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Journal of Clinical Oncology, Vol 26, No 6 (February 20), 2008: pp. 955-962 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.9941 Phase III Comparison of Vitespen, an Autologous Tumor-Derived Heat Shock Protein gp96 Peptide Complex Vaccine, With Physician's Choice of Treatment for Stage IV Melanoma: The C-100-21 Study Group
From the Istituto Europeo di Oncologia; Istituto Nazionale Tumori, Milan, Italy; Lutheran General Cancer Care Center, Park Ridge, IL; Atlantic Health System, Montclair, NJ; Royal Melbourne Hospital, Victoria, Australia; Mount Sinai Comprehensive Cancer Center, Miami Beach, FL; The University of Texas M.D. Anderson Cancer Center, Houston, TX; University of Pittsburgh School of Medicine, Pittsburgh, PA, Bristol-Myers Squibb, Wallingford, CT; Antigenics, New York, NY; and the University of Connecticut School of Medicine, Farmington, CT Corresponding author: Pramod K. Srivastava, MD, PhD, Center for Immunotherapy of Cancer & Infectious Diseases, University of Connecticut School of Medicine, Farmington, CT 06030-1601; e-mail: srivastava{at}nso2.uchc.edu
Purpose To assess the antitumor activity of vitespen (autologous, tumor- derived heat shock protein gp96 peptide complexes) by determining whether patients with stage IV melanoma treated with vitespen experienced longer overall survival than patients treated with physician's choice. Patients and Methods Patients (N = 322) were randomly assigned 2:1 to receive vitespen or physician's choice (PC) of a treatment containing one or more of the following: dacarbazine, temozolomide, interleukin-2, or complete tumor resection. This open-label trial was conducted at 71 centers worldwide. Patients were monitored for safety and overall survival. Results Therapy with vitespen is devoid of significant toxicity. Patients randomly assigned to the vitespen arm received variable number of injections (range, 0 to 87; median, 6) in part because of the autologous nature of vitespen therapy. Intention-to-treat analysis showed that overall survival in the vitespen arm is statistically indistinguishable from that in the PC arm. Exploratory landmark analyses show that patients in the M1a and M1b substages receiving a larger number of vitespen immunizations survived longer than those receiving fewer such treatments. Such difference was not detected for substage M1c patients. Conclusion These results are consistent with the immunologic mechanism of action of vitespen, indicating delayed onset of clinical activity after exposure to the vaccine. The results suggest patients with M1a and M1b disease who are able to receive 10 or more doses of vitespen as the candidate population for a confirmatory study.
Stage IV melanoma has a dismal prognosis and there is no consensus for a standard treatment. Dacarbazine (DTIC), and interleukin-2 (IL-2) are licensed agents for stage IV melanoma in the United States; however, other agents such as the DTIC precursor temozolomide, interferon-  , and complete surgical resection, where feasible, are often used alone or in combination among other approaches.1 These treatments are ineffective for the vast majority of patients. Melanoma has historically attracted the attention of immunologists because of the belief that it is particularly immunogenic. That belief has fuelled a range of immunotherapies: haptenated autologous cells,2 allogeneic cells,3 gangliosides,4 cancer testes antigens,5,6 differentiation antigens,7,8 altered differentiation antigens,9 or heat shock protein (HSP)-peptide complexes.10 Various antigens (peptides, proteins), adjuvants, immune modulators (anti-CTLA4 antibody)11,12 and means of delivery (dendritic cells [DCs], DNA) have been used. Adoptive immunotherapy with unmodified or engineered T cells of single or mixed specificities has been used.13,14 Most immunologic approaches elicit a degree of serological or T-cell activity,3,5-7,9 and most of them suggest a degree of clinical activity. A correlation between immune responses and clinical activity has been elusive, partly because of the paucity of robust clinical activity. Several approaches have been tested without evidence of benefit in randomized phase III trials in patients with stage IV melanoma.15-18 We present here the results of a randomized phase III trial in patients with stage IV melanoma comparing vaccination with the HSP gp96 peptide complexes derived from autologous tumors (vitespen, formerly known as Oncophage [Antigenics Inc, New York, NY]) versus physician's choice of treatment, including IL-2 and/or DTIC/temozolomide and/or tumor resection. The scientific basis for the treatment has been described elsewhere.19 Briefly, purified preparations of gp96 (and other HSPs) from tumors are noncovalent complexes of HSPs and peptides. The peptides are derived from self- and tumor-specific proteins expressed in tumors. Immunization with gp96 peptide complexes leads to their uptake by the skin DCs through CD91 (an HSP receptor), representation of the gp96-chaperoned peptides by the DCs on MHC molecules, and stimulation of cognate T cells. Therapy of tumor-bearing mice with gp96 peptide complexes is highly effective for micrometastatic disease, and less so for progressively growing tumors.20 Phase I/II trials with this approach in human melanoma, renal carcinoma, and colon carcinoma have demonstrated hints of clinical activity.10,21,22 The present study builds on those trials and was designed to seek evidence of superior clinical efficacy of vitespen compared with the physician's choice (PC; in the absence of a well-defined standard of care).
