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© 2000 American Society for Clinical Oncology Phase I Trial of the Anti–Lewis Y Drug Immunoconjugate BR96-Doxorubicin in Patients With Lewis Y–Expressing Epithelial TumorsFrom the Department of Medicine, Division of Hematology/Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL; the Department of Medical Oncology, M.D. Anderson Cancer Center, Houston, TX; and Bristol-Myers Squibb, Wallingford, CT. Address reprint requests to Mansoor N. Saleh, MD, Department of Medicine, Division of Hematology/Oncology, Comprehensive Cancer Center, 1824 Sixth Ave South, Wallace Tumor Institute 223, University of Alabama at Birmingham, Birmingham, AL 35294-3300; email mansoor.saleh{at}ccc.uab.edu
PURPOSE: We conducted a phase I clinical trial of BR96-Doxorubicin (BR96-Dox), a chimeric anti–Lewis Y (LeY) monoclonal antibody conjugated to doxorubicin, in patients whose tumors expressed the LeY antigen. The study aimed to determine the toxicity, maximum-tolerated dose, pharmacokinetics, and immunogenicity of BR96-Dox. PATIENTS AND METHODS: This was a phase I dose escalation study. BR96-Dox was initially administered alone as a 2-hour infusion every 3 weeks. The occurrence of gastrointestinal (GI) toxicity necessitated the administration of BR96-Dox as a continuous infusion over 24 hours and use of antiemetics and antigastritis premedication. Patients experiencing severe GI toxicity underwent GI endoscopy. All patients underwent restaging after two cycles. RESULTS: A total of 66 patients predominantly with metastatic colon and breast cancer were enrolled onto the study. The most common side effects were GI toxicity, fever, and elevation of pancreatic lipase. At higher doses, BR96-Dox was associated with nausea, vomiting, and endoscopically documented exudative gastritis of the upper GI tract, which was dose-limiting at a maximum dose of 875 mg/m2 (doxorubicin equivalent, 25 mg/m2) administered every 3 weeks. Toxicity was reversible and generally of short duration. Premedication with the antiemetic Kytril (granisetron hydrochloride; SmithKline Beecham, Philadelphia, PA), the antacid omeprazole, and dexamethasone was most effective in ameliorating GI toxicity. A dose of 700 mg/m2 BR96-Dox (doxorubicin equivalent, 19 mg/m2) every 3 weeks was determined to be the optimal phase II dose when administered with antiemetic and antigastritis prophylaxis. BR96-Dox deposition on tumor tissue was documented immunohistochemically and by confocal microscopy. At the 550-mg/m2 dose, the half-life (mean ± SD) of BR96 and doxorubicin was 300 ± 95 hours and 43 ± 4 hours, respectively. BR96-Dox elicited a weak immune response in 37% of patients. Objective clinical responses were seen in two patients. CONCLUSION: BR96-Dox provides a unique strategy to deliver doxorubicin to LeY-expressing tumor and was well tolerated at doses of 700 mg/m2 every 3 weeks. BR96-Dox was not associated with the typical side-effect profile of native doxorubicin and can potentially deliver high doses of doxorubicin to antigen-expressing tumors. A phase II study in doxorubicin-sensitive tumors is warranted.
