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Commentary on Prognostic Factors in Renal Cell Carcinoma
0022-5347)95/1544-1274$03.00/0
Vol. 154, 1274, October 1995 Printed i n U . S A
THEJOURNALOP U~orocv Copyright 8 1% by AMGRICAN UR~L~%ICM. ASSOCUTION. bC.
This Month in Investigative Urology COMMENTARY ON PROGNOSTIC FACTORS IN RXNAL CELL CARCINOMA Approximately 28,OOO adults develop r e d cell carcinoma (RCC) annually in the United States, and about one-third of these patients will have metastatic disease at the time of presentation. Curative therapy for RCC has been limited to surgical extirpation in organ-confined disease.Kidney cancer is one of the unique tumor models for studying biologic therapy in the treatment of cancer. Although encouraging and durable clinical responae rates of 15 to 35% resulting from immunologic therapy have been reported, the overall response rate remains low. Therefore, there is a need to determine prognostic tumor markers to identify and select those patients who are most likely to respond to therapy, thus sparing many patients aggressive and potentially toxic systemic therapy. To date, very little is known about biologic and molecular tumor markers in RCC. Hence, the article by Shimazui et al. in this issue of Investigative Urology characterizingnucleolar organizer regions as a possible tumor marker is a timely topic. The extent to which identification and characterization of factors with prognostic value have significancedepends on whether our knowledge of such factors affects the decision-makingprocess in diseasemanagement. Efforts to straw patients into risks of tumor recurrence, progression and survival, have resulted in a vast body of literature. These prognostic factors have been classified into clinical and laboratory parameters such as performance atatus, weight loss and erythrocyte sedimentation rate (ESR); pathologic parameters such as tumor stage and grade; biologic factors such as circulatingCD56+ ceb; and molecular characteristics such as the expression of growth factads) or mutation in tumor suppressor gends). While clinical and laboratory parameters are easily incorporated into the management process, the difticulties of administering therapy to patients with metastatic RCC have heightened our need for identifying molecular and genetic factors to serve as targets for therapy. Elson et al.1 made a significant contribution in 1988 when they performed an exhaustive multivariate analysis of risk factors in patients with metastatic RCC. Performance status and time h m initialdiagnosisto entry into a trial for systemic therapy were the most important predictors of survival. Weight loss, pulmonary metaetases, and hepatic or brain metastases were also found to be of prognostic value. By applying a scoring system according to risk factors identified, patient survival was found to correlate inversely with the number of risk factors. Patients possessing a low score were those with favorable risk factors and had superior survival compared with high scoring patients. A median survival of 12.8months was observed in patients with total points (0,l)compared with a median survival of 2.1 months in patients with scorea 25. By applying this scoring process, patients more likely to survive independent of therapy could be classified. Fossa et al.2also analyzed prognostic factors and survival in 295 patients with metastatic RCC who were bated with either chemotherapy or interferon-a. Risk factors were also . .ed and patients classified according to risk. While interferon-a was described as producing an enhanced survival, this outcome could only be found in good risk patients. In 1992, the United States FDA approved interleukin-2 (E-2) for the treatment of advanced RCC. Although durable responses can be achieved, the overall response rate is only 15 to 20%. Currently, no definitive biologic criteria have been described to predict response to therapx however, E-2 therapy generating elevated levels of tumor necrosis factor alpha (TNF-a)3was associated with prolonged progression-li-ee survival. Among reapondingand nonresponding patients treated with tumor infiltrating lymphocytdl2 therapy at UCLA, statistical differences were observed in the extent of circulating CD56+ (naturalkiller) cells and the ability of preand posttreatment serum to expand in v i b proliferation and cytotoxicityof peripheral blood lymphocytes. These studies suggest that biologic markers might be useful in distinguishingresponding from nonresponding patients. An attribute of the ideal tumor marker is a molecular sd&.ance or an abnormal gene with functional characteristics contributing to the pathogenesis and progression of tumor cells. While the ideal