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Originally published as JCO Early Release 10.1200/JCO.2004.09.154 on June 1 2004 © 2004 American Society of Clinical Oncology. Phase I Trial of Yttrium-90—Labeled Anti—Prostate-Specific Membrane Antigen Monoclonal Antibody J591 for Androgen-Independent Prostate CancerFrom the Division of Hematology and Medical Oncology, Department of Medicine, Division of Nuclear Medicine, Department of Radiology, and Department of Urology, Weill Medical College of Cornell University, New York, NY Address reprint requests to Neil H. Bander, MD, Weill Medical College of Cornell University, 525 E 68th St, E-300, New York, NY 10021; e-mail: nhbander{at}med.cornell.edu
PURPOSE: To determine the maximum-tolerated dose (MTD), toxicity, human antihuman antibody (HAHA) response, pharmacokinetics, organ dosimetry, targeting, and preliminary efficacy of yttrium-90–labeled anti–prostate-specific membrane antigen monoclonal antibody J591 (90Y-J591) in patients with androgen-independent prostate cancer (PC). PATIENTS AND METHODS: Patients with androgen-independent PC and evidence of disease progression received indium-111–J591 for pharmacokinetic and biodistribution determinations followed 1 week later by 90Y-J591 at five dose levels: 5, 10, 15, 17.5, and 20 mCi/m2. Patients were eligible for up to three re-treatments if platelet and neutrophil recovery was satisfactory. RESULTS: Twenty-nine patients with androgen-independent PC received 90Y-J591, four of whom were re-treated. Dose limiting toxicity (DLT) was seen at 20 mCi/m2, with two patients experiencing thrombocytopenia with non–life-threatening bleeding episodes requiring platelet transfusions. The 17.5-mCi/m2 dose level was determined to be the MTD. No re-treated patients experienced DLT. Nonhematologic toxicity was not dose limiting. Targeting of known sites of bone and soft tissue metastases was seen in the majority of patients. No HAHA response was seen. Antitumor activity was seen, with two patients experiencing 85% and 70% declines in prostate-specific antigen (PSA) levels lasting 8 and 8.6 months, respectively, before returning to baseline. Both patients had objective measurable disease responses. An additional six patients (21%) experienced PSA stabilization. CONCLUSION: The recommended dose for 90Y-J591 is 17.5 mCi/m2. Acceptable toxicity, excellent targeting of known sites of PC metastases, and biologic activity in patients with androgen-independent PC warrant further investigation of 90Y-J591 in the treatment of patients with PC.
Prostate-specific membrane antigen (PSMA) is a highly prostate-restricted type II integral membrane cell-surface glycoprotein expressed in both benign and malignant prostate tissue.1,2 In contrast to other prostate-related antigens such as prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), and prostate secretory protein, PSMA is not secreted. PSMA expression is increased in high-grade cancers, metastatic disease, and hormone-refractory prostate cancer (PC).1,3,4 Although PSMA has folate hydrolase and neurocarboxypeptidase activity, its function with respect to PC biology is unknown.5,6 Nevertheless, the expression pattern of PSMA makes it an excellent target for monoclonal antibody (mAb) therapy. J591 is an anti-PSMA mAb that binds with high affinity (1 nm) to the extracellular domain of PSMAext.7 The murine antibody J591 was deimmunized to allow for repeated dosing.8 J591 deimmunization involved genetic engineering into a human immunoglobulin G1 (IgG1) with identical specificity and affinity as its murine counterpart, with the added ability to induce antibody-dependent cellular cytotoxicity with human immune effector cells. This is the first report of the use of a radiolabeled anti-PSMAext mAb to treat patients with PC. 7E11, a murine mAb that binds to an intracellular epitope of the PSMA protein,9-12 labeled with indium-111 (111In; capromab pendetide) is a US Food and Drug Administration–approved imaging agent for soft tissue metastases in patients with PC.13-15 Because of its intracellular binding site, however, 7E11 binds only dead or dying PC cells. In contrast, J591 binds to the extracellular domain of PSMA, allowing for targeting of viable PC cells and internalization by PSMA-expressing cells.7,16 The radionuclide yttrium-90 (90Y) was chosen for this trial on the basis of its physical properties and preclinical data in xenograft models.17 90Y is a pure beta-emitter, with a physical half-life of 2.7 days, a maximum energy of 2.2 MeV, and a depth of penetration of 12 mm. As a radiometal, once internalized, 90Y remains trapped in the cell. Given that 90Y lacks gamma emissions, 111In must be used as a surrogate label for scintigraphy and biodistribution purposes. In a preclinical xenograft animal model with PSMA expressing LNCaP cells, treatment with one dose of 90Y-J591 resulted in an average of 70% tumor reduction in 90% of animals, whereas tumor progression was observed in control-treated mice (saline or nonradioactive antibody or 90Y-irrelevant antibody).17 We previously performed a phase I trial of mAb J591 in 14 patients with recurrent, progressing PC to determine the antibody dose that produced a satisfactory ratio of tumor targeting and nonspecific organ uptake.18 We now report the results of a phase I dose-escalation study using 90Y-J591 to define the maximum-tolerated dose (MTD), toxicity, human antihuman antibody (HAHA) response, pharmacokinetics (PK), organ dosimetry, targeting, and preliminary efficacy data in patients with androgen-independent PC.
