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Phase I Trial of 177Lutetium-Labeled J591, a Monoclonal Antibody to Prostate-Specific Membrane Antigen, in Patients With Androgen-Independent Prostate Cancer
PROSTATE CANCER
Increased Risk of Rectal Cancer After Prostate Radiation: A Population-Based Study N. N. BAXTER, J. E. TEPPER, S. B. DURHAM, D. A. ROTHENBERGER AND B. A. VIRNIG, Department of Surgery, University of Minnesota Medical School, University of Minnesota Comprehensive Cancer Center, and Division of Health Services Research and Policy, University of Minnesota School of Public Health, Minneapolis, Minnesota, and Department of Radiation Oncology and UNC/Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina Gastroenterology, 128: 819 – 824, 2005 Background & Aims: Radiation therapy for prostate cancer has been associated with an increased rate of pelvic malignancies, particularly bladder cancer. The association between radiation therapy and colorectal cancer has not been established. Methods: We conducted a retrospective cohort study using Surveillance, Epidemiology, and End Results (SEER) registry data from 1973 through 1994. We focused on men with prostate cancer, but with no previous history of colorectal cancer, treated with either surgery or radiation who survived at least 5 years. We evaluated the effect of radiation on development of cancer for 3 sites: definitely irradiated sites (rectum), potentially irradiated sites (rectosigmoid, sigmoid, and cecum), and nonirradiated sites (the rest of the colon). Using a proportional hazards model, we evaluated the effect of radiation on development of colorectal cancer over time. Results: A total of 30,552 men received radiation, and 55,263 underwent surgery only. Colorectal cancers developed in 1437 patients: 267 in irradiated sites, 686 in potentially irradiated sites, and 484 in nonirradiated sites. Radiation was independently associated with development of cancer over time in irradiated sites but not in the remainder of the colon. The adjusted hazards ratio for development of rectal cancer was 1.7 for the radiation group, compared with the surgery-only group (95% CI: 1.4 –2.2). Conclusions: We noted a significant increase in development of rectal cancer after radiation for prostate cancer. Radiation had no effect on development of cancer in the remainder of the colon, indicating that the effect is specific to directly irradiated tissue. Editorial Comment: This well performed study indicates that patients who undergo radiation therapy for the treatment of prostate cancer have a 70% increased risk of developing rectal cancer. This effect is approximately the same order of magnitude of having a first degree relative with colorectal cancer. However, overall the rates were relatively low. Over 10 years of followup 5 men per 1,000 treated with surgery developed rectal cancer as compared with 10 men per 1,000 treated with radiation. The authors conclude that men undergoing radiation therapy for prostate cancer should be considered a higher risk group for the development of rectal cancer and should undergo endoscopic evaluation beginning 5 years after radiation. Patrick C. Walsh, M.D.
Phase I Trial of 177Lutetium-Labeled J591, a Monoclonal Antibody to Prostate-Specific Membrane Antigen, in Patients With Androgen-Independent Prostate Cancer N. H. BANDER, M. I. MILOWSKY, D. M. NANUS, L. KOSTAKOGLU, S. VALLABHAJOSULA AND S. J. GOLDSMITH, Department of Urology, Division of Hematology and Medical Oncology, Department of Medicine, Division of Nuclear Medicine and Department of Radiology, Weill Medical College of Cornell University, New York, New York J Clin Oncol, 23: 4591– 4601, 2005 Purpose To determine the maximum tolerated dose (MTD), toxicity, human anti-J591 response, pharmacokinetics (PK), organ dosimetry, targeting, and biologic activity of 177Lutetium-labeled anti-prostatespecific membrane antigen (PSMA) monoclonal antibody J591 (177Lu-J591) in patients with androgenindependent prostate cancer (PC). Patients and Methods Thirty-five patients with progressing AIPC received 177Lu-J591. All patients underwent 177Lu-J591 imaging, PK, and biodistribution determinations. Patients were eligible for up to three retreatments. Results Thirty-five patients received 177Lu-J591, of whom 16 received up to three doses. Myelosuppression was dose limiting at 75 mCi/m2, and the 70-mCi/m2 dose level was determined to be the single-dose MTD. Repeat dosing at 45 to 60 mCi/m2 was associated with dose-limiting myelosuppression; however, up to three doses of 30 mCi/m2 could be safely administered. Nonhematologic toxicity was not dose limiting. Targeting of all known sites of bone and soft tissue metastases was seen in all 30 patients with positive bone, computed tomography, or magnetic resonance images. No patient developed a human anti-J591 antibody response to deimmunized J591 regardless of number of doses. Biologic activity was seen with four patients experiencing ⱖ 50% declines in prostate-specific antigen (PSA) levels lasting from 3⫹ to 8 months. An additional 16 patients (46%) experienced PSA stabilization for a median of 60 days (range, 1 to 21⫹ months).
