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EDITORIAL: TOWARDS KIDNEY CANCER CRYSTAL BALL. BETTER PROGNOSTICATION OF PATIENTS WITH RENAL CELL CARCINOMA
0022-5347/01/1661-0073/0 THE JOURNAL OF UROLOGY® Copyright © 2001 by AMERICAN UROLOGICAL ASSOCIATION, INC.®
Vol. 166, 73–74, July 2001 Printed in U.S.A.
EDITORIAL: TOWARDS KIDNEY CANCER CRYSTAL BALL. BETTER PROGNOSTICATION OF PATIENTS WITH RENAL CELL CARCINOMA invaluable way of accomplishing this. Similar nomograms for prostate cancer have found wide acceptance among clinicians.6, 7 It is expected that with time, larger patient samples and validation by outside data sets, this nomogram will be revised and refined. A question that must be addressed is the relationship between disease recurrence and survival. In general, renal cell carcinoma recurrence is often at a metastatic site, which is associated with poor prognosis. However, the development of a new primary in the contralateral kidney, which in this nomogram was grouped with all other disease recurrences, can often be treated by the same surgical principles that were used to address the initial tumor with a similar high rate of success. Therefore, it is hoped that future versions of renal cell carcinoma nomograms will focus on survival, which unlike prostate cancer, is an easier variable to measure due to the relatively short interval between the development of recurrent metastatic disease and death. Moreover, other factors associated with survival, including Furhman’s grade and the Eastern Cooperative Oncology Group performance status, were not included in this nomogram.8 A major question in regard to management of metastatic renal cell carcinoma has been the role of nephrectomy. There are 2 recent prospective phase 3 studies that examined this specific issue.9, 10 Both studies showed that patients with metastatic renal cell carcinoma who underwent nephrectomy before immunotherapy had prolonged survival relative to those who underwent immunotherapy with the primary tumor in place. What remains to be determined is what factors can be used for risk stratification among those patients undergoing cytoreductive nephrectomy before immunotherapy? Vasselli et al (page 68) examined the impact of regional lymph node involvement on survival of patients undergoing radical nephrectomy for metastatic renal cell carcinoma. Between 1985 and 1996, 154 patients with metastatic renal cell carcinoma underwent cytoreductive nephrectomy in preparation for interleukin-2 (IL-2) based immunotherapy protocols at the National Cancer Institute. The median survival of the 82 patients with no preoperative evidence of lymph node involvement was significantly longer than the 72 with lymph node involvement (14.7 versus 8.5 months, respectively, p ⫽ 0.0004). Moreover, the degree of lymphadenopathy was predictive of survival, with patients having less than 50 cm.3 retroperitoneal lymphadenopathy having improved survival compared to those with greater than 50 cm.3 (8.5 versus 5.3 months, respectively, p ⫽ 0.045). Multivariate analysis identified performance status and lack of adenopathy as predictive of improved survival. Patients who were treated with an aggressive surgical approach, including resection of adjacent organs due to direct tumor invasion, had similar survival and response to IL-2 as those who underwent nephrectomy alone. Although it did not reach statistical significance, there was a trend in patients without lymphadenopathy to have an improved response to immunotherapy. Recent data from University of California, Los Angeles confirm the poor prognostic value and decreased response to IL-2-based therapy associated with lymph node involvement in patients with metastatic renal cell carcinoma.11 As we move into the twenty-first century, the future of not only renal cell carcinoma management, but also of all oncology will shift towards personalized gene based medicine. New genomic technologies, such as DNA and tissue micro-arrays,