Patient Eligibility and Screening Eligible patients had a prior histologic diagnosis of PC with evidence of recurrent or metastatic disease as defined by an increasing PSA or abnormal radiologic studies including bone scan, computed axial tomography (CT), or magnetic resonance imaging (MRI). Patients were required to have a PSA  1.0 at study entry with three consecutive increasing PSA values over a period of 2 weeks. Eligible patients were more than 21 years of age with a Karnofsky performance status of at least 60% and life expectancy more than 6 months at the time of entry. Luteinizing hormone-releasing hormone agonist was maintained either for the duration of treatment and follow-up, or terminated 10 weeks (for 28-day depot) or 24 weeks (for 3-month depot) before entry. Antiandrogen therapy was either maintained for the duration of treatment and follow-up or terminated 6 weeks before entry. Patients were not permitted to receive aspirin or nonsteroidal anti-inflammatory agents within 2 weeks of entry; corticosteroids, adrenal hormone inhibitors, or PC-SPES within 4 weeks of entry; or systemic chemotherapy or radiation therapy within 6 weeks of entry. Patients with a history of prior radiation therapy encompassing more than 25% of the skeleton or prior treatment with strontium-89 (Metastron; Medi-Physics, Arlington Heights, IL) or samarium-153 (Quadramet; Berlex, Montvile, NJ) were ineligible for the trial. Patients were required to have adequate bone marrow function with an absolute neutrophil count (ANC) 2.0 x 109/L and a platelet count 150 x 109/L. Patients had to have a unilateral or bilateral posterior iliac crest bone marrow biopsy demonstrating  10% or 25%, respectively, of the intratrabecular marrow space involved by PC. Additional exclusion criteria included serum creatinine more than 2.0 mg/dL, serum AST 2.0x the upper limit of normal, serum total bilirubin 1.5 times the upper limit of normal, serum calcium 12.5 mg/dL, and an abnormal coagulation profile (prothrombin time and partial thromboplastin time) unless receiving anticoagulant therapy. Anticoagulant therapy was to be stopped if the platelet count decreased to less than 50 x 109/L. Patients were excluded from the study for CNS metastases, history of seizure and/or stroke, HIV infection, active serious infection, active ischemic heart disease or heart failure (New York Heart Association class III to IV), and other serious illnesses involving the cardiac, respiratory, CNS, renal, hepatic, or hematologic organ systems that might preclude completion of the study or interfere with determination of causality of any adverse effects experienced. All patients provided written institutional review board–approved informed consent. Pretreatment evaluation included a history, physical examination, and routine laboratory studies including PSA, PAP, testosterone, and an ECG. Radiologic studies included a chest x-ray; CT or MRI of the abdomen, pelvis, and brain; and a bone scan. Patients were required to have a bone marrow biopsy within 6 weeks of study entry.
Treatment Plan and Toxicity Evaluation
Dose preparation.
