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Surgical Therapy of Hepatic Colorectal Metastasis

CA Cancer J Clin 1999;49:231-255

Yuman Fong, MD Abstract

This review summarizes data demonstrating the safety and efficacy of liver resection for colorectal metastases. Hepatic resection in appropriately selected patients remains the only potentially curative treatment for patients with such metastases. Recommendations for preoperative patient evaluation, patient selection, adjuvant therapy, and postoperative follow-up are presented. Other surgical modalities utilized in the treatment of unresectable or recurrent hepatic colorectal metastases, including ablative modalities and surgical delivery of regional chemotherapy, are described.(CA Cancer J Clin 1999;49:231-255.)

Introduction

More than 50,000 patients each year in the United States present with liver metastases from colorectal cancer.¹ The liver is the most common site of colorectal metastases, and often is the only organ affected.

When untreated, such hepatic colorectal metastases are uniformly fatal, with survival usually measured in months.^2-6 Systemic chemotherapy may modestly prolong survival, but rarely results in survival longer than two years ^7-15

As the safety of liver resections has improved over the past decades,^16-21 such procedures have become the treatment of choice for hepatic colorectal metastases and remain the only potentially curative option.^22,23

Untreated Disease and Chemotherapy

Until the early 1980s, metastatic colorectal cancer to the liver was often left untreated. Data from that era clearly demonstrate untreated disease to be rapidly fatal, with a median patient survival of only five to 10 months.^2,5,24-27

Two studies attempted to identify patients with limited liver metastases to define the natural history of the disease in individuals who could be considered candidates for resection. In these studies, patients with limited but untreated disease had a one-year survival rate of 77%, a three-year survival rate of 14% to 23%, and a five-year survival rate of 2% to 8%.^4,22 Therefore, although patients with solitary lesions or unilobar disease appear to have better prognoses than patients with diffuse disease, five-year survival for any untreated patient is unusual.

The most successful chemotherapeutic regimens for metastatic colorectal cancer have been based on fluorouracil (5-FU),^{7-11,13-15,28-35} and the current standard therapy for unresectable disease is a combination of 5-FU and leucovorin. Tumor response to even the best regimens, however, is only about 25% to 30% (Table 1). ^7-10 Complete response is rare and median survival is reported to be generally a year or less.

Recently, the topoisomerase I inhibitor irinotecan (CPT-11) was approved as second-line chemotherapy for patients with unresectable disease that does not respond to 5-FU therapy.^36-38 Nevertheless, the antitumor activity of CPT-11 is not expected to be higher than 25% to 30%. Thus, chemotherapy does not offer potential for cure of colorectal hepatic metastases and is not a substitute for potentially curative resection.

Resection for Potential Cure

It was not surprising that initial reports of resection for metastatic colorectal cancer were met with skepticism, even from the surgical community.³⁹ As recently as two decades ago, liver resections were associated with sufficiently high morbidity and mortality to be deemed unjustified for what was thought to be indicative of widespread metastatic disease. The acceptance of surgical resection as standard treatment for hepatic colorectal metastases is based on the increasing safety of major liver resections, and on the growing body of data demonstrating that when metastases are isolated in the liver, resections can be potentially curative.

Perioperative Mortality and Morbidity

A large body of literature has accumulated over the past two decades demonstrating liver resection to be safe and effective. Table 2 lists surgical series published to date with more than 100 patients each. From these data, it is clear that mortality is uniformly less than 5% at most major centers.^16-19,
40-51 Perioperative death usually results from hemorrhage or liver failure.

The increasing safety of liver resection can be attributed to advances in three different areas. First, marked advancements in medical imaging allow better patient selection and surgical planning. Second, advancements in understanding of physiology have enhanced the safety of anesthetic and perioperative care. Finally, studies of hepatic anatomy and physiology have resulted in improved surgical techniques.

The mortality rate associated with liver resections seems to have plateaued at 4% to 5%. As such resections become accepted as standard therapy, increasingly aggressive resections are being performed. At many centers, more than two-thirds of resections now consist of removing half of the liver or more, and up to 80% of the liver is now routinely resected to achieve extirpation of tumor (Fig. 1).

It is not surprising that resection of as vital an organ as the liver is associated with a relatively high complication rate. Most major series report complication rates ranging from 20% to 50% (Table 3). Liver failure is the most ominous complication but occurs in only 1% to 5% of all major resections.^{17,18; 46, 52,53} Hemorrhage is also a major cause of perioperative mortality, but occurs rarely (1% to 3%). Other hepatic complications include biliary leak or fistula, which occur in approximately 3% to 4% of cases,^18,46 and perihepatic abscess, which occurs in 1% to 9%.^16-18,41,46

Cardiopulmonary complications include myocardial infarction (1% in most series),^16-18,41 sympathetic pleural effusions that may require tube thoracostomy (5% to 10%),^16,54 pneumonia (5% to 22%),^17,46 and pulmonary embolism (1%).^18,52

This high rate of complications does not translate, however, into a high mortality rate and usually does not even result in prolonged hospital stay. Median hospital stay, even for the most extensive resection—in centers experienced in liver surgery—is usually less than two weeks. In a series of 577 consecutive resections performed at Memorial Sloan-Kettering Cancer Center, for example, the median hospital stay was 13 days and admission to the intensive care unit was required for only 7% of patients.²⁰ Major liver resections can be performed with low mortality, and with reasonable demands on hospital and intensive care resources.

