|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2005.12.171 on January 18 2005 © 2005 American Society of Clinical Oncology. Phase II Trial of Individualized Rituximab Dosing for Patients With CD20-Positive Lymphoproliferative DisordersFrom the Division of Hematology/Oncology, Department of Medicine; Division of Hematopathology, Department of Pathology; Department of Radiation Oncology; University of Florida College of Medicine and Shands Cancer Center, Gainesville, FL Address reprint requests to James W. Lynch, MD, Box J-100277 JHMHC, 1600 SW Archer Road, Division of Hematology/Oncology, UF College of Medicine, Gainesville, FL 32610; e-mail: lynchjw{at}medicine.ufl.edu
PURPOSE: To determine the feasibility and efficacy of pharmacokinetic (PK) -based maintenance dosing of rituximab and possibly design a more rational maintenance schedule. PATIENTS AND METHODS: Patients with CD20-positive lymphoproliferative disorders were treated with four weekly infusions of rituximab 375 mg/m2. All patients without progressive disease were then monitored for 1 year and received a single infusion of 375 mg/m2 when the level decreased below 25 µg/mL. RESULTS: Twenty-nine of 31 patients were assessable with a variety of histologic subtypes. The overall response rate (ORR) for the entire group was 59% with 27% complete responses (CRs) and 32% partial responses. The median PFS for all patients was 19 months, with a median follow-up of 25 months. In 22 patients with low-grade non-Hodgkin's lymphoma (LGNHL), the ORR was 63% with 36% CR and median progression-free survival (PFS) has not been reached. Of 29 assessable patients, 22 were available for PK-based maintenance. The median time to repeat bolus was 5 months (range, 1 to 9 months) for the first, 3.5 months (range, 2 to 5 months) for the second, and 3 months (range, 2 to 4 months) for the third infusion. Ninety-five percent of patients required three or fewer infusions to be maintained in the therapeutic range. CONCLUSION: Individualized PK dosing for rituximab produced efficacy comparable to other published maintenance strategies. PK data from this trial suggest that a rational maintenance strategy in patients with LGNHL would be a single dose of 375 mg/m2 of rituximab every 3 to 4 months.
The use of the monoclonal antibody rituximab has been rapidly incorporated in clinical practice because of its significant clinical activity and generally favorable toxicity profile.1 Rituximab is a highly specific chimeric human and murine immunoglobulin G1 (IgG1) kappa monoclonal antibody that binds the CD20 antigen of B cells, a transmembrane phosphoprotein that is present on normal mature B cells and more than 90% of B-cell lymphomas.2 Proposed mechanisms of action of rituximab include complement-dependent and antibody-dependent cellular cytotoxicity, inhibition of tumor growth, and direct induction of apoptosis.3,4 Rituximab is effective either as a single agent or in combination with chemotherapy in the management of relapsed or de novo indolent and aggressive non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia.5-10 Furthermore, re-treatment has also been shown to be safe and effective by several investigators, most notably Davis et al,11 with response rates in the range of 40% and an estimated median time to progression of 17.8 months.12 Pharmacokinetic (PK) data obtained from the patients treated in the pivotal rituximab trial were analyzed by Berinstein et al.13 At 3 months post-treatment, they found the median serum level in 62 responders was 25.4 µg/mL compared with 5.9 µg/mL in 42 nonresponders (P = .001). In addition, serum levels correlated inversely with bulk of disease, and were lower in patients with small lymphocytic lymphoma compared with follicular NHL. The observation that rituximab serum levels correlate with clinical response, burden of disease, and histologic subtype of lymphoma suggests that the optimal therapeutic dose and schedule of rituximab may vary among different patient populations. Furthermore, the efficacy of rituximab in the re-treatment of patients with relapsed NHL and data from recently reported randomized trials suggest that maintenance therapy with rituximab may be of significant clinical benefit.14,15 The goals of this trial were to determine the feasibility of PK dosing; determine the overall response rate, complete response rate, and progression-free survival (PFS); determine the efficacy of a single-dose repeat bolus; and design a more rational maintenance schedule in patients for future clinical trials.
