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Urological Oncology: Renal, Ureteral and Retroperitoneal Tumors
Urological Survey UROLOGICAL ONCOLOGY: RENAL, URETERAL AND RETROPERITONEAL TUMORS 11C
Vinblastine Syntheses and Preliminary Imaging in Cancer Patients
C. Solbach, M. Patt, M. Reimold, A. Blocher, B. M. Dohmen, R. Bares, K. P. Zeller and H. J. Machulla, Radiopharmacy, PET-Center, University Hospital Tubingen, Tubingen, Germany J Pharm Pharm Sci 2007; 10: 266s–276s. Purpose: The primary aim of this work was to establish a radiolabeling procedure of vinblastine, a vinca alkaloid widely used in chemotherapy, with the positron-emitter carbon-11 for application in positronemission-tomography (PET) studies in cancer patients. The optimized reaction conditions were transferred to an automated radiosynthesizer system for the preparation of 11Cvinblastine under GMP conditions for human use. We report about the whole body activity distribution after injection of 11C vinblastine as well as the pharmacokinetic behavior in selected organs and the tumor in two patients that were investigated with 11Cvinblastine PET before chemotherapy. Methods: For carbon-11 labeling of vinblastine the reaction conditions were determined with respect to the two possible labeling precursors (i.e. 11Cmethyl iodide and 11Cdiazomethane), solvent, reaction temperature and reaction time. Both, 11Cdiazomethane and 11Cmethyl iodide were tested as labeling precursors with the corresponding demethyl compound of vinblastine, i.e. the vinblastine acid and the potassium salt of vinblastine acid. Two patients with renal carcinoma underwent 11Cvinblastine PET before chemotherapy. One patient underwent a second scan during infusion of unlabeled vinblastine at a therapeutic dose. Results: Best results for the labeling procedure were found when methylation was carried out at 100 degrees C within 20 min using 2 mg/mL of the potassium salt of vinblastine acid in DMSO and 11C methyl iodide as labeling precursor. Based on 11Cmethyl iodide starting activity a radiochemical yield of up 53 % 11Cvinblastine was achieved. In addition, the synthesis was transferred to a remotely controlled module for routine GMP conform production for human use. In large scale production runs up to 1 GBq of 11Cvinblastine was obtained ready for injection within 45 min after EOB. In one patient, whole body PET scans 40 min after injection of 112 MBq 11Cvinblastine showed a focally increased 11C vinblastine uptake and 11Cvinblastine metabolite uptake, respectively in the known metastases, along with a slow but continuous washout during the measurement interval (0 – 60 min p.i.). Another patient showed no focally increased 11Cvinblastine uptake and 11Cvinblastine metabolite uptake in the tumor, where radioactivity concentration was comparable to that in the blood. In this patient, a second PET scan during infusion of unlabeled vinblastine revealed similar kinetics with a trend towards delayed hepatic metabolism and higher blood and tumor concentrations. Whereas this patient showed a partial response to chemotherapy, the first patient did not, hypothetically due to the observed vinblastine washout from the tumor. Conclusions: The carbon-11 labeling of vinblastine using 11Cmethyl iodide is superior to the method using 11Cdiazomethane. A well working automated radiosynthesis was established for the production of 11Cvinblastine for PET-investigations in cancer patients. The individual pharmacokinetic behavior of the chemo-therapeutic agent to the tumor can be assessed with PET, thus, can be considered to be a realistic approach for individualized chemotherapy. Editorial Comment: The authors put a radiolabel on vinblastine that has been widely used in chemotherapy. This label is a positron emitter carbon-11 for use in PET studies. 18FFluorodeoxyglucose-PET reveal has been used in the past, and has demonstrated hypermetabolic mediastinal metastases but has not been used routinely for the evaluation of the patient with metastatic renal cell carcinoma. In this novel situation vinblastine is labeled and a PET scan can be performed. Metastatic sites can be identified and theoretically treated. Two patients were studied with identification of metastatic sites. Fray F. Marshall, M.D.