Long-Term Results

Numerous studies have also demonstrated that surgical resection can result in long-term survival for patients with hepatic colorectal metastases (Table 2). ^{17,20,21,47-51,55-60} From 25% to 35% of patients who undergo liver resection for colorectal metastases can be expected to survive for five years, with median survival of 28 to 40 months.

In three series, follow-up has been sufficiently long to document a 10-year survival rate of approximately 20% after liver resection for patients with hepatic colorectal metastases.^{21,50, 59} These results should be compared with results of no treatment, where median survivals of six to 12 months are expected and five-year survival is rare. These results can also be compared with the best chemotherapy results, where median survival is expected to be 12 to18 months, and five-year survivors are rare. In view of these data, a randomized trial comparing resection with no treatment or with systemic chemotherapy would appear unethical. Clearly, liver resection can provide long-term survival and potential cure for patients with metastatic colorectal cancer. That is why, even without rigorous trials, hepatic resection has been accepted as standard treatment for resectable colorectal metastases.

Preoperative Evaluation/Patient Selection

Patient selection criteria have been refined over the last two decades to more accurately identify patients who will tolerate and benefit from resection of their hepatic metastases. The preoperative work-up should include evaluation of the patient's medical fitness for anesthesia and surgery, as well as the appropriateness of liver resection from a prognostic standpoint. In general, all medically fit patients with metastatic disease that is isolated to the liver should be considered for liver resection.

General Medical Condition

Patients considered for liver resection are evaluated with particular vigor for pulmonary compromise, as they are at high risk for pulmonary complications. This results partly from the high transverse incision required for safe access to liver tumors, as well as the significant discomfort associated with respiratory effort postoperatively. Many patients routinely develop a sympathetic right pleural effusion, which further contributes to respiratory compromise. Cardiac evaluation is similar to that conducted for patients undergoing other major abdominal surgery.

Although some authors have suggested that advanced chronologic age is a contraindication for surgery,⁶¹ most studies have not substantiated this caveat (Table 4). ^20,49,53,62 We specifically addressed this issue in a recent report²⁰ of 128 patients over the age of 70 who underwent liver resection. Compared with patients younger than 70 undergoing liver resection at the same institution, no differences in perioperative morbidity and mortality or in long-term outcome were noted. Therefore, we do not consider advanced chronologic age alone as a contraindication to liver surgery, although these favorable results are partly due to careful patient evaluation and selection. In our practice, patients older than age 65 are routinely referred for cardiopulmonary evaluation prior to surgery.

Prognostic Variables in Patient Selection

Many studies have analyzed long-term outcomes after resection of hepatic colorectal metastases in an attempt to determine whether patient selection criteria can be refined. The variables most consistently associated with tumor recurrence and therapeutic failure are: (1) tumor involvement in the resection margin,^{19,40,41,44,63,64} and (2) detection of extrahepatic disease at the time of treatment of liver metastases (Table 4).

The most common sites of extrahepatic disease are the chest, other sites within the abdomen, and the colon. Preoperative chest, abdominal, and pelvic computed tomography (CT) scans are mandatory, as is colonoscopy. Any metachronous colorectal lesion or anastomotic recurrences may be resected at the time of liver resection. Extrahepatic metastases found at any other intra-abdominal site usually rule out a liver resection, as the prognosis is poor and cure unlikely, regardless of treatment. Disseminated pulmonary metastases are also contraindications to liver resection, although efforts to aggressively resect limited pulmonary metastases along with the liver metastases have met with reasonable success.^65,66

Bone scans have low yield, and routine use cannot be justified. All other imaging modalities to assess extent of extrahepatic disease must be considered experimental. There is certainly no proven role, for instance, for radioimmune imaging using radio-labeled monoclonal antibodies directed against specific colorectal tumor antigens^67-80 in the presurgical evaluation of patients with liver metastases, as false positive results excede 10%. In contrast, whole-body positron-emission tomography (PET) scanning after administration of [¹⁸F]5-fluorodeoxyglucose (5-FDG)^71-73 has shown promise in the preoperative evaluation of potential candidates for hepatic resection and will be discussed later in this review.

Some of the other variables associated with recurrence and therapeutic failure after liver resection are listed in Table 4. Regional lymph node involvement by the primary tumor,^17,44,74 symptomatic liver tumors,^44,74 synchronous presentation of liver metastases with the primary tumor,^18,19,74 large numbers of tumors,^19,74presence of satellite nodules,^18,19 high preoperative carcinoembryonic antigen (CEA) level,^62,75 and extent of liver involvement of more than 50%^17,63 have all been reported to predict recurrence.

In our recent analysis of 456 consecutive liver resections,⁷⁶ the following factors were associated with poor prognosis: (1) size of liver tumors greater than 5 cm; (2) disease-free interval between colon and liver disease of less than 12 months; (3) number of liver tumors greater than one; (4) lymph-node-positive primary tumor; and (5) preoperative CEA level of greater than 200 ng/ml. Nevertheless, as the presence of any one of these characteristics was still associated with five-year survival rates between 24% and 34%, none can be considered an absolute contraindication to resection. Increasing number of these negative prognostic indicators was associated with increasing risk of recurrence (Fig. 2). We have developed a clinical risk score based on these five criteria that shows promise in improving patient selection for surgery (Fig. 2).