Patient Eligibility This was a single-institution phase II trial performed at The University of Florida Shands Cancer Center (Gainesville, FL). Patients were eligible if they had a CD20-positive B-cell lymphoproliferative disorder, excluding chronic lymphocytic leukemia or small lymphocytic lymphoma based on the WHO classification system, and had received at least one prior treatment not including rituximab (two patients had been previously treated with ibritumomab tiuxetan radioimmunotherapy).16 Additional eligibility criteria included an Eastern Cooperative Oncology Group performance status of 0 to 2; age older than 18 years; life expectancy of at least 3 months; adequate hematologic, hepatic, and renal function; and no serious coexistent active medical problems or infections. Patients were excluded if they were pregnant or lactating, or if they had evidence of CNS involvement by lymphoma. Before initiation of study treatment, all patients were required to give written informed consent. The trial was approved by the Institutional Review Board at the University of Florida Health Science Center.
Initial Evaluation and Therapy Rituximab was given intravenously at doses of 375 mg/m2 weekly for 4 consecutive weeks in all patients, according to recommendations by the manufacturer. Routine premedications included diphenhydramine and acetaminophen. Additional supportive management of infusion-related toxicities was at the discretion of the treating physician. Serum levels of rituximab were obtained immediately after the fourth weekly dose, and planned for every 30 days thereafter for up to 12 months. Rituximab levels were determined by enzyme-linked immunoabsorbent assay and were performed at Genentech Inc (South San Francisco, CA) as previously described.17 Microwell plates were coated with a purified goat anti-CD20 (2B8) idiotype polyclonal antiserum. Serial dilutions of patient serum were added to the wells and a goat antihuman IgG conjugated to horseradish peroxidase was used for detection. The plates were developed using the substrate 2,2-azino-bis(3-ethylbenzthiazoline sulfonic acid) and quantitated using absorbance spectrophotometry with a known standard curve of rituximab. This assay was validated to quantify 0.5 µg/mL of rituximab in serum.
Response Evaluation
Maintenance Therapy
Statistical Considerations
Patient Characteristics From March 2000 through June 2002, 31 patients were entered onto this phase II trial. Patient characteristics are listed in Table 1. The median age was 59 years (range, 41 to 82 years) and the majority (22 or 71%) of patients were female. The most frequent histologic subtype was follicular lymphoma (62%) but a variety of other subtypes were enrolled, including lymphoplasmacytic, mucosal-associated lymphoid tissue or marginal zone lymphoma, diffuse large-cell lymphoma, transformed low-grade NHL, and mantle-cell lymphoma (Table 1). The median number of previous treatments was two (range, one to five treatments). Only two patients had bulky disease (masses > 5 cm): one with diffuse large B-cell and one with follicular lymphoma.
Thirty-one patients were enrolled, of whom 29 were assessable for response. One patient withdrew consent before any treatment and another patient died suddenly of pulmonary embolism several days after the fourth weekly infusion of rituximab (despite anticoagulation) and never underwent restaging. Of the 29 assessable patients, 17 (59%) had objective responses. Eight patients (27%) had a complete response (CR) and nine (32%) had a partial response (PR). Patients with low-grade NHL had a higher overall response rate at 63% (CR 36% and PR 27%), compared with patients with aggressive lymphoma at 43% (CR 0% and PR 43%), as listed in Table 2.