MONOCLONAL ANTIBODIES directed at tumor-associated antigens provide an attractive means to deliver cytotoxic agents to the tumor target while potentially sparing normal tissue.1-8 An essential prerequisite for the clinical application of most drug-antibody immunoconjugates is the targeting of tumor surface antigens that are rapidly internalized upon ligand binding and, thus, enable intracellular delivery of the cytotoxic agents. In this regard, the Lewis Y (LeY) glycoprotein is an especially attractive target because it is expressed on a majority of human epithelial tumors (including breast, gastrointestinal [GI] tract, non–small-cell lung, cervix, ovary, and some melanomas) and is rapidly internalized upon ligand binding.9,10 LeY is expressed at low levels on normal cells of the GI tract in humans, primarily by differentiated cells of the esophagus, stomach, and intestine, as well as acinar cells of the pancreas. The immunoconjugate BR96-Doxorubicin (BR96-Dox) is composed of the chimeric immunoglobulin (Ig) G1 anti-LeY monoclonal antibody BR9611 linked to the anthracycline doxorubicin. In vitro and in animal models, binding of BR96-Dox to the LeY antigen results in rapid internalization of the complex and intracellular release of doxorubicin by acid hydrolysis in the acidic environment of endosomes and lysosomes.12-16 The subsequent localization of doxorubicin to the nucleus leads to DNA intercalation and inhibition of cell division.10,17 The BR96-Dox has a drug/antibody molar ratio of approximately 8:1 (eight molecules of doxorubicin are bound per antibody molecule). In laboratory studies, the BR96-Dox conjugate was significantly more potent against the LeY-positive cell line L2987 than the LeY-negative cell line HCT116 and more potent than a nonbinding IgG-Dox conjugate. In animal studies, BR96-Dox produced cures in 70% of mice bearing a large tumor burden and overall prolongation of survival when compared with untreated mice or mice treated with maximum doses of doxorubicin.10 Doxorubicin is an active agent in the treatment of a variety of epithelial tumors and has been shown to possess a dose response relationship over a finite dose range.18-20 Dose escalation is limited by toxicity to normal tissue.21 The ability to deliver higher doses of cytotoxic chemotherapy specifically to antigen-expressing tumor cells while sparing normal tissues that do not express the target antigen is a novel strategy to achieve dose-intensity. We conducted a phase I dose escalation trial of BR96-Dox in patients with LeY-expressing tumors to determine the toxicity and maximum-tolerated dose (MTD), kinetics, and immunogenicity of this immunoconjugate.
Eligibility Criteria All patients with pathologically confirmed carcinoma that expressed the LeY antigen as determined by immunohistochemistry22 were eligible for this phase I study. Antigen detection was performed on formalin-fixed primary or metastatic tissue. Patients whose tumor section demonstrated  20% of malignant cells positive for the LeY antigen were eligible. Eligible patients had to have failed no more than two prior chemotherapeutic regimens. Patients with prior anthracycline exposure were permitted to enroll provided they had not exceeded a cumulative doxorubicin dose of 400 mg/m2 and their disease had not progressed while on doxorubicin-based therapy. Eligibility criteria included a World Health Organization performance status of 0 to 1, an ejection fraction of more than 50%, and adequate hematologic function (hemoglobin = 10 g/dL, WBC > 4,000/uL, and platelet count = 100,000/uL), renal function less than 1.25 x upper limit of normal blood urea nitrogen/creatinine, and hepatic function (AST, ALT, alkaline phosphatase less than 2.5 x normal, and bilirubin 1.5 mg/dL).
Treatment
Toxicity Evaluation
Clinical Response Criteria
Pharmacokinetics
Human Immune Response
Immunohistochemistry
MTD
Patient Population A total of 297 tumor samples obtained from patients referred to one of the participating centers (UAB) were analyzed by uniform techniques and evaluated by a single pathologist. These data serve to provide the prevalence of LeY in various tumors (Table 1). A majority of the tumors tested were positive for LeY, with the distribution of antigen density (1+ to 2+ v 3+ to 4+) being close to equal. A combined total of 66 patients (UAB and M.D. Anderson Cancer Center) with a performance status of 0 to 1 were entered onto the study and received BR96-Dox at doses ranging from 66 mg/m2 to 875 mg/m2 (doxorubicin equivalent of 2 mg/m2 to 25 mg/m2). Patients with metastatic colorectal and breast cancer made up a majority of the study population (52% and 24% patients, respectively). Fifty-four patients (82%) had previously received at least one but no more than two prior chemotherapy regimes (Table 2). Three patients were found to be in violation of protocol and had received more than two prior chemotherapy regimes.
Table 3 provides the overview of the enrollment at each dose level. Between three and six patients were treated at the initial dose levels. Expansion of the study population at subsequent dose levels was required to evaluate the impact of various antiemetic and/or antigastritis strategies at the respective dose levels. The median number of courses administered was two (range, two to eight courses). Four patients received six courses, and one patient received a total of eight treatments.
