Wayne H. Schwesinger, MD

[Medscape Surgery, 2001. © 2001 Medscape, Inc.]

While considerable progress has been made in our understanding of the molecular mechanisms of tumor spread,^[1] clinical outcomes have improved more slowly. Thus, metastases to the liver continue to account for much of the morbidity and nearly all of the mortality in patients with gastrointestinal malignancies. In particular, the presence of hepatic metastases is still associated with an average median survival of only 3 years.^[2] Hepatic metastases are already evident in at least 25% of all patients with colorectal cancer during the index hospitalization.

Until now, few reasonable options have been available to patients with metastatic involvement of the liver. Even though resection of all metastatic disease offers the best chance of cure (25% to 45%), its effectiveness is often limited by the heavy tumor burden, the presence of multiple metastatic sites (> 3), bilobar disease, or the need for blood transfusions during resection.^[3]

New therapeutic modalities are being investigated to help manage these difficult cases. An expert panel of 5 surgical oncologists^[4] reported their personal experiences with several innovations in the management of hepatic metastatic disease at the 86th Annual Clinical Congress of the American College of Surgeons.

Florencia G. Que, MD, Mayo Clinic, Rochester, Minnesota, examined the unique role of cytoreductive surgery in patients with liver metastases from neuroendocrine tumors. The following rationale for this generally noncurative operative approach was noted:

• Neuroendocrine tumors often have a protracted natural history.
• Tumor growth tends to be expansile.
• The severity of the associated symptomatic endocrinopathy appears to correlate with the tumor burden.
• Neuroendocrine tumors may be at least partially responsive to chemotherapeutic agents such as somatostatin.

Dr. Que reviewed the clinical outcomes of cytoreductive surgery as initially reported by the Mayo Clinic in 1995.^[5] In this study, 74 patients with metastatic neuroendocrine tumors were treated with hepatic resection. The mean age of the group was 55 years, and there were 46 women and 28 men. The excised tumors were histologically classified as carcinoid (50), islet-cell (23), or atypical (1). Sixty-nine patients had initially presented with symptomatic endocrinopathy. They were selected for hepatic resection only if the primary tumor had already been, or could be, totally resected and all metastatic disease was predominantly located in the liver.

There were 36 hemihepatectomies or extended hepatectomies and 38 nonanatomic resections performed; the procedures were performed for curative intent in 28 patients and for palliation in 46 patients. Two deaths occurred in the perioperative period (2.7%) and 18 major complications were reported (24%). Complete relief of symptoms was initially obtained in 90% of the symptomatic patients. However, symptomatic endocrinopathy recurred within 3 years in two thirds of cases. Overall, 74% of patients were still alive at 4 years. It is interesting that no differences were noted in the survival curves based on operative intent (curative vs palliative) or histologic type (carcinoid vs islet-cell).

An unpublished update of this unique experience was also summarized by Dr. Que. The total cohort now includes 170 patients who are demographically and histologically indistinguishable from the initial group. Fifty percent of the patients in this new and larger database have survived at least 6 years. Nonetheless, after 12 years, resected tumors have recurred or progressed in more than 90% of the affected patients, regardless of whether the intent of the original operation was cure or palliation.

Dr. Que concludes that hepatic resection appears to be safe and reasonably effective when used in patients with metastatic neuroendocrine tumors. Applied selectively, this approach can markedly improve quality of life by controlling often-incapacitating symptoms. It also probably prolongs overall survival.

Adequate resection is not always possible: metastatic disease may be too widespread or individual patients may be too sick. In such cases, several nonresective strategies are available. Cryoablation and radiofrequency ablation (RFA) can be used either as primary therapeutic modalities in lieu of resection (see below) or as adjuncts to resection, especially when multifocal disease is present. Chemical ablation is an inexpensive alternative that can be performed by injecting a 95% alcohol solution directly into the soft, spongy tumor. All these methods can be administered intraoperatively or percutaneously, and all are relatively effective at destroying smaller deposits of tumor.