0022-5347/08/1804-1301/0 THE JOURNAL OF UROLOGY® Copyright © 2008 by AMERICAN UROLOGICAL ASSOCIATION
1301
Vol. 180, 1301-1302, October 2008 Printed in U.S.A. DOI:10.1016/j.juro.2008.06.091
1302
RENAL, URETERAL AND RETROPERITONEAL TUMORS
Carbonic Anhydrase IX is Not an Independent Predictor of Outcome for Patients With Clear Cell Renal Cell Carcinoma B. C. Leibovich, Y. Sheinin, C. M. Lohse, R. H. Thompson, J. C. Cheville, J. Zavada and E. D. Kwon, Department of Urology, Mayo Medical School and Mayo Clinic, Rochester, Minnesota J Clin Oncol 2007; 25: 4757– 4764. Purpose: Expression of carbonic anhydrase IX (CAIX) has been reported to be an independent predictor of outcome and is being investigated as a therapeutic target for patients with clear cell renal cell carcinoma (ccRCC). We attempted to validate the prognostic utility of CAIX expression using a large cohort of ccRCC patients with long-term follow-up. Patients and Methods: We identified 730 patients with unilateral, sporadic ccRCC treated surgically between 1990 and 1999. Anti-CAIX monoclonal antibody (clone M75) was used, and tumor specimens were blindly scored for expression levels. Associations of CAIX expression with RCC death were evaluated using Cox proportional hazards regression models. Results: There were 241 RCC deaths and a median of 9.4 years of follow-up for patients still under observation. CAIX was expressed in 708 (97.0%) of the specimens; 163 tumors (22.3%) exhibited low ( 85% tumor cells positive) expression, and 567 (77.7%) exhibited high (⬎ 85% tumor cells positive) expression. Univariately, low CAIX expression was associated with increased risk of RCC death relative to high expression (risk ratio ⫽ 1.65; P ⬍ .001). However, low CAIX expression was not associated with RCC death after adjusting for nuclear grade or coagulative tumor necrosis. Additionally, we observed CAIX expression in a number of extrarenal organs. Conclusion: CAIX is strongly expressed by ccRCC. Although CAIX is associated with outcome in patients with ccRCC, it is not an independent prognostic marker. Furthermore, CAIX expression is apparent in extrarenal organs. As such, exploitation of CAIX as a prognostic marker and therapeutic target merits additional consideration. Editorial Comment: The authors investigated the expression of CAIX, which has previously been reported as an independent predictor of outcome. Carbonic anhydrase IX was strongly expressed by renal cell carcinoma. Carbonic anhydrase IX expression was demonstrated in other organs as well. High level expression was apparent in clear cell carcinoma but minimal expression was observed in papillary and chromophobe renal cell carcinomas. Low levels of CAIX expression were univariately associated with death from renal cell carcinoma. On further evaluation CAIX provided no additional prognostic value to existing scoring algorithms after more standard features of grade and necrosis were evaluated. Although CAIX expression may not be useful as a prognostic marker, it may obtain usefulness as a diagnostic marker in increasing the accuracy of interpretation of biopsy specimen. Fray F. Marshall, M.D.
Vinblastine Syntheses and Preliminary Imaging in Cancer Patients
C. Solbach, M. Patt, M. Reimold, A. Blocher, B. M. Dohmen, R. Bares, K. P. Zeller and H. J. Machulla, Radiopharmacy, PET-Center, University Hospital Tubingen, Tubingen, Germany J Pharm Pharm Sci 2007; 10: 266s–276s. Purpose: The primary aim of this work was to establish a radiolabeling procedure of vinblastine, a vinca alkaloid widely used in chemotherapy, with the positron-emitter carbon-11 for application in positronemission-tomography (PET) studies in cancer patients. The optimized reaction conditions were transferred to an automated radiosynthesizer system for the preparation of 11Cvinblastine under GMP conditions for human use. We report about the whole body activity distribution after injection of 11C vinblastine as well as the pharmacokinetic behavior in selected organs and the tumor in two patients that were investigated with 11Cvinblastine PET before chemotherapy. Methods: For carbon-11 labeling of vinblastine the reaction conditions were determined with respect to the two possible labeling precursors (i.e. 11Cmethyl iodide and 11Cdiazomethane), solvent, reaction temperature and reaction time. Both, 11Cdiazomethane and 11Cmethyl iodide were tested as labeling precursors with the corresponding demethyl compound of vinblastine, i.e. the vinblastine acid and the potassium salt of vinblastine acid. Two patients with renal carcinoma underwent 11Cvinblastine PET before chemotherapy. One patient underwent a second scan during infusion of unlabeled vinblastine at a therapeutic dose. Results: Best results for the labeling procedure were found when methylation was carried out at 100 degrees C within 20 min using 2 mg/mL of the potassium salt of vinblastine acid in DMSO and 11C methyl iodide as labeling precursor. Based on 11Cmethyl iodide starting activity a radiochemical yield of up 53 % 11Cvinblastine was achieved. In addition, the synthesis was transferred to a remotely controlled module for routine GMP conform production for human use. In