Patients and Study Design Between January 2002 and September 2004, 322 adult patients with stage IV melanoma were randomly assigned at 71 centers in the Untied States (n = 163, 50.6%), Ukraine/Russia (n = 70, 21.7%), Europe (n = 69, 21.4%), and Australia (n = 20, 6.2%). Eligibility criteria included (a) stage IV melanoma, with expected resectability of some/all lesions to obtain at least 7 g of cancer; (b) no prior therapy for stage IV melanoma; (c) no therapy with IL-2 and/or DTIC/temozolomide within 12 months before study entry; (d) Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1; (e) adequate cardiac function, with New York Heart Association class II or less; (f) normal WBC and platelet counts; and (g) bilirubin no more than 1.5 mg/dL, AST no more than 2.5x the upper limit of normal, and adequate renal function, with serum creatinine no more than 1.5 mg/dL. Patients were excluded if they had brain metastases, mucosal or ocular melanomas, immunodeficiency, prior splenectomy, uncontrolled infection or serious intercurrent medical illnesses, or other malignancies treated within the last 5 years, with the exception of in situ cervical carcinoma or nonmelanoma skin cancer. Women of childbearing potential required a negative pregnancy test result before entry and agreed to use an effective method of contraception while receiving treatment. All patients gave written informed consent to participate in the study. The study was conducted under International Conference on Harmonisation/WHO Good Clinical Practice and was approved by the respective institutions' institutional review boards or ethics committees.
Vaccine Preparation, Quality Control, and Administration
Treatments in the PC Arm
Statistical Methods
Patient Flow and Disposition, and Preparation of Individualized Vitespen A total of 450 patients were screened for accrual (Fig 1). There were 128 (28.4% of total screened) screening failures, mostly a result of brain metastases (n = 29, 22.6% of failures), nonstage IV melanoma (n = 27, 21.1%), unwillingness to undergo tumor resection (n = 21, 16.4%), prior treatment for stage IV melanoma (n = 16, 12.5%), and unwillingness to provide consent (n = 13, 10%). A total of 322 patients were randomly assigned, 215 (66.7%) to the vitespen arm, and 107 (33.3%) to the PC arm. The groups were balanced at baseline with respect to age, sex, performance status, stage of disease, and complete resection (Table 1). Tumors (range, 1 to 42 g; mean, 17.8 g) were obtained from skin lesions, nodes, lung, or visceral sites. On average, 56 µg of vitespen was obtained per gram of tumor. Vitespen could be prepared for only 133 (61.9%) of the 215 patients randomly assigned to the vaccine arm.
Safety Assessment An adverse event (AE) was categorized as related to treatment if it was considered possibly, probably, or definitely related to vitespen or PC by the investigator. The most common (  5%) reported related AEs in the vitespen arm included pyrexia (8.3%), fatigue (6.0%), and nausea (5.3%), and in the PC arm included nausea (10.3%), vomiting (6.5%), rigors (6.5%), and diarrhea (5.6%). In the vaccine arm, two serious AEs (at least grade 4) were considered by investigators as possibly related to vitespen. One patient was reported to have thyroid function disorder resulting from toxic dominant thyroid nodule, symptoms of which resolved with therapy and vaccine cessation. Another patient was reported to present with cellulitis 5 days after the last vaccine; the infection resolved with antibiotic therapy.