Toxicity Table 4 lists the most frequent study drug–related adverse events reported during the study. The toxicity represents the cumulative side-effect profile over a total of 172 courses. The most common constitutional side effects observed during the study were GI (nausea, vomiting, and gastritis), followed by fever and asthenia. Laboratory abnormalities associated with the study drug included elevation of lipase, anemia, and elevated hepatic enzymes. Nausea, vomiting, gastritis, and elevated lipase represented the most common severe toxicities (grades 3 to 4). Hematologic toxicity of clinical significance was observed in three patients at the 700 mg/m2 dose level, who experienced reversible grade 4 neutropenia, with one patient also having grade 4 reversible thrombocytopenia. Hematologic toxicity was not dose-limiting in this study.
Table 5 provides an overview of the GI toxicity observed during the study. Toxicity at the early dose range (66 to 300 mg/m2) consisted primarily of mild to moderate nausea/emesis that occurred midway into the infusion and subsided within 24 hours. Prophylactic antiemetics (PA) consisting of prochlorperazine and lorazepam were instituted at the 300 mg/m2 dose level. Initially, patients who experienced greater than grade 2 nausea/emesis after their first treatment received PA with their second treatment. Thus, of the first four patients at the 300 mg/m2 dose level, one experienced grade 3/4 emesis and received the second dose of BR96-Dox with PA. Subsequently, four additional patients were treated and received PA along with their first treatment. One of four patients experienced grade 3/4 emesis (Table 5). Emesis requiring interruption of treatment was first observed at the 550-mg/m2 dose administered with PA. Three of four patients at this dose level receiving BR96-Dox as a 2-hour infusion experienced severe vomiting, with one patient showing trace amounts of blood-tinged mucous and epithelial remnants in the vomitus. In addition, two of the patients experienced diarrhea. All three patients who experience severe emesis, underwent upper GI endoscopic evaluation within 12 hours after the infusion. Endoscopy revealed exudative gastritis with areas of superficial hemorrhage (Table 6). Recovery was documented endoscopically on follow-up studies in all three patients before retreatment on day 21.
Based upon the suggestion that GI toxicity may in part be caused by a peak serum concentration effect, the study was amended to allow all subsequent patients to receive the immunoconjugate as a continuous infusion over 24 hours. Thus, four additional patients at the 550-mg/m2 dose level received their treatments as a 24-hour continuous infusion. This prolongation of the infusion duration resulted in a modest amelioration of GI toxicity and permitted further dose escalation (Table 5). However, even with the 24-hour continuous infusion schedule, grade 3/4 nausea/vomiting was experienced by four of six patients treated at 550 to 700 mg/m2 (with PA). All four patients experiencing grade 3/4 emesis underwent upper GI endoscopy within 24 hours after immunoconjugate administration. As with the previous patients, endoscopy revealed severe acute superficial hemorrhagic gastritis principally involving the gastric body (Fig 1A). Gastric biopsies revealed focal necrosis, sloughed epithelium, and fibrin pseudomembrane formation (exudative gastritis) (Fig 1B). Immunoperoxidase staining of gastric mucosal tissue obtained at endoscopy revealed localization of BR96 to the gastric epithelium (Fig 1C). Repeat endoscopy in two patients on day 14 demonstrated complete resolution of gastritis in both patients. Two of the four patients underwent an endoscopic evaluation of the lower GI tract, and no mucosal toxicity was observed.