Twenty-nine patients completed the initial therapy, of whom 23 went on to receive at least one dose of maintenance therapy. Six patients experienced disease progression before a need for repeat bolus therapy, of whom three experienced disease progression at first evaluation of response and were removed from the protocol. The remaining three patients experienced disease progression early in the maintenance phase before receiving a repeat bolus; their latest measured levels were within the therapeutic range. Three patients demonstrated an improved response during the maintenance phase of this trial: two from a partial to a complete remission, and one from stable disease to a PR. Five patients (17%) required only one additional infusion, 14 patients (48%) required two additional infusions, three patients (10%) required three additional infusions, and one patient (3%) required five additional infusions. Of note, the patient who received five infusions had been resistant to several previous treatments and never achieved a sustained level or radiographic response. This patient was noted to have disease progression 7 months into maintenance therapy. No patient required four additional infusions. Twenty-eight (95%) patients required three or fewer additional infusions of rituximab. The timing of rituximab repeat bolus administration is shown in Table 3. The median time from the fourth weekly infusion of rituximab to the first repeat bolus of rituximab was 5 months (range, 1 to 9 months), median time from the first to the second repeat bolus was 3.5 months (range, 2 to 5 months), and median time from the second to the third repeat bolus was 3 months (range, 2 to 4 months). The median pre- and postbolus rituximab levels for all 29 patients were 8.9 µg/mL (range, 2.4 to 24 µg/mL) and 54.4 µg/mL (range, 17.5 to 480 µg/mL), respectively (P = .04). Pre- and postbolus levels are listed in Table 4 and demonstrated significant increases with each repeat bolus. The mean rituximab levels after the first, second, and third repeat bolus were 94, 46, and 41 µg/mL respectively. Although rituximab levels decreased in all patients after the first month, the median and mean levels remained in a range consistent with saturation of surface CD20 throughout the maintenance period. No trend was seen relating to the predictive value of early levels regarding the need for future infusions (data not shown).
The monthly serum rituximab levels were analyzed by comparing the responder and nonresponder groups. A trend was noted for higher rituximab levels in patients considered to be responders. Statistically significant differences were detected at month 1, with mean rituximab levels of 181 µg/mL for responders versus 93 µg/mL for nonresponders (P = .04), and at month 4, with mean rituximab levels of 49 µg/mL for responders versus 9 µg/mL for nonresponders (P = .01). With the exception of month 4, however, mean levels for the nonresponders were also maintained near the target, suggesting that the PK strategy achieved the goal of maintaining sufficient levels even in patients not responding to treatment. The median PFS for all 29 assessable patients was 19 months, with a median follow-up of 24.5 months (range, 15 to 35 months; Fig 1). When the patients were grouped according to the histologic grade, the median PFS was not reached for low-grade lymphoma patients, compared with 5 months for aggressive lymphoma patients (P = .002; Fig 2). Patients who achieved a CR had a longer PFS, compared with patients achieving PR (P = .003). Neither patient with bulky disease responded.
Serum levels of rituximab were available for seven of 14 patients immediately before progressive disease. The range was 0.57 to 28.6 µg/mL, with a mean of 8.41 µg/mL. Ten patients experienced disease progression while receiving rituximab therapy, either shortly after induction or during maintenance therapy. Four patients experienced disease progression quickly despite therapeutic levels, and clearly were biologically resistant to therapy. Two patients experienced disease progression at 4 and 5 months with adequate levels at 1 month (127 and 93 µg/mL, respectively), but due to patient noncompliance with study protocol, had no further PK measurements before progression. One patient with bulky disease experienced disease progression 6 months into maintenance therapy and never achieved a therapeutic level. The final three patients experienced disease progression with levels in the therapeutic range; one had histologic transformation. Interestingly, one patient who had resolution of nodal disease was scored as having progressive disease because of development of a spinal cord lesion treated with radiotherapy. This patient remains alive and well without evidence of disease, either in the CNS or systemically, for 2 years. In all but three patients, it was clear clinically that disease progression was not related to inadequate exposure to rituximab. None of the assessable patients experienced greater than grade 2 infusion-related toxicity and such toxicities were less frequent during the maintenance phase. One patient developed a deep venous thrombosis, which was treated during induction therapy with heparin and warfarin. Unfortunately, after discharge and before disease evaluation or PK data could be obtained, the patient experienced sudden death, presumably secondary to a pulmonary embolus. Whether this was related to therapy is unknown; however, an association between thrombosis and rituximab has not been reported to our knowledge. No other unexpected or cumulative toxicities or opportunistic infections were observed.