Age, gender,^55,77 primary tumor grade, and location^{18,42,63,78,79} have not consistently been demonstrated to affect outcome. At present, extrahepatic disease and inability to resect all hepatic disease are the only absolute contraindications to resection. All medically fit patients with completely resectable disease confined to the liver should, therefore, be considered for resection.

As extensive resections of up to 80% of the liver parenchyma can be performed with less than a 4% mortality rate at major centers, we have adopted an increasingly aggressive approach to resection. We are routinely resecting bilobar tumors, as well as livers with up to 10 tumors. Whether such an aggressive approach is justified by long-term results awaits evaluation with sufficient follow-up.

Imaging in the Preoperative Evaluation of Patients with Hepatic Metastases

Liver tumors usually produce no symptoms until they have become quite large or until extensive vascular or biliary involvement occurs. Some of the credit for improving results of hepatic resection must be attributed to rapid advancements in medical imaging techniques, allowing not only detection of metastatic disease at a resectable stage, but also precise planning of the surgical procedure. The major strengths and weaknesses of various imaging modalities are outlined below.

Computed Tomography

CT is the most widely employed imaging test for evaluation of liver metastases because it is relatively inexpensive, widely available, and allows evaluation of both hepatic and extrahepatic sites of disease.⁸⁰

CT portography is a refinement of dynamic CT where the contrast agent is given by injection into the superior mesenteric artery. This contrast material rapidly reaches the portal circulation. As colorectal metastases are mainly nourished by the hepatic artery and derive little blood supply from the portal vein, they appear as filling defects surrounded by hypervascular liver parenchyma.⁸⁰ CT portography is very sensitive for detection of hepatic colorectal metastases and is the gold standard for evaluating the number of hepatic lesions (Fig. 3). The disadvantages of CT portography are its invasive nature and cost. Furthermore, since lesions seen on CT portography are vascular perfusion defects, they are often exaggerated and cannot be relied upon to determine proximity of tumor to major vasculature.

We continue to use CT portography as the standard test for evaluating the extent of liver disease. As the accuracy of helical CT scans has improved, however, some clinicians are now using these scans instead, accepting a lower sensitivity in an attempt to avoid the cost and invasiveness of CT portography.

Transcutaneous and Intraoperative Ultrasound

Transcutaneous ultrasonic evaluation represents the least invasive and least expensive diagnostic modality for evaluation of hepatic metastases. This test is inadequate for assessing extrahepatic disease, as air-filled structures, such as the bowel, may obscure imaging of lesions. Even within the liver, there are sonographically "silent" areas, such as the dome of the liver, where overlying lung may obscure abnormalities. This modality is also highly dependent on the expertise and diligence of the operator. Nevertheless, in expert hands transcutaneous ultrasound may be as accurate as CT or magnetic resonance imaging (MRI) in determining the number and size of lesions, as well as their relationships to major vasculature.⁸¹

Intraoperative ultrasound is routinely used at major centers during surgical treatment of liver tumors. This modality is useful both for detection of small and deep hepatic lesions that are not palpable,⁸² and to assist in locating intrahepatic vasculature to guide resection. Intraoperative ultrasound is invaluable in guiding surgeons in technically difficult resections that are proximal to major vasculature. This test is not a substitute for good preoperative imaging, however, because the best time to discover unresectable disease is before, not during, surgery.

Magnetic Resonance Imaging

MRI is well suited for identification and characterization of liver lesions. Metastatic colorectal cancers are characteristically low-intensity lesions on T₁-weighted spin echo images, and intermediate in intensity on T₂-weighted images. These characteristics allow MRI to distinguish metastatic tumors from benign liver lesions, including benign cysts, hemangiomas, and fibronodular hyperplasia. MRI is also superb for visualization of vascular structures such as hepatic veins and vena cava (Fig. 4). Finally, with recent advances in magnets and computer software, accurate imaging of the biliary tree is also now possible by magnetic resonance cholangiopancreatography (MRCP).^83,84 When tumor is proximal to the vascular or biliary tree, MRI represents a single non-invasive test for tumor characterization and surgical planning.

18F-Fluoro-2-deoxyglucose Whole-body PET (FDG-PET)

Since the first half of this century, it has been recognized that malignancies utilize glucose at greater rates than does normal tissue. Tumor cells express increased levels of membrane glucose transporters and of intracellular hexokinase enzymes—enzymes that convert glucose to glucose-6-phosphatase. When the positron-emitting glucose analog 2-[¹⁸F]-fluoro-2-deoxyglucose is administered to tumor-bearing man, it is conveyed into tumor cells by hexose transporters and undergoes phosphorylation to FDG-6-phosphate, which is then selectively retained, as it is not subject to further metabolism in most tumor cells. The feasibility of using this preferential accumulation of FDG by tumor cells to image malignant disease is actively being investigated in clinical trials for lung cancer,⁸⁵melanoma,⁸⁶ pancreatic cancer,⁸⁷ and head and neck malignancies.⁸⁸