The antibody was first conjugated with a macrocyclic chelating agent, 1,4,7,10-tetraazacyclododerane-N,N1,N11,N111-tetraacetic acid (DOTA). J591-DOTA was supplied by BZL Biologics, Inc (Framingham, MA) under investigational new drug 9279. The DOTA-J591 mAb was then labeled with 111In (MDS Nordion, Ontario, Canada) or 90Y chloride (Perkin-Elmer, Shelton, CT) in an ammonium acetate buffer to produce specific activities of 111 to 222 MBq/mg (3 to 6 mCi/mg).19 Radiolabeled J591 was purified by gel filtration and sterilized by membrane filtration before administration into patients. Patients initially received a dose of 111In-J591 for PK, biodistribution, and dosimetry determinations. One week later, patients received 90Y-J591. Altered or atypical 111In-J591 biodistribution would preclude 90Y-J591 treatment. With both 111In and 90Y doses, all patients received a total of 20 mg of mAb J591. The diagnostic dose of 5 mCi of 111In-J591 (1 to 2 mg) was mixed with unchelated J591 mAb (18 to 19 mg). For 90Y, DOTA-J591 was labeled at a specific activity between 111 and 185 MBq/mg (3 to 5 mCi/mg) of antibody to reach the defined dose of 90Y. J591 mAb was infused intravenously at Pharmacokinetics and biodistribution studies with 111In-J591. Venous blood samples (4 mL) were obtained at 10 minutes; 1, 2, 4, and 24 hours; and 2, 3, 4, and 7 days. The percent injected dose was determined by measuring an aliquot of blood along with a known 111In standard. To assess the biodistribution of mAb J591, total body images were obtained within 1 hour postinfusion (day 0) and again at four additional time points in the subsequent week (eg, days 1, 2, 3, and 6 to 7). The gamma camera images were obtained using a dual-head gamma camera with a medium energy collimator (ADAC, Milpitas, CA; General Electric Medical Systems Inc, Milwaukee, WI). The percent injected dose in major organs (heart, liver, spleen, kidneys, bone marrow, gastrointestinal tract, and bladder) was estimated by drawing regions of interest, determining the relative counts in each organ, and comparing the results with a standard. Single-photon emission CT studies of the abdomen, pelvis, and/or areas of suspected metastatic lesions were performed on day 2 or 3 in selected patients. Using the values obtained from sequential biodistribution studies and plasma PK with 111In-J591, radiation dosimetry of 90Y-J591 was estimated by substituting the physical characteristics of 90Y (Vallabhajosula et al, manuscript in preparation). 90Y-J591 dose-escalation protocol. After completion of the 111In studies, each patient received a 90Y dose, which was escalated in cohorts of three to six patients at the following planned dose levels: 5, 10, 15, and 20 mCi/m2. A fifth dose level of 17.5 mCi/m2 was added to more precisely define the MTD. Dose escalation was held until at least three patients at each dose level had been observed for 6 weeks without evidence of hematologic toxicity. If any of the initial three patients at a dose level experienced grade 1 or 2 hematologic toxicity by 6 weeks, dose escalation was held until the onset of blood count recovery was demonstrated. If any patient experienced grade 3 or 4 hematologic toxicity, at least six patients were entered at that dose level and observed until onset of blood count recovery before dose escalation. If at any time, two instances of dose-limiting toxicity (DLT) were observed at a given dose level, additional entry at that dose level was terminated.
DLT was defined as the following: hematologic toxicity consisting of grade 4 thrombocytopenia (platelet < 10 x 109/L) and/or grade 4 neutropenia (ANC < 0.5 x 109) for more than 5 days; and other toxicity consisting of any The MTD was defined as the dose level at which zero of six or one of six patients experience a DLT, with the next higher dose level having at least two of six patients experiencing DLT. Once the MTD was reached, at least six patients were to be evaluated at that dose level. Patients were observed for a minimum of 12 weeks after 90Y-J591 administration. Routine clinical and laboratory assessments (including biochemical profile, PSA, PAP, and testosterone) were performed at defined intervals. CBC and platelet counts were initially monitored one to two times per week and then every 4 weeks until blood count stabilization. If the ANC was less than 1.0 x 109/L and/or platelets were less than 50 x 109/L, blood counts were monitored every other day. Chest x-ray; CT or MRI of the abdomen and pelvis; and a bone scan were performed after treatment week 12. HAHA response was monitored at defined time points.