ITT Survival Analysis for All Randomly Assigned Patients
Analysis of All Treated Patients Of the 107 patients randomly assigned to the PC arm, 21 (20.2%) were unable to receive the PC treatment, mostly as a result of consent withdrawal or disease progression before treatment. Similarly, of the 215 patients randomly assigned to the vaccine arm, 82 (38.1%) were unable to receive vaccine treatment. Most (61 of 82) did not receive vaccine treatment because vaccine could not be prepared for them because of technical difficulties; others did not receive vaccine because they did not undergo surgery, had vaccine prepared but not administered, withdrew consent, or experienced disease progression before initiation of treatment. Of the 215 patients randomly assigned to the vaccine arm, only 133 patients (61.8%) received one or more doses of vaccine. The treated patient population was also balanced with respect to the baseline demographic and disease criteria shown in Table 1 for the ITT population (data not shown). A comparative survival analysis of 133 vitespen- and 86 PC-treated patients showed similar patterns of survival to those seen in the ITT populations (Fig A1, online only; P = .25; HR = 1.29; 95% CI, 0.86 to 1.96). The patterns remain similar when analyzed by AJCC substage (Fig A1).
Exploratory Landmark Analyses We aimed to explore any differences in OS among patients who received one or more (1+), or 10 or more (10+) immunizations with vitespen (Fig 3). For this comparison, all patients in the analysis, including those in the PC arm, should have lived long enough to potentially receive at least 10 immunizations. This time period was calculated as 150 days postrandom assignment (median of 41 days to first immunization + 21 days for three additional weekly immunizations + 84 days for the remaining six immunizations). Therefore, patients who died within 150 days of random assignment were excluded from both arms, and the survival of patients who received 1+ or 10+ immunizations was compared with patients in the PC arm. The data for 1+ immunized patients are essentially identical to those shown in Figure A1. In contrast, the KM plots for 10+ immunized patients show a clear separation of the two arms in favor of the vitespen-treated patients for all patients as well as M1a (nominal P = .31; HR = 0.56; 95% CI, 0.18 to 1.72) and M1b (nominal P = .09; HR = 0.39; 95% CI, 0.13 to 1.20), but not M1c (nominal P = .81; HR = 1.08; 95% CI, 0.57 to 2.08) patients (Fig 3). Combined data from M1a + M1b patients show a clinically significant benefit of vitespen over PC in this subset of patients (nominal P = .03; HR = 0.45; 95% CI, 0.21 to 0.96).
Such an unplanned subset analysis carries obvious risks.26 Although the most obvious bias, that patients who live longer are able to receive more vaccines (rather than the converse), was addressed through exclusion from both arms, of patients who lived less than 150 days postrandom assignment, other biases through unknown or unmeasured factors may bias the analyses shown in Figure 3. Hence, a more complete analysis, looking for trends in OS as a function of increasing number of vacci-treatments (from 1+ to 10+), was undertaken. Figure 4 shows the HRs (with CIs) between the two arms for all patients as well as for patients stratified by substage, as a function of the number of vacci-treatments. With increasing number of immunizations, the HR shifts to the left (in favor of vaccine) in all patients, as well as in M1a and M1b, but not M1c, substages. The initial benefit of vitespen is most evident in the M1a substage, but the benefits of additional immunizations are most evident in the M1b substage. Combined data from M1a + M1b substages show the benefit of both trends, such that, among M1a + M1b patients who received 10+ immunizations, the benefit of vitespen is clinically significant and meaningful (nominal P = .03) and the limits of the CI for the HR (0.45; 95% CI, 0.21 to 0.96) exclude unity.