The restricted location of gastric mucosal damage to areas of acid secretion as well as the acute and readily reversible nature of the toxicity suggested the possibility of ameliorating the side effect by prophylactic antacid therapy. Thus, an expanded cohort of four additional patients at the 700-mg/m2 dose received omeprazole to inhibit gastric acid secretions (in addition to PA). Omeprazole suppresses gastric acid secretion by specific inhibition of the H+/K+ proton pump enzyme system in the secretory surface of the gastric peripheral cells and was administered at a dose of 20 mg starting on day -4 and continued until day +2. Although this had little impact on emesis, the frequency of bloody vomitus seemed to be reduced (two of two patients at 700 mg/m2 without omeprazole v one of four patients with omeprazole had bloody vomitus). Despite omeprazole premedication, severe gastritis was documented in two of three patients who underwent endoscopy (Table 6). Based upon the observation that BR96-Dox–induced GI toxicity in dogs was reduced by premedication with corticosteroids, dexamethasone was added to the premedication regime (20 mg orally on day -2 to +1). Of the four patients at the 700 mg/m2 dose level premedicated with omeprazole and dexamethasone (and PA), three had significant emesis (Table 5), but none had severe exudative gastritis compared with two of three patients not receiving dexamethasone (Table 6). All three patients at the 875-mg/m2 dose level who were administered PA plus omeprazole plus dexamethasone experienced grade 3 to 4 emesis and grade 1 to 2 diarrhea. Two of three patients who underwent endoscopy revealed severe exudative mucosal changes extending beyond the gastric fundus into the proximal duodenum. As a result, further dose escalation was halted. In an attempt to further ameliorate the emetogenic effect of the immunoconjugate, an additional group of 15 patients was treated at the 700-mg/m2 dose level and received premedication with dexamethasone and Kytril (granisetron hydrochloride, SmithKline Beecham, Philadelphia, PA), a centrally acting HT3 antagonist, to control the emesis previously observed at this dose level. Four of 15 patients experienced severe GI toxicity. Of these, only two revealed severe exudative gastritis on endoscopy. Therefore, a premedication regime consisting of dexamethasone, omeprazole, and Kytril was felt to provide the most satisfactory amelioration of the spectrum of GI toxicity. Using this combination, the severity of the subjective and endoscopically documented gastritis was reduced, and patients seemed to be able to tolerate the administered dose of immunoconjugate. Additional toxicity included fever and asthenia, which was observed in approximately half of the patients. Approximately one third of the patients experienced increased cough and abdominal pain. Laboratory toxicity at higher doses included transient elevation of serum lipase and amylase. None of the patients experienced evidence of sustained clinical pancreatitis, and the symptoms and laboratory abnormalities resolved rapidly. The 24-hour infusion schedule permitted dose escalation up to the 875-mg/m2 dose, which was determined to be the MTD. Two of the three patients at this dose level experienced grade 4 emesis and exudative hemorrhagic gastritis extending into the duodenum, a finding not observed at lower dose levels. The critical question of whether the GI toxicity observed in human subjects was mediated by the BR96 antibody or the doxorubicin component of the conjugate was studied by administering unconjugated chimeric BR96 antibody to one eligible patient. The patient received unconjugated BR96 antibody at a dose of 550 mg/m2. The patient experienced bloody diarrhea accompanied by blood-tinged emesis during treatment, necessitating interruption of the infusion. The side effects subsided after cessation of therapy. In view of the observed toxicity, no additional patients received the unconjugated antibody.
Tumor Biopsy
Clinical Response Objective clinical responses were observed in two of 58 assessable patients who received a minimum of two courses of BR96-Dox. Partial clinical responses were achieved in one patient with metastatic breast cancer and prior doxorubicin exposure and in a second patient with advanced, previously untreated gastric cancer. Both patients received six cycles of BR96-Dox at the 700-mg/m2 dose level. Twenty-one patients had stable disease after two treatments.
Pharmacokinetics/Immune Response
The phase I study of the immunoconjugate composed of the chimeric anti-LeY antibody BR96 linked to doxorubicin demonstrated important clinical features of this novel molecule. The kinetics of doxorubicin administered as the BR96 immunoconjugate provided a more prolonged drug exposure than would be expected with native doxorubicin alone, and tumor biopsy data confirmed the ability to deliver the drug to the tumor cells via the antibody.27 Interestingly, as previously noted in the dog model (P.A. Trail, personal communication, January 1999), toxicity of the immunoconjugate seemed to be caused by the biologic activity of the chimeric monoclonal antibody as opposed to doxorubicin, as was noted in the single patient who received the unconjugated antibody. The precise reason for the observed toxicity, which was primarily limited to the upper GI tract in human subjects, remains unclear. There was significant variation in the calculated circulating half-life of the antibody based upon data generated by the ELISA. At the 550-mg/m2 dose, the half-life of 300 hours is longer than has been observed with other chimeric antibodies but consistent with the ability of recombinanthuman-mouse antibodies to survive much longer than murine antibody. The calculated circulating half-life of doxorubicin is much longer than would have been projected based upon delivery of comparable doses of doxorubicin intravenously (Fig 5) and demonstrates the advantage of drug delivery via an immunoconjugate strategy. Despite the longer circulating time of doxorubicin and serum levels much higher than achieved with intravenous native doxorubicin, we did not observe the myelosuppression and alopecia expected with doxorubicin therapy.21 This observation supports the concept that drug delivery via an immunoconjugate strategy provides targeted delivery of the cytotoxic agent to antigen-expressing tissue and sparing of tissues not expressing the target antigen. The immunohistochemical staining and confocal microscopy data obtained using tumor tissue specimens are consistent with this finding. The fall in molar ratio of BR96-Dox in vivo would imply instability of the immunoconjugate. However, a molar ratio of greater than 4 molecules of doxorubicin for every molecule of BR96 was maintained over the 24-hour period after the end of infusion. Second generation molecules would need to use better linker strategies to improve the integrity of the immunoconjugate in vivo.
