|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2003 American Society for Clinical Oncology Phase II Study of the Farnesyl Transferase Inhibitor R115777 in Patients With Advanced Non–Small-Cell Lung Cancer
From the Departments of Oncology and Medicine, Mayo Clinic and Foundation, Rochester, MN; University of Chicago, Section of Hematology/Oncology and Cancer Research Center, Chicago, IL; and National Cancer Institute, Bethesda, MD. Address reprint requests to Alex A. Adjei, MD, PhD, Division of Medical Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905; email: adjei.alex{at}mayo.edu.
Purpose: This phase II study was undertaken to define the efficacy and pharmacodynamics of R115777, a farnesyl transferase inhibitor, in the first-line treatment of patients with advanced non–small-cell lung cancer. Patients and Methods: Forty-four patients with measurable stage IIIB (pleural effusion) or stage IV disease received 193 courses of treatment (median, 2.0; range, 1 to 22) with R115777 300 mg administered orally twice daily for 21 of every 28 days. Buccal mucosa samples and peripheral blood mononuclear cells (PBMCs) were collected before and after 8 days of treatment to evaluate inhibition of farnesyl transferase in vivo. Results: No objective complete or partial responses were documented. Seven patients (16%; 95% confidence interval [CI], 8% to 31%) had disease stabilization for greater than 6 months. Median survival was 7.7 months (95% CI, 6.5 to 10.5) and time to progression was 2.7 months (95% CI, 1.9 to 3.1). The most severe toxicity was neutropenia (9% grade 3, 7% grade 4) and the most common toxicities were anemia (50% grade 1 or 2, 5% grade 3) and anorexia (50% grade 1 or 2, 2% grade 3). Mild peripheral neuropathy occurred in 25% of patients. Evidence of farnesyl transferase inhibition was documented in 83% of patients. Conclusion: Single-agent R115777 was well tolerated in patients with advanced NSCLC, but demonstrated minimal clinical activity. Inhibition of farnesylation in vivo was consistently documented. On the basis of promising results of farnesyl transferase inhibitor combinations with standard chemotherapy agents, future studies of this agent in NSCLC should be in combination with systemic chemotherapy.
THE ENZYME farnesyl transferase (FT) catalyzes the first step in the posttranslational modification of a number of guanine-nucleotide binding proteins (G-proteins) involved in cell signaling. FT initially attracted attention because of its role in the processing of Ras proteins, which transduce receptor and nonreceptor tyrosine kinase activation to downstream cytoplasmic and nuclear effectors. Activating mutations in Ras proteins results in constitutive signaling, leading to cell proliferation and inhibition of apoptosis.1 Oncogenic Ras mutations have been identified in approximately 30% of human cancers,2 with K-Ras mutations occurring in 40% of non–small-cell lung cancer (NSCLC) cases.2 Because farnesylation is critical for Ras maturation and function, farnesyl transferase inhibitors (FTIs) were developed as specific and sensitive inhibitors of Ras-mediated cellular proliferation.3,4 The methylquinolone R115777 (tipifarnib; Zarnestra, Johnson and Johnson Pharmaceutical Research and Development, Raritan, NJ) is an oral agent that was the first FTI to enter human clinical trials. R115777 inhibits FT in vitro, with a 50% inhibitory concentration of 0.86 and 7.9 nmol/L when lamin B and K-RasB are used as substrates, respectively. Several observations raised the possibility that R115777 might have activity against NSCLC. First, R115777 demonstrated activity in 75% of human cancer cell lines, including NSCLC lines.5,6 Second, the growth of tumors harboring mutations in H-ras and K-ras, as well as tumors with wild-type ras, was inhibited in nude mice by clinically achievable doses of R115777 (6.25 to 100 mg/kg).7 Third, in initial phase I trials, clinical activity was documented in a patient with NSCLC.8 The most common single-agent regimen for FT is 300 mg twice daily for 21 days with 1 week off. In phase I and II studies, myelosuppression, which can be cumulative and manifests typically as neutropenia, was the most common toxicity. Thrombocytopenia was less common, and anemia was relatively rare. A pruritic erythematous maculopapular rash of mild to moderate severity was noted, but only rarely required interruption of drug dosing. Gastrointestinal toxic effects such as nausea, vomiting, and diarrhea are less common. Fatigue and hyperbilirubinemia occur. This agent has demonstrated activity in refractory leukemia and breast cancer in early clinical trials.9,10 On the basis of the presumed effect of this class of agents in interrupting oncogenic Ras signaling, the frequency of oncogenic K-ras mutations in NSCLC, and the early indications of activity in NSCLC, a phase II study of R115777 in previously untreated patients was performed. The goals of this study were to define the clinical activity and toxicity of this agent as first-line therapy for NSCLC, to describe the overall survival and time to disease progression of patients enrolled onto this study, and to evaluate inhibition of FT in vivo and to correlate such inhibition with response to treatment and/or toxicity.