The use of maintenance therapy with rituximab is an area of intense interest and controversy. Several observations suggest prolonged exposure to rituximab may be of benefit to patients with low-grade non-Hodgkin's lymphoma. First, the dosing schedule that shaped the pivotal trial for rituximab was based on PK data from single-dose and multiple-dose studies.3,21 It was observed that significant measurable serum levels could be achieved and sustained with four weekly infusions. It was then sensibly assumed that persistent measurable levels of rituximab suggested saturation of available CD20, and hence could be used as an intermediate end point for a dosing trial. There has been uncertainty from the beginning, however, about the optimal duration of exposure to rituximab, given that the in vivo mechanism(s) of action in real patients remains unknown. Theoretically, certain resistance mechanisms might be remediable with alternative dosing schedules; namely, rapid clearance leading to inadequate exposure for immune recognition, or decreased growth inhibition conferred by CD20 binding. On the other hand, biologic resistance via defects in complement or cell-mediated immunity or growth mechanisms that are independent of CD20 would be expected to be independent of dose and schedule of rituximab. In early clinical trials, several patients who experienced disease progression while receiving therapy had biopsies performed that demonstrated rituximab bound to the surface of the tumor, strongly suggesting that resistance to therapy was not due to insufficient rituximab exposure. However, the observation that 15% of patients have improved responses while receiving maintenance therapy, and the fact that 40% of patients who responded initially to rituximab will respond again when re-treated, strongly suggests that a substantial percentage of patients might benefit from a prolonged dosing schedule. The precise proportion of patients in either category is unknown. The determination of a therapeutic level is an appealing yet elusive notion. As stated above, significant measurable levels of circulating rituximab can be regarded as de facto evidence that all accessible CD20 is bound. It is therefore unlikely that sustained high levels will confer a superior therapeutic benefit relative to sustained modest levels because presumably its mechanism of action is mediated through binding to the target. In vitro data suggest that levels of 1.0 µg/mL are sufficient to achieve observed growth inhibition and might be considered a trough if generalized to measurements taken from patient serum.22 Finally, analysis of PK data from the pivotal trial identified 25 µg/mL as the median 3-month level in patients responding to therapy and was therefore regarded as an imperfect but empiric target for repeat bolus therapy.11 A concern has recently been raised that circulating soluble CD20 might interfere with antibody binding to surface target, while still allowing inactive antibody to be measurable in the serum of patients. Although this is a significant theoretical concern, determining its impact on the utility of serum rituximab levels will require a careful quantitative analysis of the amount of soluble CD20 in the serum of patients, its impact on surface CD20 binding, the degree of heterogeneity from one patient to the next, and the degree of heterogeneity in each patient as he or she moves through various treatments. At this time, data regarding this potentially obfuscating variable are not yet published and therefore its impact remains unknown. To date, a number of dosing schedules have been adopted for maintenance therapy, ranging from four single infusions every 2 months to four weekly infusions every 6 months for 2 years. These differences are due to the paucity of data informing the choice of schedules. Hainsworth et al14 recently published results of a phase II trial of rituximab as first-line and maintenance therapy for patients with indolent NHL. In this study, 62 patients were given rituximab 375 mg/m2 weekly infusion for 4 weeks (standard induction), and the same schema was repeated every 6 months for 2 years or until disease progression. The final objective response rate with maintenance therapy was 73%, with 37% CRs, and the median actuarial PFS was 34 months. Only mild and noncumulative toxicities were noted in this trial. Subsequently, Ghielmini et al15 reported a randomized trial of patients with relapsed or de novo follicular lymphoma treated with standard induction of rituximab, followed by a randomization of additional rituximab 375 mg/m2 at months 3, 5, 7, and 9 postinduction versus observation in patients without progressive disease. Among the 151 patients randomly assigned to treatment, the median PFS values for the observation and treatment arms were 12 and 23 months, respectively (P = .02), with a hazard ratio of 0.57. Among patients in the maintenance arm, there was a significant difference