It has been recognized for over a decade that PET scanning can be used to detect liver metastases from colorectal cancers after ¹⁸F-FDG administration (Fig. 5). ^88,89 Three studies have sought to determine the utility of this modality in the preoperative assessment of patients with liver metastases.^73,91,92 Beets et al⁷³examined 15 patients with resectable liver metastases. Vitola et al⁹¹ examined 24 patients with liver metastases and found PET scanning to have a higher accuracy for liver metastases than CT scans (93% versus 76%). PET scanning also detected extrahepatic lesions in four of those patients and altered management in six of the 24 patients. Lai et al⁹² compared PET scanning with conventional imaging in 34 patients. In that study, PET scanning detected unsuspected extrahepatic disease in 11 patients and altered management in 10 (29%).

Although these studies offer some evidence of the utility of PET scanning in the management of patients with metastatic colorectal cancer, they are far from conclusive. They were all small studies. Other imaging of patients was not standardized, and in none of these studies was the chest CT standard. The PET scans were not evaluated by readers blinded to readings of other imaging modalities. Furthermore, follow-up in these studies has been insufficient to determine the false-negative rates associated with the various imaging modalities. Despite the drawbacks, results observed by these investigators should encourage the design of prospective trials to examine the value of PET in this setting. Until data are available from such trials, we use FDG-PET scanning for patients at high risk of having extrahepatic disease, i.e., those with a high clinical risk score.

Laparoscopy

Laparoscopy has become invaluable in the diagnosis and treatment of gynecologic⁹³and other intra-abdominal malignancies.⁹⁴ Two recent reports have advocated diagnostic laparoscopy before formal laparotomy for liver resection.^95,96 In the first, Babineau and colleagues reported on 29 laparoscopies prior to a planned hepatic resection, 12 for hepatocellular carcinoma and 17 for metastatic tumor. In 14 cases (48%), laparoscopy provided evidence of unresectability (four cases of unsuspected cirrhosis, six cases of peritoneal metastases, and four cases of more widespread intrahepatic disease than suspected).⁹⁵

In the second report by John et al,⁹⁶ 50 consecutive patients with liver tumors (nine cases of hepoatocellular carcinoma, 37 of secondary cancers, and six cases of nonmalignant disease) were evaluated by laparoscopy and laparoscopic ultrasound. In 32 instances, laparotomy was avoided.

Of note, in the study from Barbineau et al, only 38% of the patients who underwent laparoscopy were resected,⁹⁵ and in the study from John et al, only 26% eventually came to resection.⁹⁶ Such low resectability rates call into question the adequacy of current preoperative imaging and staging techniques. These authors concluded that laparoscopy is useful prior to laparotomy for liver resection.

As part of a pilot study, we performed a comparison involving 190 consecutive patients considered for liver resection: 104 patients with hepatobiliary malignancies of all types were staged with laparoscopy and laparoscopic ultrasound before laparotomy, while a parallel group of 86 patients with similar diagnoses were explored without laparoscopy. We found that laparoscopic staging increased resectability from 66% to 83%, and that there were also significant reductions in length of hospital stay and total hospital charges.⁹⁷ The subset of patients specifically with metastatic colorectal cancer was too small for adequate subset analysis in this study. Nevertheless, we are sufficiently encouraged by these results to routinely perform staging laparoscopy in all patients with high risk for extrahepatic disease, such as those with a clinical risk score greater than 2.

There have also been recent anecdotal reports of liver resections performed laparoscopically.⁹⁸ While there is no doubt that such laparoscopic liver resections are technically feasible, certain theoretical and actual considerations will limit such resections to a minority of cases.

First, the loss of tactile sensation makes it difficult to judge and maintain surgical margins clear of tumor. Such resections will be limited, therefore, to small tumors. Second, the size of the incision necessary to remove the tumor specimen will also limit the advantage of laparoscopic resections to small tumors. The high intra-abdominal pressures generated by carbon dioxide insufflation makes carbon dioxide embolism a theoretical hazard if a sizable venotomy is inadvertently produced. Therefore, it would be particularly worrisome to perform laparoscopic resection of tumors on or near the major hepatic veins or vena cava. Nevertheless, we have performed laparoscopic resection of liver tumors using the laparoscopic harmonic scalpel and vascular staplers for control of major vasculature, and believe there is a role for such resections in cases of small tumors near the inferior edge of the liver.

Current Recommendations

For patients who are being considered for resection of metastatic colorectal cancer, chest, abdominal, and pelvic CT should be performed. Moreover, CT portography should be used for the abdominal CT to ensure the best sensitivity in detection of liver tumors. When proximity to major vascular or biliary structures is apparent, either ultrasound or MRI should be performed, depending on the expertise available at the local institution. As part of an investigational protocol at our institution, patients with a high clinical risk score (greater than 2) (Fig. 2) are assessed using both a preoperative PET scan and exploratory laparoscopy.

Adjuvant Therapy

Recurrence can be expected in up to two-thirds of patients after resection of hepatic colorectal metastases, indicating that microscopic disease commonly persists after resection. Although it would seem intuitively correct to offer adjuvant therapy in this patient population, only two studies of any size have been completed to help define the role of adjuvant chemotherapy in this population.