Patient Selection Patients with histologic or cytologic evidence of NSCLC that was metastatic or locally advanced (stage IIIB), but not amenable to combined-modality treatment with radiation and chemotherapy, were eligible for this study. Other eligibility criteria included: age  18 years; no prior systemic chemotherapy; Eastern Cooperative Oncology Group (ECOG) performance status  2; adequate bone marrow (platelets 100 x 109 cells/L, absolute neutrophil count 1.5 x 109 cells/L), hepatic (total bilirubin 2.0 mg/dL; AST 3 times the upper limit of normal), and renal (serum creatinine 2 times the upper limit of normal) functions; and no prior chemotherapy or biologic, immunologic, or gene therapy. Patients who had been diagnosed with another malignancy within the last 5 years (except basal cell carcinoma of the skin), had received radiation therapy to more than 25% of the bone marrow, or had known brain metastasis were excluded from this trial. Written informed consent was obtained according to federal and institutional guidelines.
Experimental Treatment
Clinical Care of Patients
Immunohistochemistry in Buccal Mucosa Cells
Immunoblotting for HDJ-2 in PBMCs
Statistical Design This trial was designed to test the null hypothesis that the true treatment success rate is at most 0.10. The smallest treatment success proportion that would indicate that this regimen warrants further study is 0.25. The planned accrual for this Simon-design16 study was 50 assessable patients. An interim analysis was conducted after the first 21 patients had been followed for 6 months. Accrual was not suspended while the first 21 patients were followed for 6 months. If two or fewer responses were observed during the interim analyses, the treatment arm was to be closed permanently. If three or more confirmed responses were observed during the interim analyses, accrual was to continue. At the time of the final analyses, a confirmed response among eight or more of the 50 evaluable patients would indicate that this regimen merits further investigation. Time to progression was defined as the time from registration to the date of progression. Patients who died without disease progression were censored at the date of their last evaluation. If a patient died without documentation of disease progression, the patient was considered to have had tumor progression at the time of death, unless there was sufficient documented evidence to conclude that progression did not occur before death. Survival was defined as the time from registration to death resulting from any cause. The distribution of time to progression and survival time was estimated using the Kaplan-Meier method.17 Confidence intervals for the true treatment success rate were constructed according to the method of Duffy and Santner.18
Patient Demographics A total of 46 patients were enrolled at Mayo Clinic (Rochester, MN) and University of Chicago (Chicago, IL) from July 2000 to May 2001. Patient accrual was permanently closed four patients short of the original 50-patient goal because we did not meet the interim analysis criteria. Two patients were found to have brain metastasis and were therefore ineligible. Neither of the ineligible patients received treatment and both were omitted from these analyses. The characteristics of the remaining 44 assessable patients are listed in Table 1  . Overall, these 44 patients received 193 assessable cycles of therapy. The median number of cycles administered per patient was 2.0 (range, 1 to 23). Two patients continue to receive therapy and to date have received 19 and 23 cycles of treatment, respectively. The median age of study participants was 70.5 years (range, 35 to 87 years). Twenty-two males and 22 females, all with a good performance status, received drug therapy. Ninety-three percent of patients had an ECOG performance status of 0 or 1; 7% had a performance status of 2. The majority of patients (86%) had stage IV disease; the remainder (14%) had stage IIIB disease with pleural effusions. Nine patients had previously received radiation therapy for stage III disease and were enrolled onto the study after progressive disease was documented. The median time from diagnosis to treatment was 19 days, with 70% of patients enrolled within 1 month of diagnosis. One patient with stage IIIA disease, who received radiation therapy, developed metastatic disease and was enrolled onto the study 783 days after the initial diagnosis.
Toxicities As per the NCI common toxicity criteria, any adverse event deemed at least possibly related to treatment was defined as a toxicity and is included in these analyses. The frequency and severity of the most common toxicities (occurring in at least 10% of all patients) are shown in Table 2 .
Hematologic Toxicity The frequency and severity of hematologic toxicities are shown in Table 2  . Neutropenia was the most severe hematologic toxicity after treatment with R115777. Seven percent of patients had absolute neutrophil count nadir values constituting grade 1 or 2 toxicity, 9% of patients had grade 3 toxicity, and 7% of patients had grade 4 toxicity. One patient had grade 5 febrile neutropenia. Anemia and thrombocytopenia occurred less severely, with incidences of 50% grade 1 or 2, 5% grade 3, 36% grade 1, and 2% grade 4, respectively.