The most invasive approach to metastatic tumors is liver transplantation. It has been suggested that neuroendocrine metastases may be especially amenable to this approach, since they are slow-growing and often remain limited to the liver. A recent compilation of international reports provided an analysis of 103 patients with neuroendocrine carcinomas who had undergone hepatic transplantation.^[6] Overall survival was 47% at 5 years, but one half of the survivors had already developed recurrent disease in this time period. On multivariate analysis, the outcome was adversely affected by age (> 50 years) or the addition of extended operations to transplantation (a Whipple procedure or an upper abdominal exenteration). These data suggest a possible role for hepatic transplantation in young patients with symptomatic neuroendocrine disease and otherwise favorable prognostic factors. Nonetheless, several experts have advised caution because of the limited number of hepatic donors and the availability of other ablative measures.^[7]

Pivotal randomized trials with antimelanoma vaccines are now underway. Clinical testing of vaccines for other tumor types is also progressing, albeit more slowly. Anton J. Bilchik, MD, PhD, John Wayne Cancer Institute, Santa Monica, California, surveyed the experience at his institution with vaccines for advanced colon cancer and also reviewed the work of other centers in this somewhat controversial area.

He began by noting that chemotherapy, the mainstay of treatment for stage IV colorectal cancer, results in response rates of only 10% to 30%. An anti-idiotypic carcinoembryonic antigen vaccine has shown a similar response with less toxicity.^[8]

A somewhat different approach based on the use of autologous vaccines (prepared from the patient's own tumor cells and modified with bacillus Calmette-Guérin vaccine) has been shown in at least 1 study to increase tumor-free survival in subjects with stage II colon cancer when compared with resection alone.^[9] However, the use of autologous vaccines is often impeded by difficulties encountered in harvesting and preparing adequate tumor cells.

Allogeneic vaccines (prepared from tissue culture lines) can avoid these limitations since these vaccines are generic and contain multiple immunogenic antigens. The most extensively studied of the allogeneic vaccines, CancerVax, was developed at John Wayne Cancer Institute from 3 melanoma cell lines and includes at least 11 tumor-associated antigens. When combined with resection in patients with stage IV melanoma, it has resulted in a substantial 5-year survival advantage compared with resection alone (36% vs 17%).^[10] Moreover, in the subset of patients who display a significant immune response to the vaccine, the 5-year survival is increased to 75%. The intriguing possibility that this same allogeneic vaccine may be effective when used in patients with colon cancer is suggested by the observation that many antigens present in colon cancer cell lines are also present in CancerVax. The most notable of these includes several of the gangliosides, Lewis antigens, and melanoma antigen.

Clinical experience with the use of CancerVax for patients with colorectal cancer began in 1991. Dr. Bilchik reported that in the ensuing 9 years, 27 patients with stage IV tumors were enrolled in a protocol similar to that used for the treatment of melanoma. Ninety percent of the patients had already failed systemic therapy; many subsequently underwent cytoreduction of gross metastatic colorectal tumors with resection and/or cryotherapy or RFA. When vaccine therapy was begun, 15 patients had no visible residual tumor, while 12 still had obvious synchronous metastases.

On multivariate analysis, the only factor that predicted improved survival was a vigorous posttreatment antibody response to tumor antigens. Thus, patients who responded to the antigen TA-90 exhibited a median survival of 29 months, while nonresponders had a median survival of only 14 months. Similarly, responders to the cell surface gangliosides GM2, GD1B, and GT1B had a longer median survival than nonresponders (32 months vs 15 months.) The mechanisms of these effects are unknown. However, it has been observed that gangliosides shed from the cell surface may be immunosuppressive, and their clearance from the circulation by the action of immunoglobulin M antibodies could potentially reverse this immunosuppressive effect.

It was concluded that many patients with advanced colon cancer are capable of developing an immune response when exposed to CancerVax, and that the response is specific to tumor cells and correlates with an improvement in overall survival. Few side effects are noted; most are mild and localized to the vaccine site.