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Conclusion The MTD of 177Lu-J591 is 70 mCi/m2. Multiple doses of 30 mCi/m2 are well tolerated. Acceptable toxicity, excellent targeting of known sites of PC metastases, and biologic activity in patients with androgen-independent PC warrant further investigation. Editorial Comment: J591 is a monoclonal antibody that binds specifically to the extracellular domain of PSMA. The development of this antibody, and its potential use for staging and therapeutic purposes have been highly anticipated. This study reports on the use of the antibody bound to 177lutetium. In this study bone lesions were apparent on J591 scan in 3 cases before becoming evident on conventional scans. Myelosuppression was the major rate limiting factor in treatment. In this study only 4 of 35 patients experienced a PSA decline of greater than 50% lasting from 3 to 8 months and no patient had an objective measurable disease response. Patrick C. Walsh, M.D.
UROLOGICAL ONCOLOGY: TESTIS CANCER AND ADVANCES IN ONCOLOGICAL THERAPY Retroperitoneal Lymph Node Dissection for Nonseminomatous Germ Cell Testicular Cancer: Impact of Patient Selection Factors on Outcome A. J. STEPHENSON, G. J. BOSL, R. J. MOTZER, M. W. KATTAN, J. STASI, D. F. BAJORIN AND J. SHEINFELD, Departments of Urology, Epidemiology and Biostatistics, and Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, New York J Clin Oncol, 23: 2781–2788, 2005 Purpose To investigate the impact of patient selection criteria on the outcome of patients with nonseminomatous germ cell testicular cancer (NSGCT) treated by primary retroperitoneal lymph node dissection (RPLND). Since 1999, our criteria have excluded patients with persistent postorchiectomy elevation of serum tumor markers (STM) or clinical stage (CS) IIB disease from RPLND. Patients and Methods Between 1989 and 2002, 453 patients underwent primary RPLND at our institution for CS I to IIB NSGCT. Patient information was obtained from a prospective database. Retroperitoneal pathology and relapse rates were compared for patients treated before and after application of the current selection criteria in 1999. Results By excluding patients with elevated STM or CS IIB disease after 1999, the proportion of pathologic stage II patients with low-volume (pN1) retroperitoneal disease increased significantly (40% before 1999 v 64% after 1999; P ⫽ .01), without significantly affecting the retroperitoneal teratoma (21% v 22%, respectively; P ⫽ .89) or pathologic stage I disease (56% v 67%, respectively; P ⫽ .06). For patients who did not receive adjuvant chemotherapy, the 4-year progression-free probability improved significantly from 83% before 1999 (95% CI, 79% to 88%) to 96% after 1999 (95% CI, 91% to 100%; P ⫽ .005). Elevated postorchiectomy STM (P ⬍.0001), clinical stage (P ⫽ .0002), and pre-1999 RPLND (P ⫽ .05) were independent pretreatment predictors of progression. Conclusion Excluding patients with CS IIB disease or elevated postorchiectomy STM from primary RPLND has had a favorable impact on the extent of retroperitoneal disease and has significantly reduced the risk of relapse after RPLND. For patients with normal STM and CS I to IIA disease, the low rate of systemic progression and 22% incidence of retroperitoneal teratoma supports RPLND as the preferred primary intervention. Editorial Comment: The majority of new patients diagnosed with nonseminomatous germ cell tumor will have clinical stage I disease or retroperitoneal lymph node involvement only (clinical stage IIA or IIB). Options for treatment of these patients include active surveillance, modified template and nerve sparing retroperitoneal lymph node dissection, and primary cisplatin based chemotherapy. Virtually all of these cases can be expected to be cured. Therefore, attendant morbidity and potential long-term effects become increasingly important. Since 1999, the authors have modified their approach for patients with clinical stage I to IIB nonseminomatous germ cell tumors. They now recommend induction chemotherapy in patients with persistently increased serum tumor markers following orchiectomy and in patients with clinical stage IIB disease. All others are advised to undergo retroperitoneal lymph node dissection. Overall, 41% of their patients had positive retroperitoneal lymph nodes, with more favorable findings noted after 1999. A total of 93 patients with positive retroperitoneal lymph nodes