tumor marker has not been characterized in RCC, recent papera in the oncologic literature have identified the p53 tumor suppressor gene in head and neck squamous cell carcinoma and the HER-Wneu protooncogene in breast and ovarian cancers as excellent candidates. Conflicting evidence still exists in kidney cancer regarding the role of the p53 tumor suppressor gene, epidennal growth factor (EGF) and its receptor (EGF'r) as tumor markers. Although mutations of von Hippel-Lindau(VHL) tumor suppressor gene have been observed in 57% of nonhereditary clear cell RCC, the presence of VHL mutations has not been shown to be assoCiated with tumor stage, grade, or patient survival. Identification and cloning of RCC tumor antigens, such as was recently accomplished in melanoma? will undoubtedly open a whole new field in the diagnosis and therapy of this disease. The future holds great hope for molecular classification and molecular markers for RCC. With rapid development of biomolecular technobgies the tools to analyze candidate markers are becoming more accessible to clinicians and basic scientists. Clinicd studies will be requiredto evaluate the strength of these markers. Future phase III trials need to incorporate known prognostic variables into their hypotheses and attempt to store pertinent data to evaluate yet to be defined molecular markers. Arie Belldegrun, John R. Franklin, Robert Figlin The UCLA Kidney Cancer Program Division of Urology UCLA School of Medicine Los Angeles, California REFERENCES
1. Elson, P. J.,Robert, S. W.and Trump, D. L.: Prognostic factors for survival in patients with recurrent or metastatic renal cell carcinoma Cancer Rea., 48: 7310, 1988. 2. Fossi, S. D., Kramar, A. and Droz, J. P.: Prognostic factors and survival in patients with metastatic r e n d cell ca&oma treated with chemotherapy or interferon-a. Eur. J. Cancer, 3OA: 1310, 1994. 3. Meffert, M.. %homburg, A.. Hanninen, E. L., Menzel, T., Vocke, S., Dallmann, I., Grosse, J., Duensing, S., Buer, J., Kirchner, &, Poliwoda, H. and Atzpodien, J.: In vivo tumor necrosis factor-alpha as indicator of biologic and clinical response to low-dose ,% recombinant interleukin-2. Anticancer Res., 15: 127, 1995. 4. Kawakami, Y.,Eliyahu, S., Delgado, C. H., et d: Identification of a human melanoma antigen recognized by tumor infiltratN lymphocytes associated with in vivo tumor rejection. Proc. Natl. Acad. Sci. U.S.A., 91: 6458, 1994. 1274
Vol. 154, 1274, October 1995 Printed i n U . S A
THEJOURNALOP U~orocv Copyright 8 1% by AMGRICAN UR~L~%ICM. ASSOCUTION. bC.
This Month in Investigative Urology COMMENTARY ON PROGNOSTIC FACTORS IN RXNAL CELL CARCINOMA Approximately 28,OOO adults develop r e d cell carcinoma (RCC) annually in the United States, and about one-third of these patients will have metastatic disease at the time of presentation. Curative therapy for RCC has been limited to surgical extirpation in organ-confined disease.Kidney cancer is one of the unique tumor models for studying biologic therapy in the treatment of cancer. Although encouraging and durable clinical responae rates of 15 to 35% resulting from immunologic therapy have been reported, the overall response rate remains low. Therefore, there is a need to determine prognostic tumor markers to identify and select those patients who are most likely to respond to therapy, thus sparing many patients aggressive and potentially toxic systemic therapy. To date, very little is known about biologic and molecular tumor markers in RCC. Hence, the article by Shimazui et al. in this issue of Investigative Urology characterizingnucleolar organizer regions as a possible tumor marker is a timely topic. The extent to which identification and characterization of factors with prognostic value have significancedepends on whether our knowledge of such factors affects the decision-makingprocess in diseasemanagement. Efforts to straw patients into risks of tumor recurrence, progression and survival, have resulted in a vast body of literature. These prognostic factors have been classified into clinical and laboratory parameters such as performance atatus, weight loss and erythrocyte sedimentation rate (ESR); pathologic parameters such as tumor stage and grade; biologic factors such as circulatingCD56+ ceb; and molecular characteristics such as the expression of growth factads) or mutation in tumor suppressor gends). While clinical and laboratory parameters are easily incorporated into the management process, the difticulties of administering therapy to patients with metastatic RCC have heightened our need for identifying molecular and genetic factors to serve as targets for therapy. Elson et al.1 made a significant contribution in 1988 when they