Overview and Future Prospects

Overview and Future Prospects


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The editors of this issue have chosen a clinician rather than a scientist to summarize, editorialize, and predict the future. That choice profoundly affects the nature of these comments. Understanding tumor biology, reducing tumor load, and increasing comfortable days at home for one's current patient are all most commendable goals. However, they may conflict with one another as choices for therapy are made. This article represents an attempt to put into perspective the previously presented aspects of currently available surgical therapy in order to guide a clinician charged, in 1996, with managing a patient with either primary or metastatic liver malignancy. What might be of help in the future, but whose value at present remains unclear, is discussed in a few final paragraphs under the heading of "Future Prospects." ROLE OF RESECTION

The role of resection for both primary and secondary liver tumors has been relatively well defined in the past two decades (see articles elsewhere in this issue). Techniques for both the recognition and safe resection of limited tumor deposits have been perfected so that operative mortality for major liver resection approaches that of elective gastric resection in centers of experience. Rates for longterm survival are well documented, and some patients are undoubtedly permanently rid of their cancers after removal of visible disease. A few caveats are warranted, however. First, the fact that patients who survive 5 years after resection of both primary and metastatic tumors continue to die after the 5-year mark suggests that tumor biology (natural history) and thus patient selection may play important roles in favorable cases. Second, although remarkably consistent when studied carefully, the reported long-term survival figures and their interpretation, particularly the therapeutic From the Department of Surgery, University of Connecticut School of Medicine, Farmington, Connecticut THE SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 5 . NUMBER 2 APRIL 1996




implications drawn therefrom, vary widely with statistical techniques and the enthusiasm of the authors. When the hard numbers of actual survival of welldocumented patients for 5 years after liver resection for cancer are reviewed (rather than calculated statistical projections), more realistic judgments can be made. For example, Bismuth et a1 (pp 353-364 of this issue) claim 44% 5-year survival after 55 repeat liver resections of colorectal metastases, yet 49 of those resections were performed less than 5 years ago, and no data are provided for actual survival, even for 1 or 3 years. Similarly, in another collected report of 170 cases of re-resection, 5-year survival rate is projected to be 32%, but there is no documentation of a single patient who actually survived 5 years (see reference 51 in the article by Kavolius et a1 in this issue; pp 337-352). We are indebted to the several registries organized to pool retrospective data from multiple institutions for a clearer look. Five-year rates survival after the first liver resection for colorectal cancer are variously claimed to be from 25% to 40%. The registry set u p by Hughes et a1 has data on 901 patients, 712 of whom had follow-up until death or for at least 5 years after liver resection. One hundred seventy-six of those 712 patients were alive at 5 years, 44 of whom had documented recurrence before the 5-year mark and an additional 20 of whom developed recurrence after 5 years (KS Hughes and K Leslie, personal communication, 1995). From this most venerable and complete data pool of colorectal statistics, one might calculate that the surgeon's ability to permanently rid the patient of metastatic colorectal cancer by a liver resection is 112/712 or 15.7%.I will be most grateful when some bright young person explains to me why the survival by Kaplan-Meier projection is always so much better than what actually happens to real patients. Another example deserving our careful attention is the remarkably long-term survival after transplantation for primary liver cancer tabulated so nicely by Nagorney and Gigot elsewhere in this issue. Careful review of the primary sources reveals that many, if not most, of the long-term survivors had histologic cancer found incidentally or coincidentally in their livers, which were replaced because of benign diffuse liver disease. A clinician helping a patient with a clinical liver cancer to weigh the risks and benefits of transplantation would be better served by a subset of those overall data. I believe that one could fairly conclude after 20 to 30 years of well-reported worldwide experience that the chances of a well-selected patient actually surviving free of disease for more than 5 years after liver resection would be less than 20% for metastatic colorectal cancer and less than 30% for primary cancer. These figures are less than we might have hoped but are more than we might have believed possible setting out on this experience. The place of resection today must then be decided after we look at the other available options. TECHNICAL ADVANCES

