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EDITORIALS |
Department of Surgery, Johns Hopkins University, Baltimore, Maryland.
Correspondence: Address correspondence to: Michael A. Choti, MD, Department of Surgery, Johns Hopkins University, 600 North Wolfe St., Halsted 614, Baltimore, MD 21287; Fax: 410-614-4667; E-mail: mchoti{at}welchlink.welch.jhu.edu
Hepatic resection has gained acceptance as the most effective therapy for patients with colorectal metastases confined to the liver. Long-term survival and potential for cure following surgical resection have been demonstrated in numerous studies, and clear trends in improved long-term outcome have been seen.1 As hepatic resections have become safer and indications have broadened, it is becoming increasingly important to identify criteria to accurately predict which patients will derive the greatest survival benefit from surgical therapy. Clinical prognostic factors, including number of hepatic metastases, resection margin status, disease-free interval between resection of primary and detection of metastatic tumors, and CEA level, among others, are commonly used to stratify risk for recurrence following liver resection. Nonetheless, in certain populations of patients, early recurrence, resistance to chemotherapy, and decreased survival will occur and cannot be predicted by means of these common clinical pathologic criteria. Currently there are no biomolecular markers in colorectal cancer that are routinely used in clinical practice,2 but the desire to identify tumor markers remains a worthy one.
In this issue of the Annals of Surgical Oncology, Smith et al.3 analyze two immunohistochemical tumor markers, Ki-67 and human telomerase reverse transcriptase (hTERT), for their impact on prognosis for patients following R0 resection of hepatic colorectal metastases. The authors retrospectively analyze 66 patients classified into three groups by survival time. Tumor paraffin blocks were immunohistochemically stained and analyzed by comparison of positive staining with survival. Thirty-six percent of tumors stained positive for Ki-67, and 34% were positive for hTERT. They found that both of these markers predicted poor long-term survival better than a prognosis score based on clinical factors.
Identification of useful biologic and molecular markers for the prediction of recurrence and survival among patients with colorectal cancer has been an elusive objective for many years. Histologic markers such as degree of differentiation and DNA ploidy have been shown to predict those with more aggressive disease. Molecular markers that reflect specific genetic defects have also been studied, primarily in patients following resection of primary colorectal cancer. Tumor suppressor genes, including DCC, SMAD4, and SMAD2, have been evaluated as well as K-ras and p53. Although none of these molecular markers have been successfully applied to the clinical setting, the search for new biologic markers for assessing prognosis is of vital importance.
It is not so surprising that elevated expression of these biomarkers was seen in patients with poor outcomes. It would not be unexpected for patients with poor prognosis to have tumors associated with high expression of the proliferation marker Ki-67. As the authors discuss, telomerase activation is thought to be a critical step in cellular immortalization and carcinogenesis. Of the three major subunits that compose human telomerase, the human telomerase catalytic subunit HTRT has been shown to be a weight-limiting determinant of the enzymatic activity of human telomerase.
In this article, the authors conclude that telomerase activity more than proliferation activity correlates with survival, and both are superior to the clinical prognostic scoring index. One must keep in mind, however, that it is difficult to draw conclusions on the basis of such a small number of patients. Numerous studies have identified many of these clinical parameters to be of prognostic relevance. In addition, the retrospective nature of the study and its unconventional statistical methodology, using discretized survival categories rather than actuarial survival data, limit the ability to draw sound conclusions from it. Moreover, the majority of patients in this study had a clinical prognostic score of 2 or less, different from that seen in other, larger series of patients undergoing liver resection for colorectal metastases.
One interesting observation is that only approximately one third of patients had positive stains for these markers. Other reports have suggested that in the majority of cases of colorectal cancer, particularly those of advanced disease, the tumors express Ki-67 positivity.4 On the basis of these findings, it is possible that such a group of patients in general has a better prognosis than unresectable patients with stage 4 disease. Further studies correlating these biomarkers with resectability and prognosis would be informative. Another concern is the impact of preoperative chemotherapy on expression of these biological markers. Certainly, many of these patients received various types of systemic chemotherapy in varying intervals from the time of liver resection. It is very possible that the use of chemotherapy likely impacts marker expression as well as prognosis.5
What steps are necessary to speed the progress toward identifying clinically useful biologic markers for prognosis? Clearly, in large therapeutic trials, careful consideration needs to be given to mandating tissue collection in order to eliminate the potential bias introduced by subset analyses. Evaluation of markers needs to be considered at the design stage of the trial for patients carefully stratified for known clinical prognostic factors.
New methods of locoregional therapy for liver metastases are being used with increasing frequency, including tumor ablation, intraarterial embolization, and radiation. Although they are perhaps promising, the impact on survival of many of these approaches remains unknown. Comparison of these new techniques with the "gold standard," surgical resection, and determination of potential benefit of these methods when combined with newer chemotherapeutic regimens deserve further evaluation in well-designed clinical trials. Stratification into clear prognostic groups is critically important, whether it be by clinical parameters or relevant biologic markers. This study is interesting not so much for its impact on clinical practice but because it generates testable hypotheses. Future validation of the prognostic significance of these findings must be done in the context of known prognostic factors and how they impact more rational use of therapy.
Received for publication November 11, 2003. Accepted for publication November 12, 2003.
REFERENCES
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