in the PFS in patients with and without previous treatment as well (19 v 36 months), respectively. After 1 year, the maintenance group was noted to have significantly fewer circulating B cells; however, Ig (IgG, IgA, IgM) levels were stable in both treatment groups and there were no differences in infectious complications.15 In this phase II trial of individualized dosing of rituximab for patients with CD20-positive lymphoproliferative disorders, we observed significant and durable responses, especially in patients with low-grade NHL. With a median follow-up of 24.5 months (range, 15 to 35 months), the median PFS has not been reached for this group, with an overall objective response rate of 63% and a 36% complete remission rate. The patients with more aggressive histology (ie, transformed NHL and relapsed diffuse large-cell lymphoma) fared worse, with a median PFS of only 5 months. Table 5 compares the results of this trial with those previously reported. The overall response rates and PFS are superior to that of Ghielmini et al,15 when limiting the comparison to patients who have been previously treated. Furthermore, the cost of such an approach would be significantly less than that of Hainsworth et al.7,14 It should be cautioned, however, that because of the small numbers of patients in this trial, firm conclusions regarding response rates and PFS should not be drawn.
In our study and in both maintenance trials mentioned above, the antitumor effect of rituximab persisted after the end of its administration, with objective responses improving in the maintenance phase. This suggests that a fraction of patients likely benefit from prolonged exposure to rituximab. We have also shown that the individualized maintenance strategy with rituximab was feasible, and PK data suggest significant heterogeneity with regard to individual needs to maintain therapeutic levels. Nonetheless, the process was tedious, time consuming, and compliance issues hampered full data collection. In addition, because the assay is not commercially available, it is not practical to consider in the general care of patients. The PK data collected have led to several useful observations for designing a larger randomized trial. First, serum rituximab levels increase appropriately after a single repeat bolus with rituximab for most patients and are still maintained for several months afterward, suggesting that a schedule making use of multiple infusions may be unnecessary. Second, the majority of our patients (28 of 29), required no more than three additional single-dose rituximab infusions in 12 months of follow-up with monthly rituximab serum level monitoring. It is noteworthy that although the median time from the fourth weekly infusion of rituximab to the first repeat bolus was 5 months, the median times between the first and second repeat infusions and between second and third repeat infusions were approximately 3 months, suggesting that more frequent dosing may be required for prolonged maintenance therapy. In the original pivotal trial, it was observed that patients who were not responders had statistically significantly lower levels of circulating antibody at 3 months post-treatment. Our data confirm a difference in serum levels between these two groups, but it is important to note that the mean rituximab level was near the target range for nonresponders at all time points except 4 months. This suggests that the lack of response was more likely related to inherent resistance to rituximab. Furthermore, although 10 patients experienced disease progression during either the treatment or the maintenance phases of the protocol, only three had levels that could be implicated as the cause, suggesting that the majority of patients experienced disease progression for reasons independent of drug exposure. Finally, the results of this trial provide sufficient data to suggest a rational schedule for maintenance therapy to be included in a future randomized trial. The ultimate end point for such a trial would be time to failure of rituximab and could incorporate an analysis of the cost effectiveness and quality of life for either strategy. A rational trial design would randomly assign patients to observation with re-treatment at the time of disease progression or to a maintenance schedule of a single dose of 375 mg/m2 of maintenance rituximab every 3 months until disease progression. Such a trial could include measurement of trough levels in patients to evaluate whether the 3-month interval provided sufficient antibody levels in larger numbers of patients. It might also include an analysis of soluble CD20 in patient serum as another potential correlative study. Such a trial is currently underway through the cooperative group network.
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: James W. Lynch, Genentech. Received more than $2,000 a year from a company for either of the last 2 years: James W. Lynch, Genentech.