The toxicity of BR96-Dox was primarily localized to the upper GI tract and may have been caused by binding of the antibody to antigens expressed on normal gastric mucosa. The reason for the restricted nature of the exudative gastritis observed on endoscopy is unclear because the LeY antigen is expressed along the entire GI tract. The severe enteritis observed in the dog model was not seen in our study, but both human and animal model studies indicated that the toxicity was most likely caused by the chimeric antibody itself. Antiemetic and antigastritis strategies together with dexamethasone to inhibit complement activation that could have been triggered by the chimeric antibody were useful to only a modest degree. We did not observe evidence of complement activation and deposition on the gastric biopsies by immunohistochemistry, although the timing of the biopsy was not designed to gain this information. GI toxicity could not be totally ameliorated with the premedication regime, although it did enable patients to better tolerate the regimen and permitted dose escalation. Elevation of pancreatic enzymes may have been caused by immunoconjugate deposition onto pancreatic tissue. Importantly, however, the elevation in enzymes was generally transient, and most patients experienced only mild and transient abdominal pain with no evidence of clinical pancreatitis. At the MTD of 875 mg/m2, patients had severe subjective GI toxicity, and endoscopic exams revealed exudative gastritis involving the distal upper GI tract. Based upon the toxicity profile, the dose of 700 mg/m2 administered every 3 weeks in conjunction with omeprazole, Kytril, and dexamethasone was determined to be the optimal phase II dose for BR96-Dox. Despite very encouraging animal model data,10 the clinical activity observed in this trial was very modest, even though 27 of the 66 patients received the recommended phase II dose. However, this phase I study was not designed to assess clinical activity, and a majority of the enrolled patients had advanced disease, prior therapy, and tumor types generally felt not to respond to doxorubicin. A phase II study in patients with breast cancer would be a reasonable setting to assess the clinical efficacy of this immunoconjugate strategy. Such a study has been conducted, and data await publication.
We thank Sharon Garrison for preparation of the manuscript.
1. Hellström I, Hellström KE, Siegall CB, et al: Immunoconjugates and immunotoxins for therapy of carcinomas, in August JT, Anders MW, Murad F, Coyle JT (eds): Advances in Pharmacology. San Diego, CA,Academic Press, 1995, pp 349-388 2. Schlom J: Monoclonal antibodies in cancer therapy. Biol Ther Cancer 20:507-521, 1995 3. Pietersz GA, Krauer K: Antibody-targeted drugs for the therapy of cancer. J Drug Target 2:183-215, 1994[Medline] 4. Frankel AE, Tagge EP, Willingham MC: Clinical trials of targeted toxins. Semin Cancer Biol 6:307-317, 1995[Medline] 5. Larson S: Radioisotope conjugates. Biol Ther Cancer 20:534-552, 1995 6. LoBuglio AF, Saleh MN: Monoclonal antibody therapy of cancer, in Davis S (ed): Critical Reviews in Oncology/Hematology. New York, NY,Elsevier Publishers, 1992, pp 271-282 7. LoBuglio AF, Saleh NM: Monoclonal antibodies: II. Biological therapy, in Niederhuber JE (ed): Current Therapy in Oncology. St. Louis, MO,BC Decker, 1993, pp 41-49 8. Trail PA, Willner D, Hellström KE: Site-directed delivery of anthracyclines for cancer therapy. Drug Dev Res 34:196-209, 1995
9.