Significant advances in the diagnosis, staging and treatment of patients with renal cell carcinoma during the last 2 decades resulted in improved survival of a select group of patients and an overall change in the natural history of the disease.1 However, many pertinent questions are still waiting to be answered. How aggressive should our surgical resection be for localized renal cell carcinoma? Is a limited approach for sparing the adrenal gland safe? Can we predict in whom disease recurrence is most likely to develop after surgical treatment? What is the role of nephrectomy in patients with metastatic renal cell carcinoma? When and how extensive should lymph node dissection be performed? Who should receive, and what is the optimal regimen for immunotherapy, vaccine and gene therapy for advanced renal cell carcinoma? How can we improve our selection criteria for these therapies? Will molecular markers on the tumor specimen help with the selection and prognostication of patients with various stages of disease? This issue of The Journal of Urology contains 3 elegant and timely studies that help elucidate some of these dilemmas. Radical nephrectomy, as described by Robson et al, included complete removal of the kidney, Gerota’s fascia and the ipsilateral adrenal gland.2 However, with the continued down staging that has occurred with renal cell carcinoma due to improved radiological imaging, several studies have questioned the need for routine ipsilateral adrenalectomy during radical nephrectomy.3, 4 Moreover, the low local recurrence rate after partial nephrectomy for renal cell carcinoma, in which by definition adrenalectomy is not performed, further questions the value of adrenalectomy.5 Paul et al (page 59) examined 866 patients who underwent radical nephrectomy, including ipsilateral adrenalectomy for renal cell carcinoma between 1983 and 1999, to determine the factors that predicted the presence of adrenal metastasis. Of the 866 patients only 27 (3.1%) had adrenal metastasis, of whom 4 had bilateral or contralateral adrenal involvement. These patients had larger tumors and were more likely to have metastatic disease. Multivariate analysis revealed that tumor size greater than 8 cm. and M stage were independent predictors of adrenal involvement. The low incidence (3.1%) of adrenal metastasis is similar to other recent studies.3, 4 Moreover, recent series using modern day imaging modalities have shown that computerized tomography is greater than 99% specific and nearly 90% sensitive to detect adrenal involvement preoperatively.3 Given the low percentage of patients with adrenal involvement and use of detailed preoperative imaging, the vast majority of those with renal cell carcinoma can be spared the potential morbidity associated with ipsilateral adrenalectomy. To provide better risk stratification of patients undergoing surgical treatment for renal cell carcinoma, Kattan et al (page 63) developed a postoperative nomogram to predict disease recurrence with data from 601 patients who underwent radical or partial nephrectomy. Disease recurrence was defined as any newly detected kidney cancer, which included bilateral asynchronous disease. A comparison of multiple statistical models found that a Cox proportional hazards model provided the highest predictive value for assessing the likelihood of disease recurrence, with an area under the receiver operating characteristics curve of 0.74. Prognostication of patients undergoing surgery for renal cell carcinoma is an extremely important issue, and nomograms are an 73
74
TOWARDS KIDNEY CANCER CRYSTAL BALL
now enable simultaneous evaluations of expression levels of thousands of genes and permit the discovery of chromosomal markers in hundreds of tumor samples providing effective ways to fingerprint individual tumors. Although we have improved our understanding of the molecular genetics underlying renal cell carcinoma, much remains to be determined. For example, it has recently been shown that the expression of 2 closely related factors, vascular endothelial growth factor C and D, promote lymphangiogenesis and tumor spread via the lymphatic system.12, 13 However, the significance in renal cell carcinoma, and impact on tumor spread and survival are unknown. Perhaps renal cell carcinoma with significant lymphatic involvement that is associated with reduced survival over expresses vascular endothelial growth factor C and/or D. If so, these lymphangiogenic factors may be potential therapeutic targets. The poorer survival and reduced response to immunotherapy in patients with lymphatic involvement is disconcerting, and future research is needed to determine why lymph node involvement indicates a worse prognosis. Perhaps the fact that the tumor was able to grow in the lymph nodes, a hotbed of immune activity, implies that by necessity the tumor is relatively resistant to immune based therapies. It is possible that lymphatic spread developed first in patients with lymphatic involvement and widespread metastasis. Therefore, they have a relatively later form of disease than those without lymph node involvement. Clearly, further research is needed to address these questions. It is anticipated that future advances in our understanding of the basic biology of renal cell carcinoma will improve our crystal ball and allow not only better prognostication, but also allow superior therapies for prolonged survival. Stephen J. Freedland and Arie S. Belldegrun Department of Urology University of California School of Medicine Los Angeles, California REFERENCES