Nonhematologic Toxicity Because the visual proteins rhodopsin kinase and transducin are farnesylated,19,20 particular attention was paid to visual complaints. No evidence of ocular toxicity was found. In addition, because QT-wave prolongation occurred with an FTI that was withdrawn from clinical testing,21 ECGs were performed at baseline and as clinically indicated during the study. No abnormalities were found, and no patients developed treatment-related arrhythmia on this study. There was one grade 5 event reported on this study. An 83-year-old female with an ECOG performance status of 1 died after one cycle of therapy. Disease progression was noted, but a contribution from drug effects could not be ruled out because there was concomitant febrile neutropenia.
Dose Reductions
Clinical Activity
Inhibition of FT in Surrogate Tissues We previously described the development of an immunohistochemical assay for detecting prelamin A accumulation in buccal mucosa cells, as well as an immunoblotting assay evaluating accumulation of unfarnesylated HDJ-2 in PBMCs that could be used as surrogate markers of FT inhibition.12,13 In this study, we sought to demonstrate that the dose of R115777 used in this study was adequate for inhibition of FT in patient tissues. In addition, we sought to correlate FT inhibition in patient tissues with response to treatment and/or toxicity.
Buccal mucosa samples taken 12 hours after the R115777 dose on day 8 were received from 42 patients and 41 samples were analyzable. Figure 2
Likewise, Fig 3 is a representative panel from Western blot analysis of PBMC lysates. Paired blood samples were received from 37 patients. Fifteen of these were not interpretable because the pretreatment sample seemed to contain unfarnesylated HDJ-2 (see Fig 3, lanes 3 and 5). In the samples of the 22 patients with interpretable results, 18 patients (82%) demonstrated accumulation of unfarnesylated HDJ-2, whereas four patients (18%) failed to demonstrate accumulation of unfarnesylated protein. Table 3 summarizes the results of the immunohistochemistry and immunoblotting analyses. The immunohistochemistry assay could be reliably performed in all but one of the patient samples received, whereas the immunoblotting assay could only be reliably performed in 60% of samples. However, the proportion of positive samples was similar between the two methods (83% and 82%, respectively). Because of the small number of samples, no conclusions could be drawn regarding concordance between the two methods.
Table 4 shows the correlation of FT inhibition with treatment success and the incidence of grade 3 and 4 toxicity. Of the 34 patients with in vivo FT inhibition, 18% had a stable response for 6 or more months, whereas of the seven patients without in vivo inhibition, 14% had a stable response for 6 or more months. There was no correlation between FT inhibition in surrogate tissue and treatment success. Likewise, there was no correlation between FT inhibition and the incidence and severity of toxicity.
This report describes the first single-agent phase II study of an FTI in NSCLC. This trial provided the opportunity to not only describe the efficacy and toxicity of R115777 in this setting, but also the possibility of testing the relationship between FT inhibition and response. Unfortunately, the failure of single-agent R115777 to produce objective responses in NSCLC rendered the relationship between FT inhibition and efficacy moot. Instead, results of the present study are consistent with a moderate disease-stabilizing effect of the FTIs that may be better explored in combination with other treatments.