That primary and metastatic tumor deposits in the liver have been supplied largely by the hepatic artery rather than the portal vein has been known for decades. However, tumor reduction by artery ligation, even by heroic attempts at total liver dearterialization, has proved discouragingly transient. Regional intraarterial chemoperfusion also has been used for more than 30 years. Recent technical advances have allowed more direct tumor embolization and more prolonged tumor perfusion. Yet even in combination, these imaginative (and expensive) methods have not produced any clear-cut survival advantage. Increased "response rates" have unhappily not translated into increased comfortable days at home. One must credit the ingenuities of the techniques used but admire even more the



remarkable abilities of the growing cancer cell to induce growth of needed blood supply and to avoid the nicely crafted antitumor strategies of some thoughtful scientists. We also must admit reluctantly that the chemotherapeutic drugs currently available for primary liver cancer and for most of the common solid tumors that metastasize to the liver are quite ineffective, whether used regionally or systemically. Currently, any positive effects are often negated by their tremendous cost in toxicity, in dollars, and in the distress caused by frequent treatment visits. A few quotes from the foregoing chapters may help to solidify these somewhat negative evaluations: ". . . a meta-analysis of more than 1300 patients treated with 5-FU-based systemic chemotherapies as well as a recent randomized phase I1 review serve as a sobering reminder of the lack of efficacy for such systemic treatments" (Venook). "Four large prospective randomized trials comparing systemic fluorpyrimidine chemotherapy versus hepatic intra-arterial (HIA) FUDR via the implanted pump . . . . demonstrated superior response activity in the HIA arm compared with the systemic treatment group. However, the apparent superiority of HIA response did not translate into a survival benefit" (Venook). "In the only prospective, randomized study to date combining chemotherapy and embolization of hepatocellular carcinomas (cisplatin and gelatin sponge) and comparing the combination to no chemotherapy or embolization, there was no clinical benefit to the regional therapy" (August). Currently, attempts at regional perfusion, with or without liver isolation and concurrent embolization, should probably be limited to protocol studies, preferably ones with control patients receiving supportive therapy alone. This writer believes that research dollars will be much more effectively spent on understanding the nature of the neoplastic and metastatic processes and the hosts' reaction to them than on the ad infiniturn manipulation, combination, and recombination of dosage and delivery schemes for agents and techniques of well-established ineffectiveness. OTHER OPTIONS

What else do we have to offer our patients? In situ tumor ablation with freezing probes or direct injections of ethyl alcohol-techniques pioneered decades ago in China for primary cancer-are in vogue today as safer alternatives to resection in patients with decreased liver function reserve or in patients with tumor bulk or geography that might increase the risk of resection. Ravikumar (pp 365-377 in this issue) reports early experience with laparoscopic cryosurgery and with laser ablation, but not enough clinical experience has yet accumulated to either recommend or discourage the use of these complex technologies. Although articles by Zhou and colleagues (pp 379-390), and Morris and Ross (pp 391-397) nicely document that tumor size may be reduced by cryosurgery, adequately controlled reports on randomized studies have yet to appear. That tumor reduction probably does not translate into increased survival is disappointing but not surprising. Debulking has failed in most other settings, with the possible exception of cancer of the ovary. "Cytoreduction" by radiation or other local treatments or by systemic drug therapy as a technique to allow a subsequent resection also has proven ineffective. However, Zhou et a1 (pp 379-390 of this issue) provide an outstanding exception. These Chinese authors report 66% 5-year survival rate in 71 patients after resection of primary liver cancers initially believed to be unresectable. Cytoreduction by multimodal anticancer treatments allowed eventual resection after an interval of about 6 months. There are no data provided about the number of patients undergoing attempts at cytoreduction from which these fortunate 71 were chosen for resection. A Japanese report has claimed 80% 3-year survival rate in



patients with primary liver cancer treated with a combination of chemoembolization and ethanol injection (see reference 20 in the article of Ravikumar, p 377). If others can repeat and thus confirm these most unusual results, a more optimistic and aggressive approach may be warranted. Finally, the absolute limit in aggressive local therapy for liver tumor is provided by total hepatectomy and transplantation. That this extraordinary operation is so often unsuccessful in controlling cancer testifies either to the systemic nature of the disease or to the importance of immunocompetence in controlling neoplasia. Each such experience constitutes an important experiment in understanding the neoplastic process and should be viewed as a tremendous research opportunity.


Are there encouraging developments to put up against this list of often ineffective treatments? Yes, to be sure. Our abilities to image and to safely resect liver tumors have increased markedly in the last decade. The use of intraoperative ultrasound after conventional incision or even through a laparoscope has added to our diagnostic skills. However, older surgeons cannot help but wonder whether too much dependence on such technology does not result in some atrophy of the surgeon's traditional expertise in palpation and observation. The numerator of moderate technical advance can be made much more impressive by a denominator of clinical ineptitude. The pooling of retrospective data and cooperative multi-institution clinical trials has allowed both negative and positive information and experience to mature more rapidly. Some pediatric liver tumors have responded well to chemotherapy, often allowing effective combination with resection, thus perhaps providing a model for adult tumors in the future. And finally, careful documentation has shown us that for both metastatic and primary cancers of the liver, there are clinical variants with a wide range of rate of growth. Some fortunate patients can coexist with their tumors for many years before deterioration sets in, even with no treatment. These data reinforce the importance of concurrent control patients in any prospective trial.