1. Pantuck, A. J., Zisman, A. and Belldegrun, A. S.: The changing natural history of renal cell carcinoma. J Urol, in press
2. Robson, C. J., Churchill, B. M. and Anderson, W.: The results of radical nephrectomy for renal cell carcinoma. J Urol, 101: 297, 1969 3. Tsui, K. H., Shvarts, O., Barbaric, Z. et al: Is adrenalectomy a necessary component of radical nephrectomy? UCLA experience with 511 radical nephrectomies. J Urol, 163: 437, 2000 4. Kletscher, B. A., Qian, J., Bostwick, D. G. et al: Prospective analysis of the incidence of ipsilateral adrenal metastasis in localized renal cell carcinoma. J Urol, 155: 1844, 1996 5. Fergany, A. F., Hafez, K. S. and Novick, A. C.: Long-term results of nephron sparing surgery for localized renal cell carcinoma: 10-year followup. J Urol, 163: 442, 2000 6. Partin, A. W., Kattan, M. W., Subong, E. N. et al: Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multiinstitutional update. JAMA, 277: 1445, 1997 7. Kattan, M. W., Eastham, J. A., Stapleton, A. M. et al: A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst, 90: 766, 1998 8. Zisman, A., Pantuck, A. J., Dorey, F. et al: Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol, 19: 1649, 2001 9. Flanigan, R. C., Blumenstein, B. A., Salmon, S. et al: Cytoreduction nephrectomy in metastatic renal cancer: the results of Southwest Oncology Group Trial 8949. J Urol, suppl., 163: 154, abstract 685, 2000 10. Mickisch, G. H., Garin, A., Madej, M. et al: Tumor nephrectomy plus interferon ␣ is superior to interferon ␣ alone in metastatic renal cell carcinoma. J Urol, suppl., 163: 176, abstract 778, 2000 11. Pantuck, A. J., Zisman, A., Chao, D. et al: Regional lymphadenopathy during cytoreductive nephrectomy predicts IL-2 failure in patients with metastatic renal cell carcinoma. Unpublished data 12. Stacker, S. A., Caesar, C., Baldwin, M. E. et al: VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med, 7: 186, 2001 13. Skobe, M., Hawighorst, T., Jackson, D. G. et al: Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med, 7: 192, 2001
Vol. 166, 73–74, July 2001 Printed in U.S.A.
EDITORIAL: TOWARDS KIDNEY CANCER CRYSTAL BALL. BETTER PROGNOSTICATION OF PATIENTS WITH RENAL CELL CARCINOMA invaluable way of accomplishing this. Similar nomograms for prostate cancer have found wide acceptance among clinicians.6, 7 It is expected that with time, larger patient samples and validation by outside data sets, this nomogram will be revised and refined. A question that must be addressed is the relationship between disease recurrence and survival. In general, renal cell carcinoma recurrence is often at a metastatic site, which is associated with poor prognosis. However, the development of a new primary in the contralateral kidney, which in this nomogram was grouped with all other disease recurrences, can often be treated by the same surgical principles that were used to address the initial tumor with a similar high rate of success. Therefore, it is hoped that future versions of renal cell carcinoma nomograms will focus on survival, which unlike prostate cancer, is an easier variable to measure due to the relatively short interval between the development of recurrent metastatic disease and death. Moreover, other factors associated with survival, including Furhman’s grade and the Eastern Cooperative Oncology Group performance status, were not included in this nomogram.8 A major question in regard to management of metastatic renal cell carcinoma has been the role of nephrectomy. There are 2 recent prospective phase 3 studies that examined this specific issue.9, 10 Both studies showed that patients with metastatic renal cell carcinoma who underwent nephrectomy before immunotherapy had prolonged survival relative to those who underwent immunotherapy with the primary tumor in place. What remains to be determined is what factors can be used for risk stratification among those patients undergoing cytoreductive nephrectomy before immunotherapy? Vasselli et al (page 68) examined the impact of regional lymph node involvement on survival of patients undergoing radical nephrectomy for metastatic renal cell carcinoma. Between 1985 and 1996, 154 patients with metastatic renal cell carcinoma