In any negative study there is a question of whether adequate drug was administered. The toxicity profile observed with R115777 in this study is consistent with that observed in previous phase I studies of this agent.8,9 In addition, a dose of 300 mg orally bid has been shown to lead to body exposure of R115777 levels that are associated with consistent FT inhibition.8,22,23 In an earlier phase II study, a higher dose of 400 mg orally bid was associated with severe (grade 4) myelosuppression and could not be administered.10 Dose reductions were required in 23% of patients because of toxicity, indicating that dosing was adequate. Moreover, two different assays indicated inhibition of FT in normal tissues in more than 80% of the samples examined (Figs 2 The reasons for the presence of unfarnesylated HDJ-2 at baseline in some patient samples remain unclear. This pattern has been noted in other FTI studies that are ongoing (L.M. Bruzek, A.A. Adjei, unpublished observations October 2002). These results would indicate that, in surrogate tissues, the accumulation of prelamin A may be a better marker of FT inhibition. Although FT was inhibited in the vast majority of patients, this translated into stable disease in only a few patients and no objective responses were observed. Unfortunately, limited understanding of the mechanism of cytotoxicity of FTIs makes it difficult to interpret this disparity. As discussed above, FTIs were originally designed to target oncogenic Ras and potentially eradicate human tumors with Ras mutations. Although FTIs clearly inhibit H-Ras farnesylation and cause regression of H-Ras-transfected tumors in rodents, it has become clear in recent years that the critical targets of FTIs might not be Ras proteins, or might include other polypeptides in addition to Ras.24,25 Several observations have led to this conclusion. First, after FT inhibition, K-Ras and N-Ras proteins can be alternatively prenylated by geranylgeranylation.26 These geranylgeranylated Ras proteins are capable of inducing malignant transformation when overexpressed in cells. Despite this, FTIs are active in vitro and in vivo in cells harboring activating K-ras mutations.27 Second, several cell types without Ras mutations are sensitive to FTIs in vivo and in vitro. In fact, such cells bearing wild-type Ras genes are in general more sensitive to inhibition by R115777.5 To date, more than 100 polypeptides possessing a CAAX sequence that can potentially be farnesylated have been identified.25 Theoretically, the inhibition of farnesylation of any of these polypeptides could result in the antiproliferative effects of the FTIs in human tumors. Up to 20 of these polypeptides, including Rho B, lamins A and B, transducin, centromere protein (CENP)-E and -F, and rhodopsin kinase have been shown to actually undergo farnesylation.19,20,28–30 Accumulating data have identified at least two polypeptides, the inhibition of which may be the basis for the cytotoxic actions of FTIs. These are the G-protein Rho B, which regulates cytoskeletal cytoskeleton organization,28 and polypeptides associated with the phosphatidylinositol 3-OH kinase/AKT pathway.29 Another possibility is that the cytotoxicity of FTIs may be the result of inhibition of farnesylation of several critical polypeptides, including some or all of the Ras isoforms. This study was designed at a time when Ras proteins were still considered the predominant targets of FTIs.6,24 With this more recent information, it has become clear that NSCLC may be an inappropriate target for single-agent R115777 therapy. Instead, current data indicate that single-agent FTIs may show the greatest single-agent activity in tumors with H-Ras mutations and those with a highly activated wild-type Ras pathway because of overexpression of growth factor receptors. In support of this hypothesis, R115777 has demonstrated clinical activity in breast cancer and acute leukemia.9,10 It is important to emphasize, however, that these conclusions do not necessarily apply when FTIs are administered as part of combination therapies. Preclinical studies have examined the effect of combining FTIs with several classes of antineoplastic agents in various human tumor models. Synergistic interactions have been described between R115777 or other FTIs and cisplatin31 or the taxanes,32,33 whereas additive and synergistic interactions have been described with FTIs and gemcitabine.31,34 In view of the activity of cisplatin, taxanes, and gemcitabine in NSCLC, as well as recent evidence indicating dependence of NSCLC on the phosphatidylinositol 3-OH kinase pathway,35–37 combination studies with chemotherapy and R11577 in NSCLC are warranted. A study of R15777 in combination with gemcitabine and cisplatin will open for accrual this year.
We thank Candus Bergh, Jennifer Frank, and Ming An for data management, Michelle Daiss for protocol development, and Raquel Ostby for secretarial assistance.
Supported by grants from the National Institutes of Health (CA69912, N01-CM-17102-02, P30-CA-14599-27) and the American Cancer Society (RSG-01-155-01-CCE).
1. Downward J: Ras signaling and apoptosis. Curr Opin Genet Dev 8:9–54, 1998[CrossRef][Medline]