Re-Treatment
HAHA
Response Criteria
In patients with measurable disease, the following definitions were used: complete response was the complete disappearance of all measurable lesions by physical examination or imaging studies, with no appearance of new lesions for Duration of response was the time interval from treatment initiation until progression as documented by either an increase in PSA, enlargement of a measurable lesion(s), or new lesion(s) on bone scan. Response assessments were performed at 12 weeks. The increasing PSA was confirmed by a second, serially increasing PSA, and the duration was defined as the time from initiation of treatment to the time of the first increasing PSA.
General Twenty-nine patients with advanced PC, whose pertinent demographic and personal characteristics are shown in Table 1, were enrolled onto the study between October 2000 and May 2002. All patients continued to receive luteinizing hormone-releasing hormone agonist therapy during the trial except for one patient who had a prior orchiectomy. Only one patient continued to receive antiandrogen therapy.
Pharmacokinetics, Biodistribution, and Dosimetry On the basis of plasma-time activity data and fit to a monoexponential curve, the plasma terminal half-life for 111In-J591 was determined to be 32 ± 8 hours. The volume of distribution was estimated to be 4,467 ± 811 mL, with a clearance rate of 98 ± 43 mL/h. The biexponential curve fit of plasma-time activity data showed that more than 80% of labeled antibody clears from circulation with a half-life (beta component) of 44 ± 14 hours. Early images document most of the activity in the circulation, with the liver as the only organ sequestering a significant amount of 111In activity. By day 6, the whole body activity was almost 70% of the injected dose; the liver activity was 28% ± 8% of the injected dose. The radiation dosimetry of 90Y-J591, estimated on the basis of 111In-J591 data, is summarized in Table 2. The critical organ with the highest radiation dose is liver (0.24 ± 0.08 Gy/mCi), followed by spleen and kidneys. The radiation dose to bone marrow, on the basis of blood radioactivity, is 0.034 ± 0.016 Gy/mCi of 90Y administered. Dosimetry did not correlate with the degree of myelosuppression (data not shown).
J591 Targeting Among the 29 patients receiving 111In-J591, 19 patients had bone lesions and 13 patients had soft tissue lesions. Seventeen of 19 patients (89%) with bone lesions and nine of 13 patients (69%) with soft tissue lesions were accurately targeted, resulting in an overall targeting sensitivity of 26 of 32 (81%; Fig 1; Table 3). 22 There were no false-positive 111In-J591 scans.
90Y-J591 Dose Escalation The 90Y-J591 dose-escalation scheme, numbers of patients treated at each dose level, and number of re-treated patients are listed in Table 4. Four patients were treated at the initial 5 mCi/m2 dose level and seven patients were treated at the 10 mCi/m2 dose level. At the 15 mCi/m2 dose level, the first patient had a history of venous thrombosis and died of a presumed pulmonary embolus after self-discontinuing his warfarin. Although this was considered a DLT, the event was unlikely to be related to the study drug. An additional seven patients were treated at the 15 mCi/m2 dose level with no further episodes of DLT. At the 20 mCi/m2 dose level, after two patients developed grade 3 thrombocytopenia with grade 3 non–life-threatening bleeding episodes requiring transfusions, accrual was ended after a total of four patients. Although this was not the predefined DLT, these events were considered to be dose limiting. The 17.5 mCi/m2 dose level was added to better define the MTD. A total of six patients were treated at this dose level with no DLTs, and this dose level represents the MTD.
Hematologic Toxicity All single-dose hematologic toxicity is summarized in Table 5. Grade 3 thrombocytopenia with grade 3 bleeding episodes were seen in two patients at the 20 mCi/m2 dose level. One patient, who developed melena with a platelet count of 11 x 109/L and a hemoglobin level of 9.5 g/dL, was hospitalized and received platelet transfusions with cessation of bleeding. The platelet count of 11 x 109/L was the patient's platelet nadir. The patient refused an evaluation to determine the source of bleeding. The second patient had an episode of lower gastrointestinal bleeding with a platelet count of 12 x 109/L and a hemoglobin level of 10.2 g/dL and refused hospitalization. The platelet count of 12 x 109/L was the patient's platelet nadir. He received outpatient platelet transfusions with cessation of bleeding. A sigmoidoscopy revealed a small area of ulceration in the rectum, a previously irradiated field. The rectum has no known PSMA expression and imaging revealed no focal accumulation of radioisotope.