large scale production runs up to 1 GBq of 11Cvinblastine was obtained ready for injection within 45 min after EOB. In one patient, whole body PET scans 40 min after injection of 112 MBq 11Cvinblastine showed a focally increased 11C vinblastine uptake and 11Cvinblastine metabolite uptake, respectively in the known metastases, along with a slow but continuous washout during the measurement interval (0 – 60 min p.i.). Another patient showed no focally increased 11Cvinblastine uptake and 11Cvinblastine metabolite uptake in the tumor, where radioactivity concentration was comparable to that in the blood. In this patient, a second PET scan during infusion of unlabeled vinblastine revealed similar kinetics with a trend towards delayed hepatic metabolism and higher blood and tumor concentrations. Whereas this patient showed a partial response to chemotherapy, the first patient did not, hypothetically due to the observed vinblastine washout from the tumor. Conclusions: The carbon-11 labeling of vinblastine using 11Cmethyl iodide is superior to the method using 11Cdiazomethane. A well working automated radiosynthesis was established for the production of 11Cvinblastine for PET-investigations in cancer patients. The individual pharmacokinetic behavior of the chemo-therapeutic agent to the tumor can be assessed with PET, thus, can be considered to be a realistic approach for individualized chemotherapy. Editorial Comment: The authors put a radiolabel on vinblastine that has been widely used in chemotherapy. This label is a positron emitter carbon-11 for use in PET studies. 18FFluorodeoxyglucose-PET reveal has been used in the past, and has demonstrated hypermetabolic mediastinal metastases but has not been used routinely for the evaluation of the patient with metastatic renal cell carcinoma. In this novel situation vinblastine is labeled and a PET scan can be performed. Metastatic sites can be identified and theoretically treated. Two patients were studied with identification of metastatic sites. Fray F. Marshall, M.D.
0022-5347/08/1804-1301/0 THE JOURNAL OF UROLOGY® Copyright © 2008 by AMERICAN UROLOGICAL ASSOCIATION
1301
Vol. 180, 1301-1302, October 2008 Printed in U.S.A. DOI:10.1016/j.juro.2008.06.091
1302
RENAL, URETERAL AND RETROPERITONEAL TUMORS
Carbonic Anhydrase IX is Not an Independent Predictor of Outcome for Patients With Clear Cell Renal Cell Carcinoma B. C. Leibovich, Y. Sheinin, C. M. Lohse, R. H. Thompson, J. C. Cheville, J. Zavada and E. D. Kwon, Department of Urology, Mayo Medical School and Mayo Clinic, Rochester, Minnesota J Clin Oncol 2007; 25: 4757– 4764. Purpose: Expression of carbonic anhydrase IX (CAIX) has been reported to be an independent predictor of outcome and is being investigated as a therapeutic target for patients with clear cell renal cell carcinoma (ccRCC). We attempted to validate the prognostic utility of CAIX expression using a large cohort of ccRCC patients with long-term follow-up. Patients and Methods: We identified 730 patients with unilateral, sporadic ccRCC treated surgically between 1990 and 1999. Anti-CAIX monoclonal antibody (clone M75) was used, and tumor specimens were blindly scored for expression levels. Associations of CAIX expression with RCC death were evaluated using Cox proportional hazards regression models. Results: There were 241 RCC deaths and a median of 9.4 years of follow-up for patients still under observation. CAIX was expressed in 708 (97.0%) of the specimens; 163 tumors (22.3%) exhibited low ( 85% tumor cells positive) expression, and 567 (77.7%) exhibited high (⬎ 85% tumor cells positive) expression. Univariately, low CAIX expression was associated with increased risk of RCC death relative to high expression (risk ratio ⫽ 1.65; P ⬍ .001). However, low CAIX expression was not associated with RCC death after adjusting for nuclear grade or coagulative tumor necrosis. Additionally, we observed CAIX expression in a number of extrarenal organs. Conclusion: CAIX is strongly expressed by ccRCC. Although CAIX is associated with outcome in patients with ccRCC, it is not an independent prognostic marker. Furthermore, CAIX expression is apparent in extrarenal organs. As such, exploitation of CAIX as a prognostic marker and therapeutic target merits additional consideration. Editorial Comment: The authors investigated the expression of CAIX, which has previously been reported as an independent predictor of outcome. Carbonic anhydrase IX was strongly expressed by renal cell carcinoma. Carbonic anhydrase IX expression was demonstrated in other organs as well. High level expression was apparent in clear cell carcinoma but minimal expression was observed in papillary and chromophobe renal cell carcinomas. Low levels of CAIX expression were univariately associated with death from renal cell carcinoma. On further evaluation CAIX provided no additional prognostic value to existing scoring algorithms after more standard features of grade and necrosis were evaluated. Although CAIX expression may not be useful as a prognostic marker, it may obtain usefulness as a diagnostic marker in increasing the accuracy of interpretation of biopsy specimen. Fray F. Marshall, M.D.