Increased Risk of Rectal Cancer After Prostate Radiation: A Population-Based Study N. N. BAXTER, J. E. TEPPER, S. B. DURHAM, D. A. ROTHENBERGER AND B. A. VIRNIG, Department of Surgery, University of Minnesota Medical School, University of Minnesota Comprehensive Cancer Center, and Division of Health Services Research and Policy, University of Minnesota School of Public Health, Minneapolis, Minnesota, and Department of Radiation Oncology and UNC/Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina Gastroenterology, 128: 819 – 824, 2005 Background & Aims: Radiation therapy for prostate cancer has been associated with an increased rate of pelvic malignancies, particularly bladder cancer. The association between radiation therapy and colorectal cancer has not been established. Methods: We conducted a retrospective cohort study using Surveillance, Epidemiology, and End Results (SEER) registry data from 1973 through 1994. We focused on men with prostate cancer, but with no previous history of colorectal cancer, treated with either surgery or radiation who survived at least 5 years. We evaluated the effect of radiation on development of cancer for 3 sites: definitely irradiated sites (rectum), potentially irradiated sites (rectosigmoid, sigmoid, and cecum), and nonirradiated sites (the rest of the colon). Using a proportional hazards model, we evaluated the effect of radiation on development of colorectal cancer over time. Results: A total of 30,552 men received radiation, and 55,263 underwent surgery only. Colorectal cancers developed in 1437 patients: 267 in irradiated sites, 686 in potentially irradiated sites, and 484 in nonirradiated sites. Radiation was independently associated with development of cancer over time in irradiated sites but not in the remainder of the colon. The adjusted hazards ratio for development of rectal cancer was 1.7 for the radiation group, compared with the surgery-only group (95% CI: 1.4 –2.2). Conclusions: We noted a significant increase in development of rectal cancer after radiation for prostate cancer. Radiation had no effect on development of cancer in the remainder of the colon, indicating that the effect is specific to directly irradiated tissue. Editorial Comment: This well performed study indicates that patients who undergo radiation therapy for the treatment of prostate cancer have a 70% increased risk of developing rectal cancer. This effect is approximately the same order of magnitude of having a first degree relative with colorectal cancer. However, overall the rates were relatively low. Over 10 years of followup 5 men per 1,000 treated with surgery developed rectal cancer as compared with 10 men per 1,000 treated with radiation. The authors conclude that men undergoing radiation therapy for prostate cancer should be considered a higher risk group for the development of rectal cancer and should undergo endoscopic evaluation beginning 5 years after radiation. Patrick C. Walsh, M.D.
Phase I Trial of 177Lutetium-Labeled J591, a Monoclonal Antibody to Prostate-Specific Membrane Antigen, in Patients With Androgen-Independent Prostate Cancer N. H. BANDER, M. I. MILOWSKY, D. M. NANUS, L. KOSTAKOGLU, S. VALLABHAJOSULA AND S. J. GOLDSMITH, Department of Urology, Division of Hematology and Medical Oncology, Department of Medicine, Division of Nuclear Medicine and Department of Radiology, Weill Medical College of Cornell University, New York, New York J Clin Oncol, 23: 4591– 4601, 2005 Purpose To determine the maximum tolerated dose (MTD), toxicity, human anti-J591 response, pharmacokinetics (PK), organ dosimetry, targeting, and biologic activity of 177Lutetium-labeled anti-prostatespecific membrane antigen (PSMA) monoclonal antibody J591 (177Lu-J591) in patients with androgenindependent prostate cancer (PC). Patients and Methods Thirty-five patients with progressing AIPC received 177Lu-J591. All patients underwent 177Lu-J591 imaging, PK, and biodistribution determinations. Patients were eligible for up to three retreatments. Results Thirty-five patients received 177Lu-J591, of whom 16 received up to three doses. Myelosuppression was dose limiting at 75 mCi/m2, and the 70-mCi/m2 dose level was determined to be the single-dose MTD. Repeat dosing at 45 to 60 mCi/m2 was associated with dose-limiting myelosuppression; however, up to three doses of 30 mCi/m2 could be safely administered. Nonhematologic toxicity was not dose limiting. Targeting of all known sites of bone and soft tissue metastases was seen in all 30 patients with positive bone, computed tomography, or magnetic resonance images. No patient developed a human anti-J591 antibody response to deimmunized J591 regardless of number of doses. Biologic activity was seen with four patients experiencing ⱖ 50% declines in prostate-specific antigen (PSA) levels lasting from 3⫹ to 8 months. An additional 16 patients (46%) experienced PSA stabilization for a median of 60 days (range, 1 to 21⫹ months).