Surgery is the only treatment modality that offers an opportunity for actual cure of liver metastases. Unfortunately, many patients are already unresectable when initially diagnosed. Lawrence D. Wagman, MD, City of Hope National Medical Center, Duarte, California, proposed that neoadjuvant chemotherapy can "downsize" some metastatic deposits and should be considered for use in this "unresectable" group because:

• Colorectal cancer may respond to such a chemotherapy protocol.
• The liver is the sole site of metastases in half the cases.
• Long-term survival can be achieved after resection, even if multiple metastases are present.

It was acknowledged that patient selection may be problematic, since no single definition of "unresectable" liver disease has been universally accepted. Moreover, the choice of drugs is also expanding. Since the time-tested standards 5-fluorouracil (5-FU) and leucovorin have shown only modest effectiveness, they are now being combined with newer agents such as oxaliplatin and irinotecan (CPT-11) for their synergistic effects. Additionally, different routes and methods of administration are being evaluated. In particular, systemic venous infusion and hepatic arterial infusion are being compared with chronomodulated infusion administered at specific times each day. This latter method is based on the observation that both the proliferative activity of tumor cells and the metabolism of chemotherapeutic drugs are subject to circadian rhythms.

The reported experience with neoadjuvant therapy for metastatic liver disease is gradually expanding. However, currently available trials are nonrandomized and only marginally comparable. A partially mechanical approach was advocated in one French study, in which preoperative portal vein embolization (PVE) was performed to induce a compensatory hypertrophy of normal liver tissue in patients considered ineligible for resection. In 19 of 30 patients (63%), hypertrophy of the hepatic remnant after PVE was sufficient to allow hepatectomy.^[11] Prior to PVE, all patients had received chronomodulated chemotherapy consisting of 5-FU, folinic acid, and oxaliplatin. There was 1 postoperative death, and the actuarial survival rates were 81%, 67%, and 40% at 1, 3, and 5 years, respectively. These rates are comparable with those for primary liver resection.

In another highly selective study from France, 53 of 330 (16%) patients who initially had unresectable colorectal metastases were downstaged after receiving chronomodulated systemic chemotherapy.^[12] A variety of hepatic resections were subsequently performed without a mortality, and again produced a 5-year survival of 40%. In 15 of these cases, further recurrences were amenable to repeat hepatectomy.

A similar experience was reported from the University of Texas MD Anderson Cancer Center.^[13] Hepatic artery infusion therapy was used in 383 patients with unresectable liver metastases, resulting in sufficient downstaging of tumors to allow exploratory surgery in 22 patients (6%). Ultimately, 10 patients underwent resection, 6 had resection with RFA or cryoablation, and 2 underwent RFA only. Fifteen of the 18 treated patients (83%) developed recurrence within a median follow-up of 17 months, and the other 3 died of other causes.

Based on these and other studies, Dr. Wagman concluded that most patients who are initially categorized as unresectable will remain so even after aggressive neoadjuvant therapy. However, some patients may be downstaged to allow resection and some of these may experience long-term survival. Studies to clarify the appropriate predictors and identify more effective neoadjuvant regimens are still needed.

Because of the unique anatomy of the liver, vascular isolation and regional perfusion can be reliably achieved. Regional perfusion has the advantage of allowing marked escalation of chemotherapeutic dosages while minimizing systemic exposure and toxicity. However, the efficacy and safety of this approach remain to be established.

H. Richard Alexander, Jr, MD, National Cancer Institute, Bethesda, Maryland, described the use of one standardized method for isolated hepatic perfusion and discussed some of the preliminary results.^[14] The entire procedure was performed in an operating room using an extracorporeal perfusion circuit to infuse blood into the liver via the hepatic artery. An external veno-veno bypass was simultaneously used to return blood from the infrahepatic vena cava and portal vein to the heart. The system was continuously monitored for intraoperative leaks.