underwent cytoreductive nephrectomy in preparation for interleukin-2 (IL-2) based immunotherapy protocols at the National Cancer Institute. The median survival of the 82 patients with no preoperative evidence of lymph node involvement was significantly longer than the 72 with lymph node involvement (14.7 versus 8.5 months, respectively, p ⫽ 0.0004). Moreover, the degree of lymphadenopathy was predictive of survival, with patients having less than 50 cm.3 retroperitoneal lymphadenopathy having improved survival compared to those with greater than 50 cm.3 (8.5 versus 5.3 months, respectively, p ⫽ 0.045). Multivariate analysis identified performance status and lack of adenopathy as predictive of improved survival. Patients who were treated with an aggressive surgical approach, including resection of adjacent organs due to direct tumor invasion, had similar survival and response to IL-2 as those who underwent nephrectomy alone. Although it did not reach statistical significance, there was a trend in patients without lymphadenopathy to have an improved response to immunotherapy. Recent data from University of California, Los Angeles confirm the poor prognostic value and decreased response to IL-2-based therapy associated with lymph node involvement in patients with metastatic renal cell carcinoma.11 As we move into the twenty-first century, the future of not only renal cell carcinoma management, but also of all oncology will shift towards personalized gene based medicine. New genomic technologies, such as DNA and tissue micro-arrays,
Significant advances in the diagnosis, staging and treatment of patients with renal cell carcinoma during the last 2 decades resulted in improved survival of a select group of patients and an overall change in the natural history of the disease.1 However, many pertinent questions are still waiting to be answered. How aggressive should our surgical resection be for localized renal cell carcinoma? Is a limited approach for sparing the adrenal gland safe? Can we predict in whom disease recurrence is most likely to develop after surgical treatment? What is the role of nephrectomy in patients with metastatic renal cell carcinoma? When and how extensive should lymph node dissection be performed? Who should receive, and what is the optimal regimen for immunotherapy, vaccine and gene therapy for advanced renal cell carcinoma? How can we improve our selection criteria for these therapies? Will molecular markers on the tumor specimen help with the selection and prognostication of patients with various stages of disease? This issue of The Journal of Urology contains 3 elegant and timely studies that help elucidate some of these dilemmas. Radical nephrectomy, as described by Robson et al, included complete removal of the kidney, Gerota’s fascia and the ipsilateral adrenal gland.2 However, with the continued down staging that has occurred with renal cell carcinoma due to improved radiological imaging, several studies have questioned the need for routine ipsilateral adrenalectomy during radical nephrectomy.3, 4 Moreover, the low local recurrence rate after partial nephrectomy for renal cell carcinoma, in which by definition adrenalectomy is not performed, further questions the value of adrenalectomy.5 Paul et al (page 59) examined 866 patients who underwent radical nephrectomy, including ipsilateral adrenalectomy for renal cell carcinoma between 1983 and 1999, to determine the factors that predicted the presence of adrenal metastasis. Of the 866 patients only 27 (3.1%) had adrenal metastasis, of whom 4 had bilateral or contralateral adrenal involvement. These patients had larger tumors and were more likely to have metastatic disease. Multivariate analysis revealed that tumor size greater than 8 cm. and M stage were independent predictors of adrenal involvement. The low incidence (3.1%) of adrenal metastasis is similar to other recent studies.3, 4 Moreover, recent series using modern day imaging modalities have shown that computerized tomography is greater than 99% specific and nearly 90% sensitive to detect adrenal involvement preoperatively.3 Given the low percentage of patients with adrenal involvement and use of detailed preoperative imaging, the vast majority of those with renal cell carcinoma can be spared the potential morbidity associated with ipsilateral adrenalectomy. To provide better risk stratification of patients undergoing surgical treatment for renal cell carcinoma, Kattan et al (page 63) developed a postoperative nomogram to predict disease recurrence with data from 601 patients who underwent radical or partial nephrectomy. Disease recurrence was defined as any newly detected kidney cancer, which included bilateral asynchronous disease. A comparison of multiple statistical models found that a Cox proportional hazards model provided the highest predictive value for assessing the likelihood of disease recurrence, with an area under the receiver operating characteristics curve of 0.74. Prognostication of patients undergoing surgery for renal cell carcinoma is an extremely important issue, and nomograms are an 73