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TESTIS CANCER AND ADVANCES IN ONCOLOGICAL THERAPY
Conclusion The MTD of 177Lu-J591 is 70 mCi/m2. Multiple doses of 30 mCi/m2 are well tolerated. Acceptable toxicity, excellent targeting of known sites of PC metastases, and biologic activity in patients with androgen-independent PC warrant further investigation. Editorial Comment: J591 is a monoclonal antibody that binds specifically to the extracellular domain of PSMA. The development of this antibody, and its potential use for staging and therapeutic purposes have been highly anticipated. This study reports on the use of the antibody bound to 177lutetium. In this study bone lesions were apparent on J591 scan in 3 cases before becoming evident on conventional scans. Myelosuppression was the major rate limiting factor in treatment. In this study only 4 of 35 patients experienced a PSA decline of greater than 50% lasting from 3 to 8 months and no patient had an objective measurable disease response. Patrick C. Walsh, M.D.
UROLOGICAL ONCOLOGY: TESTIS CANCER AND ADVANCES IN ONCOLOGICAL THERAPY Retroperitoneal Lymph Node Dissection for Nonseminomatous Germ Cell Testicular Cancer: Impact of Patient Selection Factors on Outcome A. J. STEPHENSON, G. J. BOSL, R. J. MOTZER, M. W. KATTAN, J. STASI, D. F. BAJORIN AND J. SHEINFELD, Departments of Urology, Epidemiology and Biostatistics, and Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, New York J Clin Oncol, 23: 2781–2788, 2005 Purpose To investigate the impact of patient selection criteria on the outcome of patients with nonseminomatous germ cell testicular cancer (NSGCT) treated by primary retroperitoneal lymph node dissection (RPLND). Since 1999, our criteria have excluded patients with persistent postorchiectomy elevation of serum tumor markers (STM) or clinical stage (CS) IIB disease from RPLND. Patients and Methods Between 1989 and 2002, 453 patients underwent primary RPLND at our institution for CS I to IIB NSGCT. Patient information was obtained from a prospective database. Retroperitoneal pathology and relapse rates were compared for patients treated before and after application of the current selection criteria in 1999. Results By excluding patients with elevated STM or CS IIB disease after 1999, the proportion of pathologic stage II patients with low-volume (pN1) retroperitoneal disease increased significantly (40% before 1999 v 64% after 1999; P ⫽ .01), without significantly affecting the retroperitoneal teratoma (21% v 22%, respectively; P ⫽ .89) or pathologic stage I disease (56% v 67%, respectively; P ⫽ .06). For patients who did not receive adjuvant chemotherapy, the 4-year progression-free probability improved significantly from 83% before 1999 (95% CI, 79% to 88%) to 96% after 1999 (95% CI, 91% to 100%; P ⫽ .005). Elevated postorchiectomy STM (P ⬍.0001), clinical stage (P ⫽ .0002), and pre-1999 RPLND (P ⫽ .05) were independent pretreatment predictors of progression. Conclusion Excluding patients with CS IIB disease or elevated postorchiectomy STM from primary RPLND has had a favorable impact on the extent of retroperitoneal disease and has significantly reduced the risk of relapse after RPLND. For patients with normal STM and CS I to IIA disease, the low rate of systemic progression and 22% incidence of retroperitoneal teratoma supports RPLND as the preferred primary intervention. Editorial Comment: The majority of new patients diagnosed with nonseminomatous germ cell tumor will have clinical stage I disease or retroperitoneal lymph node involvement only (clinical stage IIA or IIB). Options for treatment of these patients include active surveillance, modified template and nerve sparing retroperitoneal lymph node dissection, and primary cisplatin based chemotherapy. Virtually all of these cases can be expected to be cured. Therefore, attendant morbidity and potential long-term effects become increasingly important. Since 1999, the authors have modified their approach for patients with clinical stage I to IIB nonseminomatous germ cell tumors. They now recommend induction chemotherapy in patients with persistently increased serum tumor markers following orchiectomy and in patients with clinical stage IIB disease. All others are advised to undergo retroperitoneal lymph node dissection. Overall, 41% of their patients had positive retroperitoneal lymph nodes, with more favorable findings noted after 1999. A total of 93 patients with positive retroperitoneal lymph nodes