Adjuvant Systemic Chemotherapy

Four retrospective studies have examined the potential benefit of systemic 5-FU-based chemotherapy for patients who have undergone resection of hepatic colorectal metastases. Two of these studies found no benefit of adjuvant chemotherapy,^41,42 while two studies have suggested some benefit.^43,74 No prospective, randomized study completed to date has examined the utility of adjuvant systemic chemotherapy after hepatic resection of metastatic colorectal cancer.

At present, the justification for using adjuvant therapy after hepatic resection for metastases is based largely on extrapolation of data supporting the use of chemotherapy after resection of nodal metastases from colorectal cancer.⁹⁹Our current practice is to offer adjuvant 5-FU-based chemotherapy after hepatic resection to patients who have had no previous chemotherapy. For patients who have had prior chemotherapy, particularly if the liver tumors grew while chemotherapy was ongoing, additional adjuvant treatment is not offered. There are currently no data supporting use of CPT-11 in an adjuvant setting, although studies are in progress.

Adjuvant Intra-arterial Chemotherapy (Hepatic Arterial Infusion—HAI)

The most common site of tumor recurrence after resection of hepatic colorectal metastases is the residual liver.^{16,63,100-102} Investigators have therefore proposed regional hepatic arterial infusional, or HAI, chemotherapy as a potential adjuvant strategy to treat local microscopic residual tumors.

Four single-arm trials have examined adjuvant regional hepatic chemotherapy in patients after liver resection.^103-105 Data from these small series serve more to demonstrate the feasibility of such an approach than to provide data demonstrating efficacy.

One recent non-randomized comparative study, for example, reported a series of 57 patients undergoing resection for hepatic colorectal metastases.¹⁰⁶ In this series, 31 of the patients received intra-arterial chemotherapy consisting of either 5-FU, doxorubicin, or epirubicin. The treated patients had an actuarial five-year survival rate of 57%, compared with 23% for the 26 untreated patients. There has also been one small (36 patients randomized to four treatments) randomized trial examining regional chemotherapy after liver resection that also found a lower local recurrence rate in patients who received regional adjuvant therapy.¹⁰⁷

Two large randomized trials have recently been completed addressing the utility of adjuvant HAI chemotherapy after liver resection, with conflicting results and conclusions. In the first trial,¹⁰⁸ 226 patients from 25 centers were randomized to receive either no adjuvant therapy, or adjuvant HAI 5-FU plus systemic folinic acid. Although no differences were noted between the treatment groups, this study was compromised by a number of technical factors such that only 34 of the 107 patients randomized to chemotherapy completed their treatment.

In another study, Kemeny et al¹⁰⁹randomly assigned 156 patients to receive either systemic 5-FU plus leucovorin, or HAI floxuridine (FUDR) plus systemic 5-FU after complete resection of tumor. These investigators found a significant survival advantage with HAI that is most likely related to local liver tumor control. We believe HAI chemotherapy is effective and should be considered as an adjuvant to resection of hepatic colorectal metastases.

Neoadjuvant Chemotherapy

Although there is no established role for neoadjuvant chemotherapy in the treatment of metastatic colorectal cancer to the liver, there is sparse evidence that chemotherapy may convert unresectable cases to resectable cases in a minority of patients. A recent report by Bismuth and colleagues¹¹⁰ described 330 patients referred for liver resection of hepatic colorectal metastases that were found to be unresectable. These patients were given chemotherapy consisting of 5-FU, folinic acid, and oxaliplatin. After treatment, 53 (16%) patients were found to be resectable. The five-year survival rate of these resected patients was 40%, which was comparable to that for those resected initially.

These data should not be construed to support routine administration of chemotherapy prior to consideration for liver resection. In our experience, only rare unresectable cases become resectable by chemotherapy. This is due to the fact that although chemotherapy may reduce the bulk of the tumor, such treatment rarely changes the intimate relationship of tumor to major vasculature that is a more frequent reason for unresectability. Nevertheless, patients placed on chemotherapy for initially unresectable disease should be subsequently re-evaluated for resection, as resection still represents the only potentially curative option. Furthermore, difficult cases should be evaluated at a tertiary center, since many cases deemed unresectable by the less experienced liver surgeon may be safely and routinely performed at a major center, independent of the use of chemotherapy.

Adjuvant Immunotherapy

There is increasing experimental evidence that liver resection, and the process of liver regeneration may stimulate growth of microscopic residual tumors within the liver. As two-thirds of resected patients are expected to have tumor recurrence and more than half of these will first recur within the liver, this is a problem with significant clinical implications. The causes of this tumor stimulatory effect after hepatectomy are likely to be multifactorial. Elaboration of local growth factors during the liver regeneration process is likely to play a role,¹¹¹ as is the local and systemic immunosuppression that has been noted in this setting.¹¹² After liver resection, local macrophage antitumor activity, as well as systemic lymphocyte tumor surveillance, are suppressed.¹¹³

In experimental models, administration of gamma-interferon to stimulate macrophage function,¹¹² as well as administration of cytokine-secreting tumor vaccines to stimulate lymphocyte function,¹¹³ have proven useful in reducing tumor growth in the liver after resection. These strategies are likely to be tested clinically in the near future.