Supported in part by a grant from Genentech Inc, South San Francisco, CA. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Boye J, Elter T, Engert A: An overview of the current clinical use of anti-CD20 monoclonal antibody rituximab. Ann Oncol 14:520-535, 2003
2. Reff ME, Carner K, Chambers KS, et al: Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 83:435-445, 1994 3. Maloney DG, Smith B, Rose A: Rituximab: Mechanism of action and resistance. Semin Oncol 29:2-9, 2002 (suppl 2)
4. Shan D, Ledbetter JA, Press OW: Apoptosis of malignant human B cells by ligation of CD20 with monoclonal antibodies. Blood 91:1644-1652, 1998
5. Cohen Y, Solal-Celigny P, Polliack A: Rituximab therapy for follicular lymphoma: A comprehensive review of its efficacy as primary treatment, treatment for relapsed disease, re-treatment and maintenance. Haematologica 88:811-823, 2003
6. Coiffier B, Lepage E, Briere J, et al: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235-242, 2002
7. Hainsworth JD, Litchy S, Barton JH, et al: Single agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic leukemia: A phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 21:1746-1751, 2003
8. Maloney DG, Grillo-Lopez AJ, White CA, et al: IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood 90:2188-2195, 1997
9. Davis TA, White CA, Grillo-Lopez AJ, et al: Single-agent monoclonal antibody efficacy in bulky non-Hodgkin's lymphoma: Results of a phase II trial of rituximab. J Clin Oncol 17:1851-1857, 1999 10. Feuring-Buske M, Kneba M, Unterhalt M, et al: IDEC-C2B8 (rituximab) anti-CD20 antibody treatment in relapsed advanced-stage follicular lymphomas: Results of a phase-II study of the German Low-Grade Lymphoma Study Group. Ann Hematol 79:493-500, 2000[CrossRef][Medline]
11. Davis TA, Grillo-Lopez AJ, White CA, et al: Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: Safety and efficacy of re-treatment. J Clin Oncol 18:3135-3143, 2000 12. Igarashi T, Ohtsu T, Fujii H, et al: Re-treatment of relapsed indolent B-cell lymphoma with rituximab. Int J Hematol 73:213-221, 2001[Medline]
13. Berinstein NL, Grillo-Lopez AJ, White CA, et al: Association of serum rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol 9:995-1001, 1998
14. Hainsworth JD, Litchy S, Burris HA, et al: Rituximab as first-line and maintenance therapy for patients with indolent non-Hodgkin's lymphoma. J Clin Oncol 20:4261-4267, 2002
15. Ghielmini M, Schmitz SF, Cogliatti SB, et al: Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x4 schedule. Blood 103:4416-4423, 2004 16. Harris NL, Jaffe ES, Diebold J, et al: The World Health Organization classification of neoplasms of the hematopoietic and lymphoid tissues: Report of the Clinical Advisory Committee meeting-Arlie House, Virginia, November 1997. Hematol J 1:53-66, 2000[CrossRef][Medline]
17. Mangel J, Buckstein R, Imrie K, et al: Pharmacokinetic study of patients with follicular or mantle cell lymphoma treated with rituximab as ‘in vivo purge’ and consolidative immunotherapy following autologous stem cell transplantation. Ann Oncol 14:758-765, 2003
18. Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas: NCI Sponsored International Working Group. J Clin Oncol 17:1244, 1999 19. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 20. Mantel N, Haenszel W: Statistical aspects of the analysis of data from the retrospective study of disease. J Natl Cancer Inst 27:719-748, 1959 21. Maloney DG, Grillo-Lopez AJ, Bodkin DJ, et al: IDEC-C2B8: Results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma. J Clin Oncol 15:3266-3274, 1997[Abstract] 22. Flieger D, Renoth S, Beier I, et al: Mechanism of cytotoxicity induced by chimeric mouse human monoclonal antibody IDEC-C2B8 in CD20-expressing lymphoma cell lines. Cell Immunol 204:55-63, 2000[CrossRef][Medline] Submitted December 26, 2003; accepted May 6, 2004.
Related Editorial
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