Vitespen is the first, and thus far the only, autologous tumor-derived protein therapeutic vaccine tested in a randomized phase III trial to our knowledge. ITT analysis shows that the outcome of treatment with vitespen is statistically indistinguishable from treatment with PC including chemotherapy with DTIC/temozolomide and/or IL-2 and surgery. Vitespen was noted to be safe and without significant toxicity. Questions of efficacy are inextricably linked with whether patients were adequately treated, and that in turn is linked with the number of injections of vitespen administered. Of the 215 patients randomly assigned to the vitespen arm, vitespen could not be prepared for 82 patients (62% success rate). However, even that modest success rate represents an exaggerated number, because it counts even a single vial of vitespen as a success. Animal experiments suggest a minimum threshold of four administrations of vitespen (gp96) to be necessary for protection from tumor growth.20,24 Using this criterion as a measure of feasibility, the success rate for production of vitespen was a mere 49%. Moreover, patients in the vitespen arm who could not receive vaccine generally received PC therapy, further diluting the ability to detect a difference between both arms. In light of these handicaps in the formal ITT analysis, we find it notable that the outcome of therapy with vitespen was statistically indistinguishable from the best standard of care. Exploratory landmark analyses, carried out to assess the impact of vitespen on patients who received multiple immunizations, show two notable phenomena: (a) among AJCC M1a and M1b substage patients, particularly among the latter, there is a clear trend toward improved survival as patients received more immunizations, from 1 to 10 or more; (b) among M1c substage patients, there is no such trend. The HR for OS in M1c patients remains steady at approximately 1.0, regardless of the number of immunizations they received. These landmark analyses are subset analyses that must be interpreted with caution because the primary analysis itself does not show significant differences between the arms. Figure 4 shows the results of approximately 40 subset analyses; the fact that one of them (10+ immunizations in M1a + M1b patients) achieves nominal statistical significance could well be a matter of chance. It is of interest to recognize, however, that the data in Figure 4 show a consistent and sustained trend through all of the analyses, and not simply a significant result in a single subset of patients; the trend is consistent with the idea that patients with less advanced disease (M1a and M1b) benefit from increasing doses of vacci-treatments, whereas patients with more advanced disease (M1c) do not. An obvious source of bias in this analysis (ie, that patients who live longer can receive more immunizations) has been eliminated by the design of the landmark analyses as described in the Results section. The lack of efficacy as a function of increasing doses of vacci-treatments in the M1c patients, in addition to being consistent with the mechanism of action of vitespen, may be viewed as a negative control for methodologic biases in the subset analyses. Because there exists a greater collective experience with chemotherapies than with vacci-therapies, it is easy, and dangerous in our view, to judge one by the standards of the other. Appropriate evaluation of the results from the two approaches requires recognition that the mechanisms of action of immunotherapy are distinct from those of most chemotherapies in two fundamental ways. First, chemotherapies act directly on cancers, whereas immunotherapy stimulates the host immune response, which must then act on the cancer. This difference has important implications; patients need to be sufficiently healthy for a sufficiently long time to benefit from immunotherapy. Such constraints apply to chemotherapies to a more limited extent. Second, because immunotherapy relies on a secondary inducible mechanism (ie, immunologic