In addition, investigators have evaluated the effects of neoadjuvant interleukin-2 administration prior to liver resection for metastatic colorectal cancer.^114,115 This immunostimulatory cytokine was administered to 12 patients as a continuous intravenous infusion for five days prior to liver resection, with doses ranging from 3 x 10⁶ IU/m²/day to 12 x 10⁶ IU/m²/day. At high doses, lymphocyte counts were higher in treated subjects than in controls, and in vitro tumoricidal activity was improved. This is clearly too small a study to demonstrate clinical efficacy, but it does demonstrate the feasibility of such an approach from a toxicity standpoint. Further studies are indicated.

Follow-up After Liver Resection

Careful follow-up after resection of hepatic colorectal metastases is essential, as recurrence can be expected in two-thirds of patients. Such follow-up is justified as subsequent liver or lung resections can still provide cure, and palliative treatment using chemotherapy or ablative therapy is possible.

Patterns of Recurrence

The strategy for follow-up outlined below is based on the known pattern of recurrence after liver resection. The first sites of recurrence for 235 recurrences documented in 456 consecutive liver resections for colorectal metastases are listed in Table 5. ⁷⁶ Of these recurrences, nearly half involved the liver. The lungs were the next most common site, with one-quarter of the recurrences occurring at this site. Most of the other 25% of recurrences occur in other intra-abdominal sites.

Outcomes of Treatment for Recurrence

As the most common site of recurrence after hepatic resection of colorectal metastases is the residual liver, an increasing number of investigators have examined the utility of second resections as treatment for recurrent liver disease^{16,42,101,116-124} (Table 6). Early studies with limited numbers of patients served to demonstrate the safety of repeat resections.^{16,42,101,116-119} More recent studies, however, have had sufficient sample size and duration of follow-up to verify long-term survival after repeat resection of hepatic colorectal metastases.^125-127

The five-year survival rate in one recent study,¹²⁷ for example, was found to be 41%; patients who had experienced a long interval between the first and second liver resection had particularly favorable outcomes. In a recent study of 96 five-year survivors after liver resection, nearly half had a further recurrence in the first five years that was successfully treated by repeat resection,¹²⁸ demonstrating that locating and removing all metastatic disease at the time of the first liver resection is not a prerequisite for long-term survival and cure.

Pulmonary and Colorectal Recurrences

Patients with limited pulmonary recurrence should also be considered for resection, as long-term survival can be achieved.^65,66 In fact, the best results after liver and lung resections for metastatic colorectal cancer are achieved for those in whom liver and pulmonary recurrences were discovered metachronously.⁶⁶ The final group of patients to be considered for further resectional therapy are those with metachronous second colorectal cancers or with limited colorectal anastomotic recurrences.

Chemotherapy for Patients with Unresectable Recurrences

Recurrences not treatable with resection should be considered for chemotherapy or ablation. For patients who have not been previously treated with chemotherapy, a 5-FU-based regimen can provide tumor regression in up to 40% of patients.¹⁵ For those previously treated with 5-FU-based chemotherapy, CPT-11 is now an accepted alternative chemotherapeutic option if unresectable disease is confined to the liver.¹²⁹ Many ablative techniques, including cryoablation, embolization, and percutaneous ethanol injection, have also been proposed as alternative treatments.

Recommended Evaluations

The routine follow-up of a patient after resection of metastatic colorectal cancer should include an office visit two to three weeks after hospital discharge. Liver function tests, as well as CEA level, should be assessed. For those patients with an elevated CEA level preoperatively, a return of the tumor marker to normal levels postoperatively serves to confirm that the goals of resection have been achieved, and routine follow-up should be initiated. This routine follow-up consists of office visits every three months with physical exam and measurement of liver function tests and CEA level. Patients are also followed with an abdominal/pelvic CT scan every six months, and a chest x-ray and colonoscopy should be obtained yearly. This close follow-up should continue for five years.

In patients whose elevated preoperative CEA level does not return to normal, persistence of tumor must be suspected and scanning must be performed to search for treatable disease.

Therapies with Palliative Intent

Cryoablation

Rapid freezing and thawing of tissues—cryoablation—produces significant cellular damage and cell death. Although investigators have long sought to use cryoablation as therapy for liver tumors,¹³⁰ until very recently, technical considerations have made this modality impractical. Development of vacuum-insulated cryoprobes cooled by liquid nitrogen or argon delivery systems allow precise, controlled freezing of tumors at even great depths within the liver. Additionally, intraoperative ultrasound is now widely available to guide placement of these cryoprobes, as well as to delineate the extent of freezing.

A number of studies have demonstrated the safety of this ablative technique in treatment of well-selected patients with colorectal metastases. Ravikumar and Steele^131,132 at the New England Deaconess Hospital reported only two major complications (8%) (a subphrenic abscess and a wound dehiscence) in 25 patients with metastatic colorectal cancer treated by cryotherapy. With a median follow-up of two years, seven of these patients (28%) have remained in remission.¹³¹ Likewise, Morris and colleagues from the University of New South Wales reported only one death out of 162 cryosurgical procedures.¹³³

The safety of cryosurgery, however, is clearly related to the aggressiveness of the investigators. Complications, including pleural effusions, myoglobinuria,¹³⁴ hemorrhage, biliary fistulation, hepatic abscess, and renal failure have all been reported.¹³⁴ At centers where very aggressive ablation is performed, mortality rates are reported to be as high as 4%¹³⁵—comparable to those for resection.