The median time to platelet nadir was day 28 and the median time to ANC nadir was day 35. The median time to full platelet recovery (> 150 x 109/L) was day 49 and the median time to full ANC recovery (> 2.0 x 109/L) was day 63. With a single dose, full platelet recovery and full ANC recovery was seen in 20 and 23 of 25 patients, respectively. All single-dose patients without complete count recovery had an ANC 1.3 x 109/L and platelets more than 70 x 109/L. Three patients received a second dose of 90Y-J591: two patients at 17.5 mCi/m2, with one of two experiencing grade 3 thrombocytopenia and neutropenia; one patient at 20 mCi/m2 experienced grade 3 thrombocytopenia and neutropenia. Both patients recovered a platelet count to more than 120 x 109/L. One patient at the 17.5 mCi/m2 dose level received three 90Y-J591 doses and experienced grade 3 thrombocytopenia (platelet recovery was 61 x 109/L) after the third dose. No DLTs were seen in the re-treated patients. A total of two patients, one at the 10 mCi/m2 dose level and the other at the 17.5 mCi/m2 dose level, had grade 3 anemia.
Nonhematologic Toxicity
Formation of HAHA There was no evidence of HAHA in any of the patients entered onto this trial. In the patients who received multiple doses, there was no HAHA detected and no change in drug clearance or targeting.
Antitumor Activity
There was strong association between PSA and measurable disease responses. Of 13 patients with soft tissue disease, 12 had measurable disease. Of the 12, six demonstrated progression, four had stable disease, and two had major objective responses. In nine of these 12 patients, PSA response agreed with the measurable observation. In two patients, PSA progressed while measurable disease was stable. In one patient, PSA was stable while measurable disease progressed (Table 7).
This phase I clinical trial has established that the anti-PSMAext mAb 90Y-J591 is well tolerated, with an MTD of 17.5 mCi/m2. Our findings with respect to toxicity, MTD, and DLT are consistent with those of other 90Y-labeled mAbs.23-26 Among the antibodies evaluated for radioimmunotherapy of PC, two 90Y-labeled mAbs have been studied previously. With the murine mAb m170, the MTD was 20 mCi/m2.27 Two trials of 90Y-capromab yielded the atypically low MTD of less than 9 mCi/m2.28,29
DLT in radioimmunotherapy trials, in general, is limited to short-lived, reversible myelotoxicity. The consistency of findings across different tumor types, different antigenic systems, mAb derivation (mouse, chimeric, humanized), and site and bulk of tumor suggests that the myelotoxicity is a function of the physical characteristics of the isotope (half-life, energy, range) and presumably its plasma half-life. This can be explained by the fact that the overwhelming majority of the administered radiolabeled mAb circulates free in the plasma, unavoidably irradiating the marrow with nonspecific radiation, while only a very small proportion of the injected dose (
Also consistent with previous radiolabeled antibody experience, we found that within any given dose level, there was significant interpatient variability in the degree of hematologic toxicity. For example, at the MTD of 17.5 mCi/m2, the mean platelet nadir was 41 x 109/L, with a range of 15 to 77 x 109/L. Similarly, in a phase I/II trial with 90Y–anti-CD20 (ibritumomab tiuxetan) in patients with non-Hodgkin's lymphoma, at the MTD dose of 0.4 mCi/m2, the median platelet nadir was 49.5 x 109/L, with a range of 2 to 136 x 109/L.25 In a phase I study of 90Y–anti-Lewis Y mAb B3, at the MTD, three of six patients had grade 1 platelet toxicity and the remaining three patients had grade 4 toxicity.24 In our study, we found no clear relationship between toxicity and prior chemotherapy or radiation treatment. In addition, there was no relationship to the extent of bone marrow involvement. Similar observations with respect to bone involvement were made by Knox et al30 and O'Donnell et al.27 In the latter trial of 90Y-m170 in PC, the authors comment that "[n]o obvious pretreatment parameter predicted hematological toxicity. ..." The variability in degree of myelotoxicity, despite the use of dosing adjusted to body weight or surface area, leads to the adoption of a (MTD) dose that, by definition, induces DLT-level toxicity in On the basis of two grade 3 non–life-threatening bleeding episodes with grade 3 thrombocytopenia at a 90Y dose of 20 mCi/m2, we chose to amend the predefined dose-limiting