What can we conclude from the encyclopedic review of current therapy outlined in the previous articles? What then, should we recommend to a patient with a malignant tumor of the liver in 1996? A dispassionate scientist might quite rationally conclude that nothing should be offered outside of a research protocol except to those few patients with limited disease, excellent liver function, and performance status who also have tumor geography conducive to safe ablation by an experienced team. Alas, the problems presented by clinical medicine cannot be so simply defined or solved. After stating some general principles underlying my own opinions, I will attempt some recommendations for treatment off protocol. Because so many questions remain unanswered and because few therapies have clear superiority, protocol trials are important. Understanding patients should be urged to participate. These few nonscientific concepts may aid the clinician in advising his or her patient about active treatment for liver cancer. These thoughts reflect considerable personal bias nurtured during a long referral practice of admittedly selected patients:



(1) Asymptomatic patients cannot be palliated (Hoerr's Law). (2) The units of useful survival are comfortable days at home. (3) Frequent, careful documentation of tumor size is important in assessing experimental therapy on protocol. Such documentation is often excessive off protocol. In most instances, the negative effect of repetitive tests and procedures exceeds the positive. They reduce the store of good days left by focusing the patient's attention on the disease, by increasing discomfort, and by reducing monies. (4) If the algebraic sum of overall survival is unchanged by a specific treatment, the positive effect seen in some patients must be balanced by a negative effect in others. (5) In 1996, no treatment except resection affords patients with most primary and secondary cancers any chance at permanent cure. (6) The emotional tyranny of the sword of cancer hanging over their heads can be more effectively reduced for most patients, even for the great majority who eventually die of their disease, by a single dramatic, although traumatic, treatment (i.e., resection) that carries a chance of cure rather than by frequent, repetitive, disease-reminding, often malaise-producing, visits for treatments that, at best, offer only palliation.

This concept brings us to the most unscientific concept of all, the matter of hope. Hope motivates patients to seek help and it motivates physicians to use active therapies even when such therapies are known to be ineffective in most cases. Our propensity toward active treatment is aggravated by a referral tradition for patients with advanced cancer that transfers management responsibility from a surgeon who knows the patient well to a specialist who knows much about the tumor and little about the patient. After full discussion of treatment alternatives with an unrushed and knowledgeable clinician, many asymptomatic patients with unresectable disease choose to decline active treatment until discomfort occurs. Hope for cure can be replaced successfully by hope for comfort if trust is not lost. Such trust can be based only on working closely with the primary physician, knowing the patient well, being knowledgeable and scrupulously honest about the range and effectiveness of current therapies, and taking sufficient time to talk to and listen to the patient.


Isolated deposits of primary liver cancer and metastatic colorectal cancer found in the otherwise normal liver of a fit patient should be resected by an experienced team. Limited metastatic disease from other primary sources, particularly from those outside of the gastrointestinal tract, should be resected only when there are unusual extenuating circumstances (e.g., a young patient with a long primary-to-liver interval) and a full understanding of the unlikely benefit. The guidelines off protocol should be different for patients with and without symptoms. Asymptomatic patients with cirrhosis and a small primary cancer found by imaging or alpha-fetoprotein testing should be offered resection if their liver function is good. If borderline, it is often best to delay treatment decisions for a few months to observe progression of both the tumor and the chronic liver disease. Despite Nagorney and Gigot's impressive data, I am still not convinced that Western patients with cirrhosis do as well as their Eastern counterparts after liver resection for primary cancer. Currently available chemotherapy should not be recommended, either systemically or regionally, to asymptomatic patients with primary or metastatic cancer off protocol.



What should be recommended to the patient who presents with symptoms directly attributable to malignant tumor in the liver? Fortunately, symptoms come late to most patients with liver cancer. The interval between discomfort and death is often short. A small number of patients with symptomatic cancer occurring in a normal liver may still be candidates for resection. Other patients may derive transient benefit from local measures such as cryosurgery or alcohol injection. A short trial of systemic chemotherapy identifies the fortunate few who have responsive tumors. Higher doses and sequential agents usually add to, rather than subtract from, the misery of patients with resistant tumors. Many patients at this point should be treated with supportive care alone or be strongly urged to participate in control trials. FUTURE PROSPECTS