Hellström I, Garrigues HJ, Garrigues U, et al: Highly tumor-reactive, internalizing, mouse monoclonal antibodies to LeY-related cell surface antigen. Cancer Res 50:2183-2190, 1990
10.
Trail PA, Willner D, Lasch SJ, et al: Cure of xenografted human carcinomas by BR96-doxorubicin immunoconjugates. Science 261:212-215, 1993
11.
Yarnold S, Fell PH: Chimerization of antitumor antibodies via homologous recombination conversion vectors. Cancer Res 54:506-512, 1994
12.
Comereski CR, Peden WM, Davidson TJ, et al: BR96-doxorubicin conjugate (BMS-182248) versus doxorubicin: A comparative toxicity assessment in rats. Toxicol Pathol 22:473-488, 1994 13. Garrigues J, Garrigues U, Hellström I, et al: LeY specific antibody with potent antitumor activity is internalized and degraded in lysosomes. Am J Pathol 142:607-622, 1993[Abstract] 14. Willner D, Trail PA, Hofstead SJ, et al: (6-Maleimidocaproyl) hydrazone of doxorubicin: A new derivative for the preparation of immunoconjugates of doxorubicin. Bioconjug Chem 4:521-527, 1993[Medline] 15. Trail PA, Slichenmyer WJ, Birkhofer MJ, et al: BR96-doxorubicin immunoconjugate for treatment of patients with carcinoma. Proc Am Assoc Cancer Res 37:626, 1996 (abstr 3212)
16.
Sjogren HO, Isaksson M, Willner D, et al: Antitumor activity of carcinoma-reactive BR96-doxorubicin conjugate against human carcinomas in athymic mice and rats and syngeneic rat carcinomas in immunocompetent rats. Cancer Res 57:4530-4536, 1997
17.
Trail PA, Willner D, Lasch SJ, et al: Antigen specific activity of carcinoma reactive BR64-adriamycin conjugates evaluated in vitro and in human tumor xenograft models. Cancer Res 52:5693-5700, 1992
18.
Hryniuk W, Levine MN: Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer. J Clin Oncol 4:1162-1170, 1986
19.
Wood WC, Budman DR, Korzun AH, et al: Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med 330:1253-1259, 1994 20. Fetting J, Gray R, Abeloff M, et al: CAF vs a 16-week multidrug regimen as adjuvant therapy for receptor-negative, node-positive breast cancer: An intergroup study. Proc Am Soc Clin Oncol 14:96, 1992 (abstr 83) 21. Doroshow JH: Anthracyclines, in Chabner BA, Longo DL (eds): Cancer Chemotherapy and Biotherapy: Principles and Practice (ed 2). Philadelphia, PA,Lippincott-Raven, 1996, pp 409-434 22. Myers RB, Srivastava S, Grizzle WE: Lewis Y antigen as detected by the monoclonal antibody BR96 is expressed strongly in prostatic adenocarcinoma. J Urol 153:1572-1574, 1995[Medline] 23. Saleh MN, LoBuglio AF, Sugarman S, et al: Gastrointestinal effects of chimeric BR96-doxorubicin conjugate. Proc Am Assoc Cancer Res 36:483, 1995 (abstr 2876) 24. Grasela D, LoBuglio AF, Saleh MN, et al: Parametric model for BR96-doxorubicin pharmacokinetics (PK) in cancer patients. Proc Am Assoc Cancer Res 36:234, 1995 (abstr 1393) 25. Sugarman S, Murray JL, Saleh MN, et al: A phase I study of BR96-doxorubicin (BR96-DOX) in patients with advanced carcinoma expressing the LewisY antigen. Proc Am Soc Clin Oncol 14:472, 1995 (abstr 1532) 26. Saleh MN, LoBuglio AF, Sugarman S, et al: Pharmacokinetics and immunogenicity of chimeric BR96-doxorubicin (BR96-DOX) in patients with LewisY positive metastatic cancer. Antibody Immunoconjug Radiopharm 8:61, 1995 (abstr 15) 27. Trail P, Onetto N, Lasch S, et al: Tumor penetration and functional activity of BMS-182248 following administration in a phase I clinical trial. Proc Am Assoc Cancer Res 36:499, 1995 (abstr 2974) Submitted June 9, 1999; accepted February 17, 2000.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