hematologic toxicity criteria and selected 17.5 mCi/m2 as the MTD. This conservative approach may have underestimated the true MTD, particularly in the context of two major responses seen at the 20 mCi/m2 dose level. Given that this was a phase I trial, our major concern was toxicity, and additional trials may be necessary to clarify whether the 20 mCi/m2 dose level can be administered safely. In this study, as in RIT studies in general, nonhematologic toxicity was minimal and not dose limiting. Radiation dosimetry estimates of 90Y-J591 indicate that administration of 40 mCi of 90Y dose would deliver less than 10 Gy to liver, spleen, and kidney (well below the acceptable radiation doses to these organs). Although only four patients received more than a single dose of mAb J591, re-treatment appears possible and should be evaluated further. No HAHA response was seen in any patients, including those re-treated patients. This study also demonstrates that mAb J591 can target known sites of PC metastases in both bone and soft tissue. PSA and objective measurable disease responses were seen in several patients. The concordance between PSA responses and measurable disease responses suggests that, with RIT, PSA might be used as a marker of response in patients without measurable disease in phase I and/or phase II trials. Among solid tumors, PC is a reasonable target for RIT because it is relatively radiosensitive and its predilection for forming small foci in the marrow and lymph nodes makes its target antigens readily accessible to circulating mAbs. In addition, adjunctive factors such as radiosensitizers, stem-cell support/rescue, multiple low-dose schedule, and/or addition of marrow-sparing agents capable of inducing additive or synergistic antitumor activity might provide additional benefit. Our own data in PC xenograft models12 (Smith-Jones and Vallabahajosula, manuscript in preparation) demonstrated the ability to deliver higher cumulative doses and improved antitumor activity by the use of a fractionated dose schedule. Other preclinical data in human PC xenografts using 90Y-based radioimmunotherapy combined with taxanes has demonstrated therapeutic synergy without excess toxicity. 31 Taxanes are known to have radiosensitizing properties, are active agents in PC, and cause little myelosuppression, making them an obvious choice to consider combining with RIT in PC clinical trials. Others have investigated the use of autologous peripheral-blood stem-cell rescue after radionuclide therapy to overcome the hematologic DLT.32 In the latter case, the investigators were able to increase the administered radionuclide dose approximately two-fold. On the basis of acceptable toxicity and evidence of biologic activity, additional investigation with 90Y-J591 is warranted. In addition to the use of different radionuclides and phase II trials of radiolabeled J591, an ongoing trial is evaluating J591 as a targeted mAb vehicle attached to the chemotherapeutic agent, maytansinoid-1, in the treatment of patients with androgen-independent PC.
N.H.B. developed the J591 antibody used in the study and served as Principal Investigator of the reported trial. J591 and companion anti-PSMAext monoclonal antibodies were patented by the Cornell Research Foundation and licensed to BZL Biologics, Inc.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Neil H. Bander, BZL Biologics, Inc; Shankar Vallabhajosula, BZL Biologics, Inc, Millennium Pharmaceuticals, Inc. Performed contract work within the last 2 years: Shankar Vallabhajosula, Millennium Pharmaceuticals, Inc. Received more than $2,000 a year from a company for either of the last 2 years: Neil H. Bander, BZL Biologics, Inc; Shankar Vallabhajosula, Millennium Pharmaceuticals, Inc.
We thank the following individuals for their substantial assistance in this trial: Peter Smith-Jones, PhD, Maureen Joyce, Felicia Berger, Alyssa S. Rosmarin, Sae Kim, He Liu, Mark R. Navarro, and Lana Winter.
Supported in part by National Institutes of Health General Clinical Research Center Program (NCRR grant M01RR00047); US Department of Army (DAMD17-98-1-8594); Cancer Research Institute; CaP CURE; the David H. Koch Foundation; the Peter Sacerdote Foundation; the McCoey Fund; the Laurent and Alberta Gerschel Foundation, the Yablans Family Foundation, BZL Biologics Inc; and Millennium Pharmaceuticals Inc. Previously presented, in part, at the poster presentation of the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