Cryoablation is palliative in nature and should not be considered an alternative to potentially curative resections. Three-quarters of patients undergoing cryosurgery alone had relapse of their preoperative CEA levels within six months.¹³⁶ Most investigators are therefore restricting cryoablation to unresectable tumors and combining it with adjuvant regional or systemic chemotherapy as part of an investigational approach.

Cryosurgical techniques are subject to certain important limitations. As the freezing of each tumor takes between 30 and 40 minutes, cryoablation procedures are often lengthy, lasting four hours or longer.¹³³ A single probe is capable of freezing an area of no more than approximately seven cm in diameter. Therefore, most investigators are willing to freeze up to only five tumors, each up to five cm in diameter. Freezing near major vessels is problematic, both because of risk of hemorrhage and because the warm blood passing through such vessels precludes complete freezing.

In cirrhotic patients with hepatocellular carcinoma, limited liver reserve often makes resection of tumors impossible and ablative methods such as cryoablation have a more established role. As complete recovery can be expected even after resection of up to 85% to 90% of a non-cirrhotic liver, the precise role for cryotherapy in the treatment of metastatic colorectal cancer is incompletely defined. We find it most useful for treating patients with scattered unresectable lesions of limited size after failure of conventional chemotherapy. We are currently treating such patients with a combination of cryoablation, intra-arterial FUDR, and systemic CPT-11 in the context of an investigational study.

Radiofrequency Ablation

Radiofrequency is a new ablative technique that relies on heat to effect tumor killing.¹³⁷ A radiofrequency electrode is passed into a tumor under sonographic-, CT, or MR-guidance. The tumor is then ablated by the thermal energy generated by the electrode.

Radiofrequency ablation can be administered by open surgery, laparoscopic surgery, or percutaneously. The major advantage of radiofrequency ablation over cryoablation is the lower cost of the equipment involved. The small size of the electrodes used also allows percutaneous delivery of therapy.

The major obstacle to use of this technique is the limited size of the lesions that can be ablated by current instrumentation. As heat is generated within the tumor, charring of tissues occurs, decreasing the conduction of heat. Only lesions of 3 cm or smaller can be ablated with confidence using available apparatuses, although modifications of the electrodes are underway to increase the size of the area that may be ablated. In addition, it is easier to assess areas of ablation during cryoablation, where the iceball generated appears unequivocally as a homogeneous, hypoechoic lesion on ultrasound.

At present, radiofrequency ablation must be regarded as investigational. Cryoablation allows ablation of larger lesions, has a longer track record, and is the ablative modality of choice with both open laparotomy and laparoscopic procedures. Radiofrequency ablation, on the other hand, is technically easier to perform percutaneously than is cryoablation. Comparisons of radiofrequency ablation with percutaneous cryoablation using safety and long-term effectiveness as outcome measures are urgently needed.

Regional Infusional Therapy

Rationale

Regional infusional chemotherapy is based on the vascular physiology of the liver: The portal vein provides most of the nutrient blood flow to the normal liver, while the major nutrient flow to hepatic metastases is through the hepatic artery.¹³⁸ HAI chemotherapy is therefore likely to be more toxic to the tumor than to the normal liver. When chemotherapeutic agents with short half lives and high hepatic extraction ratios are used, HAI concentrates such agents in the tumor and limits their appearance in the systemic circulation, maximizing the therapeutic effect while minimizing systemic side effects.

Agents

The agent most commonly used for regional treatment of hepatic colorectal metastases is FUDR. This agent is an analog of 5-FU that has a short circulating half-life and high liver uptake. Greater than 90% of FUDR delivered by HAI is extracted by the liver on the first pass, causing it to be concentrated in the liver 100- to 400-fold.¹³⁹ These characteristics make FUDR an attractive agent for regional infusional therapy and the subject of numerous trials in which it has been evaluted for treatment of unresectable hepatic metastases from colorectal cancer isolated to the liver.^140-143

Catheter Placement

Although percutaneous placement of hepatic arterial catheters can be performed under radiologic guidance,¹⁴⁴ the procedure is associated with a high complication rate. The long intra-arterial length of such percutaneous catheters may increase the risk of thrombogenesis when used for sustained therapy, while inadvertent perfusion of adjacent organs is an additional risk. Therefore, for prolonged hepatic regional chemotherapy, we favor delivery through surgically implanted catheters connected to subcutaneously implanted pumps. Catheters are implanted into a large branch of the hepatic artery, usually the gastroduodenal artery, while small arterial branches from the hepatic artery to the gastrointestinal tract are meticulously ligated, thereby limiting the misperfusion that is a major cause of morbidity. This method has been shown to be safe for administration of continuous infusion of the chemotherapeutic agent without the inconvenience of maintaining an external device.