To forecast the future in this day of rapidly changing science and technology is foolish. but such is mv charge. With more ovtimism than exhibited heretofore. I shall speculate on the hirectivons that future t'herapy will take. For patients with metastatic cancer in the liver, I predict that the advent of effective cytotoxic chemotherapy or immunomodulation will eliminate the necessity for primary local attacks on metastatic liver deposits. Secondary resection may still be useful for residual islands of mature tumor cells remaining after successful drug ablation of the more anaplastic clones. Biologic modifiers of neovascularity, wound healing, and other features of the process of metastasis will also probably be used systemically. As detection continues to improve and new agents bring greater effectiveness with reduced toxicity, multimodal treatment off protocol of asymptomatic patients with metastatic cancer in the liver may become justified (if cost constraints permit). The possibilities for patients with primary liver cancer are even brighter. Epidemiologic studies have documented, perhaps more clearly than with any other tumor, the association of liver cancer with chronic Liver injury due to viral infection, alcohol abuse, hemochromatosis, and so forth. Several important questions remain unanswered about the fundamental nature of liver injury, such as, why do most heavy users of alcohol never develop cirrhosis? Clinical and experimental evidence also has suggested associations of benign and malignant neoplasia with changes in diet and the sex hormone milieu. The combination of hyperplasia and hypertrophy that we call regeneration is capable of restoring lost volumes of functioning liver tissue. Somehow, remarkably, the regenerating liver can sense not only when to start this process but also when to stop. Is this unique phenomenon related to neoplastic change? Can it be manipulated and regulated to prevent or control cancer? When we better understand the nature of chronic liver injury and repair, we may be close to controlling the incidence of liver cancer. Currently, such measures as immunization against hepatitis, better sanitation and hygiene, and moderation in alcohol consumption probably prevent more cancer than doctors can hope to cure. The last two decades of earlier detection and more aggressive attacks on established liver cancer have shown us that the disease is often quite slow growing. Remember, too, that autopsy studies have shown that that 50% of patients who die of liver cancer do not have disease beyond Glisson's capsule. If we can develop sensitive and specific markers for early liver cancer in patients without cirrhosis, I suspect that resection will remain the mainstay of treatment in this select group. Currently, screening with alpha-fetoprotein of populations at high risk due to chronic hepatitis has uncovered occasional patients with resectable tumors, but long-term cure is unusual, probably due to persistence of those factors promoting



cancer in patients with injured livers resulting in multifocal change. Systemic therapy to control cancer in those persons with chronic diffuse liver injury may, in the future, prove to be more effective, less costly, and more humane than heroic and gymnastic attempts at tumor reduction by major resection or transplantation. In the future, manipulation of the hormonal milieu or of wound healing factors may play a more important role than cytotoxic chemotherapy, at least until we have better tumorocidal agents at hand. For this reader, the article by Panis et a1 on gene therapy (pp 461-473 of this issue) was the most interesting and exciting in this issue. It should be read carefully by those interested in the remainder of this issue, even by those with little current knowledge of molecular biology. Tumor response in animals has already been achieved for metastatic colorectal cancer and primary liver cancer by gene manipulation of the host immune response or by transfer of "suicide genes" or tumor suppressor genes such as p53. The remarkable number of already conceived and attempted strategies and the almost limitless possibilities for future innovation, as our knowledge of tumor biology and resistance unfolds, bring excitement and hope to those of us who have labored so long using treatments with limited effectiveness. As we understand and then better manipulate the neoplastic process, the role of the future surgeon should evolve. Primary resection may give way to secondary debridement of residual clones after initial cytoreduction by systemic therapy. Surgeons may inject genes more often than poisons directly into tumors or into the liver blood vessels. In cooperation with invasive radiologists, they may perfuse with biologic modifiers more often than they embolize or ligate for tumor infarction. Laparoscopy will complement radiology in diagnosis by finding surface lesions not visible by imaging. Surgeons may even be asked to perform partial resections of normal liver tissue in order to enhance gene uptake in residual hepatocytes excited by an urge to regenerate. Finally, total hepatectomy and transplantation will probably play an increasing role for malignant disease as we better control systemic disease and as we find that we must destroy normal liver to eradicate liver cancer. Although our current efforts are ineffective for most patients, remarkable progress has been made in recent decades in earlier detection of liver cancer and in our understanding of its incidence and epidemiology. That the liver is so prone to neoplasia, that it has unique properties in regard to both injury and repair, that it has a dual vascular inflow, and that it is a wholly resectable and transplantable organ provide together some magnificent research opportunities for the future. Some optimism is justified for the eventual prevention and cure of these common and too often lethal diseases. Address reprint requests to James H. Foster, MD 435 Waterville Road Avon, CT 06001