether the patient’s liver will be able to recover from a second surgery. To determine this and to increase the size of the healthy liver that will remain after the second surgery, a radiologist performs a portal vein embolization 2 weeks after the first surgery. Three-dimensional CT scans taken before and 3 weeks after the portal vein embolization are used to calculate the degree of hypertrophy. “We don’t know exactly why, but some people’s livers regenerate better than others’,” Dr. Vauthey said. “Portal vein embolization provides an in vivo test telling us whether the patient is likely to have hepatic insufficiency after the second surgery.”

In addition to poor response to chemotherapy or lack of hypertrophy, complications from the first surgery or disease progression after the first surgery may prevent a patient from undergoing the second surgery. According to Dr. Vauthey, nearly a third of patients who undergo the first stage do not undergo the second stage.

Prolonged survival has been documented among patients who undergo two-stage liver resection. In fact, chemotherapy plus two-stage resection is considered curative for a small subset of patients. But the benefits of chemotherapy plus surgery compared with chemotherapy alone for colorectal cancer liver metastases have only recently been studied.

Solving the mystery

To determine whether two-stage liver resection was independently associated with survival in patients with colorectal cancer liver metastases, Drs. Vauthey and Kopetz, along with other researchers at MD Anderson, conducted a retrospective study comparing the outcomes of patients who underwent the surgery and chemotherapy to those of patients who received chemotherapy only.

The researchers reviewed the records of 65 patients who had undergone chemotherapy plus at least the first stage of two-stage liver resection and 62 patients who had received chemotherapy only between June 2002 and February 2010. The two groups were similar in terms of their performance status, absence of extrahepatic metastases, extent of hepatic metastases on pretreatment imaging, and objective response to first-line chemotherapy regimens that included irinotecan or oxaliplatin with or without bevacizumab or cetuximab.

The results of the study were recently reported in the Journal of Clinical Oncology. The 3- and 5-year overall survival rates were 67% and 51%, respectively, for patients who underwent at least the first stage of two-stage resection versus 41% and 15%, respectively, for patients who underwent chemotherapy only. The 3- and 5-year overall survival rates were significantly higher (84% and 64%, respectively) among patients who underwent the second stage of resection than among those who underwent the first stage only.

While these data support the survival benefits of surgery over chemotherapy only, they also indicated that newer chemotherapy regimens confer a greater survival benefit than previous regimens. In fact, the MD Anderson authors noted that the 5-year overall survival rate of 15% for patients receiving chemotherapy only was the highest reported rate for patients whose colorectal cancer liver metastases were treated nonsurgically. A previous study found that patients diagnosed with colorectal cancer liver metastases between 1990 and 1997 had a 5-year overall survival rate of only 9%. Dr. Vauthey said the recently published data are encouraging because they demonstrate that advances in treatment have been followed by improved patient survival rates.

“To answer the question of whether the surgical procedure or the drugs are responsible for the improved survival durations for these patients—the answer is both,” Dr. Vauthey said.

A Patient’s Perspective

John Schnitzer was diagnosed with colorectal cancer in 1998 at age 48.

While recovering from the resection of his primary tumor at a hospital in Florida, he received the bad news that the cancer had metastasized to his liver. He was treated with a chemotherapy regimen of 5-fluorouracil and leucovorin and referred to Dr. Jean-Nicolas Vauthey for a two-stage liver resection in 1999. A portal vein embolization was used to increase the amount of the healthy liver tissue before the second stage of surgery.

After recovering from surgery, Mr. Schnitzer was able to return to his normal activities, including competitive long-distance running. For the past 12 years, he has had no recurrence of his colorectal cancer, although he was treated for an apparently unrelated prostate cancer in 2007. He is examined twice a year at a cancer center near his current home in Utah, but otherwise has a more active lifestyle than many people who have never had cancer.

Mr. Schnitzer continues to work full-time in a job that requires international travel, and he still runs marathons. “I pretty much live a normal life,” he said.
Photo: John Schnitzer

For more information, contact Dr. Jean-Nicolas Vauthey at 713-792-2022 or Dr. Scott Kopetz at 713-792-2828.

Other articles in OncoLog, April-May 2011 issue:

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