Response and Survival

A 30% to 80% tumor response rate was reported in phase I and II trials of HAI performed in the early and mid-1980s,^140-142 and led to randomized trials comparing that modality with systemic therapy. Results from these randomized trials clearly demonstrated a significantly higher tumor response rate—42% to 62%—for HAI compared with systemic chemotherapy, which was associated with rates of 0% to 21%.^145-149 However, due to flaws in study design, only a single study has documented an increase in survival. In that study from the National Cancer Institute,¹⁴⁶ when patients with metastatic disease truly confined to the liver were considered, the two-year survival rate after intra-arterial chemotherapy was 47%, while systemic chemotherapy resulted in a survival rate of 13% (p=0.03).

Two other studies, one from Memorial Sloan-Kettering Cancer Center¹⁴⁵ and one from the Northern California Oncology Group,¹⁴⁷ have had sufficient numbers of patients to draw meaningful conclusions. In both studies, however, patients failing to respond to systemic chemotherapy were switched to HAI chemotherapy.^145,147 In these studies, because 60%¹⁴⁵ and 43%,¹⁴⁷ respectively, of patients randomized to systemic chemotherapy eventually received HAI, no meaningful comparison of survival between the two treatment groups could be performed.

A randomized, prospective study is now ongoing, coordinated by the Eastern Cooperative Oncology Group (ECOG), with no crossover in design that, it is hoped, will establish definitively whether HAI chemotherapy using FUDR will have an impact on survival.

Cost

The cost of placing a hepatic chemotherapy pump and ongoing follow-up for HAI is not insubstantial. In a retrospective study by the Meta-Analysis Group in Cancer, investigators examined the cost of HAI at the Henri Mondor Hospital in Paris and at the Stanford University Medical Center in Palo Alto, California.¹⁵⁰ The cost of HAI, including the initial pump placement and hospitalization was calculated to be $29,562 in Paris and $25,208 in Palo Alto. Added costs of HAI over conventional 5-FU-based chemotherapy were calculated to be $13,020 and $15,327, respectively, for the two sites.

The ongoing ECOG study has incorporated cost, quality of life, and cost-effectiveness analyses into the trial design. It is hoped that this prospective trial will answer many of the cost-effectiveness questions that retrospective studies could not address. Furthermore, how these costs will compare with costs of CPT-11 administration is unknown and awaits future studies.

Hepatic infusional therapy clearly provides an improved response rate compared with systemic chemotherapy. We are currently engaged in a phase I study examining the effects of combining the three most promising therapeutic strategies—namely cryoablation, intra-arterial infusional FUDR, and systemic CPT-11—for patients with unresectable colorectal metastases isolated to the liver who have previously been treated with systemic chemotherapy.

Isolated Liver Perfusion

Regional delivery of chemotherapy can also be achieved by isolated perfusion of the liver, and first attempts at achieving high local chemotherapeutic concentrations by such techniques date back to the 1950s.¹⁵¹ Isolation perfusion of the liver has most commonly been accomplished surgically by isolating the portal and arterial blood flow to the liver, as well as hepatic venous drainage from the liver. Venous bypass is performed to allow venous return from the splanchnic circulation and lower extremities to the heart. Perfusion of the liver is then performed through a catheter placed in the hepatic artery and/or by a catheter in the portal vein with venous drainage of the liver collected through a catheter placed in the retrohepatic vena cava. Alternatively, investigators are attempting to simplify isolated perfusions by using percutaneous balloon occlusion catheters.¹⁵²

Isolated perfusion is best when agents used are tumoricidal but highly toxic when administered systemically. Additionally, as such isolated perfusion can only be performed for a limited time, it would be advantageous to use a therapeutic agent that is not cell-cycle specific. These techniques are therefore being tested with cardiotoxic agents such as doxorubicin, and agents, such as tumor necrosis factor, that if leaked into the systemic circulation would cause cardiovascular collapse. Theoretically, isolated perfusion would be a particularly useful way to administer agents—such as the alkylating agent melphalan—with a steep dose-response curve, where a small increase in the intracellular concentration would result in significant improvements in tumor response. Melphalan is being tested in isolated perfusion for unresectable colorectal metastases.¹⁵³

Any role for isolated perfusion in the clinical treatment of patients with colorectal metastases is likely to be limited. The technical and resource demands of such perfusions, as well as the significant morbidity associated with this technique, will limit its use to highly specialized centers.

The drug with greatest proven efficacy for colorectal cancer is 5-FU. Since an analog of 5-FU—FUDR—is rapidly cleared by the liver, and prolonged administration of this medication can be given through an implantable infusion pump with tolerable levels of the drug in the systemic circulation, isolated perfusion is not necessary for delivery of therapy. Furthermore, as 5-FU is cell-cycle dependent, theoretically, it would be more attractive to administer the agent in a prolonged, continuous fashion.

Summary

Liver resection has been shown to be safe and is considered the only potentially curative treatment for metastatic colorectal cancer to the liver. Operative mortality is uniformly less than 5% at major centers, and the procedure results in five-year survival in over one-third of resected patients. Patients in good general health, with technically resectable metastatic disease limited to the liver, should be considered for resection. For unresectable disease, systemic or intra-arterial chemotherapy is standard. Cryosurgery is a promising ablative modality that will be comparatively assessed versus chemotherapy in future trials.

Dr. Fong is an Associate Attending Physician in the Hepatobiliary Service of the Department of Surgery at Memorial Sloan-Kettering Cancer Center, New York, NY.

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