activation of the host), its activity is modulated by physiologic parameters. Because cancers in earlier stages are less likely to have acquired immune-subversive armamentarium than are cancers in later stages simply as a consequence of immunologic editing,27 the former are more susceptible to immunotherapy. This principle does not directly apply to chemotherapies. Attention to these considerations suggests that the results of the landmark analyses presented here are consistent with the immunologic mechanisms of action of vitespen and with the natural history or biology of stage IV melanoma. Our results require formal confirmation through a randomized trial in which patients in the M1a and M1b substages are treated with a suitable number of vacci-treatments with vitespen.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Axel Hoos, Antigenics Inc (C); Lianng Yuh, Antigenics Inc (C); Renu Gupta, Antigenics Inc (C); Pramod K. Srivastava, Antigenics Inc (U) Consultant or Advisory Role: Giorgio Parmiani, Antigenics (C); John M. Kirkwood, Antigenics Inc (C); Renu Gupta, Antigenics Inc (C); Pramod K. Srivastava, Antigenics Inc (C) Stock Ownership: Axel Hoos, Antigenics Inc; Lianng Yuh, Antigenics Inc; Renu Gupta, Antigenics Inc; Pramod K. Srivastava, Antigenics Inc Honoraria: None Research Funding: Pramod K. Srivastava, Antigenics Inc Expert Testimony: Pramod K. Srivastava, Antigenics Inc (U) Other Remuneration: Pramod K. Srivastava, Antigenics Inc
Conception and design: Axel Hoos, Pramod K. Srivastava Financial support: Pramod K. Srivastava Administrative support: Alessandro Testori, Axel Hoos, Lianng Yuh, Renu Gupta Provision of study materials or patients: Alessandro Testori, Jon Richards, Eric Whitman, G. Bruce Mann, Jose Lutzky, Luis Camacho, Giorgio Parmiani, Giulio Tosti, John M. Kirkwood Collection and assembly of data: Alessandro Testori, Jon Richards, Eric Whitman, G. Bruce Mann, Jose Lutzky, Luis Camacho, Giorgio Parmiani, Giulio Tosti, John M. Kirkwood, Lianng Yuh, Renu Gupta Data analysis and interpretation: Jon Richards, Luis Camacho, Giorgio Parmiani, John M. Kirkwood, Lianng Yuh, Renu Gupta, Pramod K. Srivastava Manuscript writing: Pramod K. Srivastava Final approval of manuscript: Alessandro Testori, Jon Richards, Eric Whitman, G. Bruce Mann, Jose Lutzky, Luis Camacho, Giorgio Parmiani, Giulio Tosti, John M. Kirkwood, Axel Hoos, Lianng Yuh, Renu Gupta, Pramod K. Srivastava, Antigenics Inc
Authorship: Mark Albertini, University of Wisconsin, Madison, WI; Mamed Aliev, Blokhin Cancer Research Center, Moscow, Russia; Thomas Amatruda, Hubert Humphrey Cancer Center, Robbinsdale, MN; Clay Anderson, University of Missouri Health Sciences Center, Columbia, MO; Michael Atkins, Beth Israel Deaconess Medical Center, Boston, MA; Jane Beith, Sydney Melanoma Unit, Sydney, Australia; Boris Bilynsky, Lviv State Oncology Regional Clinical Diagnostic Center, Lviv, Ukraine; Boris Bolyukh, Vinnitsa Regional Oncology Center, Vinnitsa, Ukraine; Igor Bondarenko, Dneporpetrovsk State Medical Academy, Dnepropetrovsk, Ukraine; Mikhail Byakhov, Semashko Central Clinical Hospital of the Russian Ministry of Transportation, Moscow, Russia; Luis Camacho, M.D. Anderson Cancer Center, Houston, TX; David Chao, Royal Free Hospital, London, UK; Valery Cheshuk, Kiev Municipal Oncology Hospital, Kiev, Ukraine; Robert Conry, University of Alabama, Birmingham, AL; Brendon Coventry, Royal Adelaide Hospital, Adelaide, Australia; Irina Davidenko, Krasnodar City Oncology Center, Krasnodar, Russia; Lev Demidov, Blokhin Cancer Research Center, Moscow, Russia; John Eckardt, The Center for Cancer Care and Research, St Louis, MO; Howard Edington, University of Pittsburgh, Pittsburgh, PA; Thomas Gajewski, University of Chicago Medical Center, Chicago, IL; Joseph Germino, The Cancer Institute of New Jersey, New Brunswick, NJ; Peter Gibbs, Western Hospital, Melbourne, Australia; Oleg Gladkov, Chelyabinsk Regional Oncology Center, Chelyabinsk, Russia; Rene Gonzalez, University of Colorado, Aurora, CO; Martin