performed an exhaustive multivariate analysis of risk factors in patients with metastatic RCC. Performance status and time h m initialdiagnosisto entry into a trial for systemic therapy were the most important predictors of survival. Weight loss, pulmonary metaetases, and hepatic or brain metastases were also found to be of prognostic value. By applying a scoring system according to risk factors identified, patient survival was found to correlate inversely with the number of risk factors. Patients possessing a low score were those with favorable risk factors and had superior survival compared with high scoring patients. A median survival of 12.8months was observed in patients with total points (0,l)compared with a median survival of 2.1 months in patients with scorea 25. By applying this scoring process, patients more likely to survive independent of therapy could be classified. Fossa et al.2also analyzed prognostic factors and survival in 295 patients with metastatic RCC who were bated with either chemotherapy or interferon-a. Risk factors were also . .ed and patients classified according to risk. While interferon-a was described as producing an enhanced survival, this outcome could only be found in good risk patients. In 1992, the United States FDA approved interleukin-2 (E-2) for the treatment of advanced RCC. Although durable responses can be achieved, the overall response rate is only 15 to 20%. Currently, no definitive biologic criteria have been described to predict response to therapx however, E-2 therapy generating elevated levels of tumor necrosis factor alpha (TNF-a)3was associated with prolonged progression-li-ee survival. Among reapondingand nonresponding patients treated with tumor infiltrating lymphocytdl2 therapy at UCLA, statistical differences were observed in the extent of circulating CD56+ (naturalkiller) cells and the ability of preand posttreatment serum to expand in v i b proliferation and cytotoxicityof peripheral blood lymphocytes. These studies suggest that biologic markers might be useful in distinguishingresponding from nonresponding patients. An attribute of the ideal tumor marker is a molecular sd&.ance or an abnormal gene with functional characteristics contributing to the pathogenesis and progression of tumor cells. While the ideal tumor marker has not been characterized in RCC, recent papera in the oncologic literature have identified the p53 tumor suppressor gene in head and neck squamous cell carcinoma and the HER-Wneu protooncogene in breast and ovarian cancers as excellent candidates. Conflicting evidence still exists in kidney cancer regarding the role of the p53 tumor suppressor gene, epidennal growth factor (EGF) and its receptor (EGF'r) as tumor markers. Although mutations of von Hippel-Lindau(VHL) tumor suppressor gene have been observed in 57% of nonhereditary clear cell RCC, the presence of VHL mutations has not been shown to be assoCiated with tumor stage, grade, or patient survival. Identification and cloning of RCC tumor antigens, such as was recently accomplished in melanoma? will undoubtedly open a whole new field in the diagnosis and therapy of this disease. The future holds great hope for molecular classification and molecular markers for RCC. With rapid development of biomolecular technobgies the tools to analyze candidate markers are becoming more accessible to clinicians and basic scientists. Clinicd studies will be requiredto evaluate the strength of these markers. Future phase III trials need to incorporate known prognostic variables into their hypotheses and attempt to store pertinent data to evaluate yet to be defined molecular markers. Arie Belldegrun, John R. Franklin, Robert Figlin The UCLA Kidney Cancer Program Division of Urology UCLA School of Medicine Los Angeles, California REFERENCES
1. Elson, P. J.,Robert, S. W.and Trump, D. L.: Prognostic factors for survival in patients with recurrent or metastatic renal cell carcinoma Cancer Rea., 48: 7310, 1988. 2. Fossi, S. D., Kramar, A. and Droz, J. P.: Prognostic factors and survival in patients with metastatic r e n d cell ca&oma treated with chemotherapy or interferon-a. Eur. J. Cancer, 3OA: 1310, 1994. 3. Meffert, M.. %homburg, A.. Hanninen, E. L., Menzel, T., Vocke, S., Dallmann, I., Grosse, J., Duensing, S., Buer, J., Kirchner, &, Poliwoda, H. and Atzpodien, J.: In vivo tumor necrosis factor-alpha as indicator of biologic and clinical response to low-dose ,% recombinant interleukin-2. Anticancer Res., 15: 127, 1995. 4. Kawakami, Y.,Eliyahu, S., Delgado, C. H., et d: Identification of a human melanoma antigen recognized by tumor infiltratN lymphocytes associated with in vivo tumor rejection. Proc. Natl. Acad. Sci. U.S.A., 91: 6458, 1994. 1274