This system, first introduced 4 decades ago, is labor- and facility-intensive. Operating room time averaged more than 8 hours, and individual blood losses ranged from 500 cc to 6000 cc. In addition, the median hospital stay was 12 days, and one third of this time was spent in the intensive care unit.

Still, isolated hepatic perfusion has a number of potential advantages over other local therapies. Notably, it is uniquely capable of treating numerous and bulky hepatic lesions (> 5 cm) because therapy is delivered to the entire organ at risk. Dr. Alexander and colleagues recently reported the outcomes of this regimen in 50 patients who presented with a variety of primary and metastatic liver lesions, mostly of colorectal origin. All patients underwent 60-minute hyperthermic perfusions with a solution containing tumor necrosis factor and melphalan. The overall response rate in the 48 evaluable patients was 75%, with a median time to recurrence of 6 months. One patient (2%) exhibited a complete response but, after 14 months, developed systemic and hepatic recurrences. Hepatic toxicity of grade 3 or higher was noted in 76% of patients but was completely reversible in most. However, 2 patients failed to improve and ultimately died of liver failure. Studies are continuing to determine the role of isolated perfusion and to define the most useful agents and the most effective methods.

In contrast to isolated perfusion, the purpose of local ablative therapies is to target individual hepatic lesions while sparing most of the surrounding normal liver. Until recently, the most common form of localized therapy was cryosurgical ablation (CSA), which destroys targeted tissue with 1 or more rapid freeze-thaw cycles. However, its acceptance has been somewhat impeded by a relatively high complication rate.

Lee Ellis, MD, MD Anderson Cancer Center, Houston, Texas, reported on the increasing use of RFA as an arguably safer alternative. This software-driven technique employs a special generator to produce high-frequency alternating current with consequent ionic agitation, frictional heat, and cell death. A number of different probe arrays are now available, and several therapeutic approaches can be used. Currently, percutaneous, laparoscopic, and open methods are all described. Typically, the RFA probe is inserted into the tumor, internal tines are deployed, and the appropriate current is applied. Cellular protein denatures as the temperature of the affected tissue reaches 45^o C. Real-time ultrasound is used to assure accurate positioning and to confirm evolving tissue destruction.

The few available clinical studies are nonrandomized and retrospective. In one large study from the John Wayne Cancer Institute, CSA and RFA were compared in the management of a variety of unresectable malignant tumors of the liver.^[15] The median follow-up was 12 months. The length of hospital stay, average blood loss, and complication rates were significantly greater for patients treated with CSA; however, the local recurrence rates for lesions initially larger than 3 cm were higher following RFA (38% vs 17%).

Dr. Ellis reviewed the experience at the University of Texas MD Anderson Cancer Center, where 123 patients with assorted hepatic malignancies were treated with RFA either percutaneously (25%) or intraoperatively (75%).^[16] The complication rate and local recurrence rate were low (both 2%), but metastatic disease developed at other sites in 34 patients. It was concluded that RFA is a safe and relatively effective procedure, but adjunctive chemotherapy with hepatic artery or systemic venous infusions may be necessary to inhibit the development of new metastatic disease. Moreover, metastatic lesions measuring 4 cm or more are difficult to ablate, and multiple overlapping ablations or larger RFA arrays may be necessary.

The current management of metastatic tumor in the liver is generally inadequate, and mortality rates remain high. Fortunately, newer techniques for controlling metastases are beginning to show promise. In particular, neoadjuvant chemotherapy, cancer vaccines, and liver perfusion can be used selectively to reduce total intrahepatic tumor burden and, in some cases, allow definitive resection. Alternatively, radiofrequency ablation is now available to control tumor deposits in high-risk patients who would not tolerate or benefit from resection. For the moment, these various approaches (and others) are still preliminary, and each will require further study and additional critical review.

Wayne H. Schwesinger, MD, Professor of Surgery and Head of General Surgery Section, Department of Surgery, University of Texas Health Science Center; Director of Surgical Endoscopy, Department of Surgery, University Health System, San Antonio, Texas