Gore, Royal Marsden Hospital, London, UK; Eugene Gotko, Zakarpatskiy Regional Oncology Center, Uzhgorod, Ukraine; Vinay Gupta, University of Tennessee, Knoxville, Knoxville, TN; Naomi Haas, Fox Chase Cancer Center, Philadelphia, PA; Upendra Hegde, University of Connecticut, Farmington, CT; Peter Hersey, John Hunter Hospital, Newcastle Melanoma Unit, Newcastle, Australia; Janos Hunyadi, University of Debrecen, Medical & Health Science Center, Debrecen, Hungary; Christian Ingvar, Kirurgkliniken, Universitetssjukhuset, Lund, Sweden; David Irwin, Alta Bates Comprehensive Cancer Center, Berkeley, CA; Denise Johnson, Stanford University, Stanford, CA; Rick Kefford, Westmead Institute for Cancer Research, Wentworthville, Australia; Rustem Khasanov, Tatarstan Rupublican Oncology Center, Kazan, Russia; Vladimir Komissarenko, Krivoy Rog City Oncology Center, Krivoy Rog, Ukraine; Mikhail Kopp, Samara Regional Oncology Center, Samara, Russia; Ippolit Kostinsky, Ivano-Frankovsk Medical Academy, Ivano-Frankovsk, Ukraine; David Lawson, Emory University, Atlanta, GA; Paul Lorigan, The Christie Hospital, Manchester, UK; Jose Lutzky, Mount Sinai Comprehensive Cancer Center, Miami, FL; Bruce Mann, Royal Melbourne Hospital, Melbourne, Australia; William Maples, Mayo Clinic, Jacksonville, FL; Svetomir Markovic, Mayo Clinic, Rochester, MN; Richard Maziarz, Oregon Health and Science University, Portland, OR; Edward McClay, San Diego Melanoma Research Center, Vista, CA; Kelly McMasters, Norton Healthcare, Louisville, KY; Sergei Mikhailov, Stavropol Regional Oncology Center, Stavropol, Russia; Lance Miller, St John Medical Center, Tulsa, OK; Barry Mirtsching, Center for Oncology Research/Treatment, Dallas, TX; Vladimir Moiseyenko, Cancer Research Center, St Petersburg, Russia; Magnus Nillson, Vaxjo Central Hospital, Vaxjo, Sweden; Nickolay Ognerubov, Voronezh Regional Oncology Center, Voronezh, Russia; Giorgio Parmiani, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy; Anna Pavlick, New York University Medical Center, New York, NY; Marek Pawlicki, Oncological Institute, Krakow, Poland; Alexander Popovich, Donetsk Regional Oncology Center, Donetsk, Ukraine; Doug Reintgen, Lakeland Regional Cancer Center, Lakeland, FL; Antoni Ribas, University of California, Los Angeles Medical Center, Los Angeles, CA; Jon Richards, Lutheran General Cancer Care Center, Park Ridge, IL; Armando Sardi, St Agnes Healthcare Clinical Research Center, Baltimore, MD; Lynne Schuchter, University of Pennsylvania, Philadelphia, PA; Peter Selby, St James University Hospital, Leeds, UK; Roberto Sertoli, Instituto Nazionale Tumori, Genova, Italy; Marina Shomova, Ryazan Regional Oncology Center, Ryazan, Russia; Sergei Sidorov, City Hospital #1, Novosibirsk, Russia; Vilen Stepula, Odessa Regional Oncology Center, Odessa, Ukraine; Ulrika Stierner, Jubileumskliniken, Sahlgrenska Universitetssjukhuset, Gotenborg, Sweden; Jeffrey Sussman, University of Cincinnati Cancer Program, Barrett Cancer Center, Cincinnati, OH; Alessandro Testori, Istituto Europeo di Oncologia, Milan, Italy; Sergei Tjulandin, Blokhin Cancer Research Center, Moscow, Russia; Walter Urba, Providence Medical Center, Portland, OR; Gennadiy Varlan, Moscow City Hospital #33, Moscow, Russia; Olga Vtoraya, Arkhangelsk Regional Oncology Center, Arkhangelsk, Russia; Eric Whitman, Mountainside Hospital, Montclair, NJ; Steven Williamson, University of Kansas, Kansas City, KS; and Marek Wojtukiewicz, Regional Center of Oncology, Bialystock, Poland.
We thank all of the investigators who participated in the trial (members of the C-100-21 Study Group are listed in the Appendix, online only), Brent Blumenstein for many statistical consultations, and Hyam Levitsky, Janet Wittes, and Kerry Wentworth for their critical reading of the manuscript.
P.K.S. is supported by Physicians Health Services Chair in Cancer Immunology, National Institutes of Health Grant No. CA84479, and a sponsored research agreement with Antigenics Inc. Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