74
TOWARDS KIDNEY CANCER CRYSTAL BALL
now enable simultaneous evaluations of expression levels of thousands of genes and permit the discovery of chromosomal markers in hundreds of tumor samples providing effective ways to fingerprint individual tumors. Although we have improved our understanding of the molecular genetics underlying renal cell carcinoma, much remains to be determined. For example, it has recently been shown that the expression of 2 closely related factors, vascular endothelial growth factor C and D, promote lymphangiogenesis and tumor spread via the lymphatic system.12, 13 However, the significance in renal cell carcinoma, and impact on tumor spread and survival are unknown. Perhaps renal cell carcinoma with significant lymphatic involvement that is associated with reduced survival over expresses vascular endothelial growth factor C and/or D. If so, these lymphangiogenic factors may be potential therapeutic targets. The poorer survival and reduced response to immunotherapy in patients with lymphatic involvement is disconcerting, and future research is needed to determine why lymph node involvement indicates a worse prognosis. Perhaps the fact that the tumor was able to grow in the lymph nodes, a hotbed of immune activity, implies that by necessity the tumor is relatively resistant to immune based therapies. It is possible that lymphatic spread developed first in patients with lymphatic involvement and widespread metastasis. Therefore, they have a relatively later form of disease than those without lymph node involvement. Clearly, further research is needed to address these questions. It is anticipated that future advances in our understanding of the basic biology of renal cell carcinoma will improve our crystal ball and allow not only better prognostication, but also allow superior therapies for prolonged survival. Stephen J. Freedland and Arie S. Belldegrun Department of Urology University of California School of Medicine Los Angeles, California REFERENCES
1. Pantuck, A. J., Zisman, A. and Belldegrun, A. S.: The changing natural history of renal cell carcinoma. J Urol, in press
2. Robson, C. J., Churchill, B. M. and Anderson, W.: The results of radical nephrectomy for renal cell carcinoma. J Urol, 101: 297, 1969 3. Tsui, K. H., Shvarts, O., Barbaric, Z. et al: Is adrenalectomy a necessary component of radical nephrectomy? UCLA experience with 511 radical nephrectomies. J Urol, 163: 437, 2000 4. Kletscher, B. A., Qian, J., Bostwick, D. G. et al: Prospective analysis of the incidence of ipsilateral adrenal metastasis in localized renal cell carcinoma. J Urol, 155: 1844, 1996 5. Fergany, A. F., Hafez, K. S. and Novick, A. C.: Long-term results of nephron sparing surgery for localized renal cell carcinoma: 10-year followup. J Urol, 163: 442, 2000 6. Partin, A. W., Kattan, M. W., Subong, E. N. et al: Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multiinstitutional update. JAMA, 277: 1445, 1997 7. Kattan, M. W., Eastham, J. A., Stapleton, A. M. et al: A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst, 90: 766, 1998 8. Zisman, A., Pantuck, A. J., Dorey, F. et al: Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol, 19: 1649, 2001 9. Flanigan, R. C., Blumenstein, B. A., Salmon, S. et al: Cytoreduction nephrectomy in metastatic renal cancer: the results of Southwest Oncology Group Trial 8949. J Urol, suppl., 163: 154, abstract 685, 2000 10. Mickisch, G. H., Garin, A., Madej, M. et al: Tumor nephrectomy plus interferon ␣ is superior to interferon ␣ alone in metastatic renal cell carcinoma. J Urol, suppl., 163: 176, abstract 778, 2000 11. Pantuck, A. J., Zisman, A., Chao, D. et al: Regional lymphadenopathy during cytoreductive nephrectomy predicts IL-2 failure in patients with metastatic renal cell carcinoma. Unpublished data 12. Stacker, S. A., Caesar, C., Baldwin, M. E. et al: VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med, 7: 186, 2001 13. Skobe, M., Hawighorst, T., Jackson, D. G. et al: Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med, 7: 192, 2001