2. Bos JL: Ras oncogenes in human cancer: A review. Cancer Res 49:4682–4689, 1989
3. Kato K, Cox AD, Hisaka MM, et al: Isoprenoid addition to Ras proteins is the critical modification for its membrane association and transforming activity. Proc Natl Acad Sci U S A 89:6403–6407, 1992
4. Sepp-Lorenzino L, Ma Z, Rands E, et al: A peptidomimetic inhibitor of farnesyl:protein transferase blocks the anchorage-dependent and independent growth of human tumor cell lines. Cancer Res 55:5302–5309, 1995 5. End DW: Farnesyl protein transferase inhibitors and other therapies targeting the Ras signal transduction pathway. Invest New Drugs 17:241–258, 1999[CrossRef][Medline]
6. Rowinsky EK, Windle JJ, Von Hoff DD: Ras protein farnesyltransferase: A strategic target for anticancer therapeutic development. J Clin Oncol 17:3631–3652, 1999
7. End DW, Smets G, Todd AV, et al: Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res 61:131–137, 2001
8. Crul M, de Klerk GJ, Swart M, et al: Phase I clinical and pharmacologic study of chronic oral administration of the farnesyl protein transferase inhibitor R115777 in advanced cancer. J Clin Oncol 20:2726–2735, 2002
9. Karp JE, Lancet JE, Kaufmann SH, et al: Clinical and biologic activity of farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: A phase 1 clinical trial. Blood 97:3361–3369, 2001 10. Johnston SR, Hickish T, Houston S, et al: Efficacy and tolerability of two dosing regimens of R115777, a farnesyl protein transferase inhibitor, in patients with advanced breast cancer. Proc Am Soc Clin Oncol 21:138a, 2002 (abstr 138)
11. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216, 2000
12. Adjei AA, Erlichman C, Davis JN, et al: A phase I trial of the farnesyl transferase inhibitor SCH66336: Evidence for biological and clinical activity. Cancer Res 60:1871–1877, 2000
13. Adjei AA, Davis JN, Erlichman C, et al: Comparison of potential markers of farnesyltransferase inhibition. Clin Cancer Res 6:2318–2325, 2000
14. Kaufmann SH, Svingen PA, Gore SD, et al: Altered formation of topotecan-stabilized topoisomerase I-DNA adducts in human leukemia cells. Blood 89:2098–2104, 1997 15. Smith PK, Krohn RI, Hermanson GT, et al: Measurement of protein using bicinchoninic acid. Anal Biochem 150:76–85, 1985[CrossRef][Medline] 16. Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1–10, 1989[Medline] 17. Kaplan E, Meier P: Nonparametric estimation for incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef] 18. Duffy D, Santner T: Confidence intervals for a binomial parameter based on multistage tests. Biometrics 43:81–93, 1987[CrossRef]
19. Inglese J, Glickman JF, Lorenz W, et al: Isoprenylation of a protein kinase: Requirement of farnesylation/alpha-carboxyl methylation for full enzymatic activity of rhodopsin kinase. J Biol Chem 267:1422–1425, 1992
20. Lai RK, Perez-Sala D, Canada FJ, et al: The gamma subunit of transducin is farnesylated. Proc Natl Acad Sci U S A 87:7673–7677, 1990
21. Adjei AA: Blocking oncogenic ras signaling for cancer therapy. J Natl Cancer Inst 93:1062–1074, 2001
22. Zujewski J, Horak ID, Bol CJ, et al: Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R115777 I advanced cancer. J Clin Oncol 18:927–941, 2000 23. Hudes G, Schol J, Baab J, et al: Phase I clinical and pharmacokinetic trial of the farnesyl transferase inhibitor R115777 on a 21-day dosing schedule. Proc Am Soc Clin Oncol 18:156a, 1999 (abstr 601)
24. Reuter CW, Morgan MA, Bergman L: Targeting Ras signaling pathway: A rational, mechanism-based treatment for hematologic malignancies. Blood 96:1655–1669, 2000 25. Adjei AA: Farnesyltransferase inhibitors, in Schlisky R, Giaccone G, Sondel P (eds): Cancer Chemotherapy and Biologic Response Modifiers: Annual 19. New York, NY, Elsevier Science, 2001, pp 149–164
26. Zhang FL, Kirschmeier P, Carr D, et al: Characterization of Ha-ras, N-ras, Ki-Ras4A, and Ki-Ras4B as in vitro substrates for farnesyl protein transferase and geranylgeranyl protein transferase type I. J Biol Chem 272:10232–10239, 1997 27. Karp JE, Kaufmann SH, Adjei AA, et al: Current status of clinical trials of farnesyltransferase inhibitors. Curr Opin Oncol 13:470–476, 2001[CrossRef][Medline] 28. Lebowitz PF, Prendergast GC: Non-Ras targets of farnesyltransferase inhibitors: Focus on Rho. Oncogene 17:1439–1445, 1998[CrossRef][Medline]
29. Jiang K, Coppola D, Crespo NC, et al: The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis. Mol Cell Biol 20:139–148, 2000
30. Ashar HR, James L, Gray K, et al: FTIs block the farnesylation of CENP-E and CENP-F and alter the association of CENP-E with the microtubules. J Biol Chem 275:30451–30457, 2000 31. Adjei AA, Bruzek LM, Erlichman C, et al: Combination studies with the farnesyltransferase inhibitor R115777 and chemotherapy agents. Eur J Cancer 37:792, 2001 (suppl 6) 32. Shi B, Yaremko B, Hajian G, et al: The farnesyl protein transferase inhibitor SCH66336 synergizes with taxanes in vitro and enhances their antitumor activity in vivo. Cancer Chemother Pharmacol 46:387–393, 2000[CrossRef][Medline]
33. Moasser MM, Sepp-Lorenzino L, Kohl NE, et al: Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol and epothilones. Proc Natl Acad Sci U S A 95:1369–1374, 1998
34. Sun J, Blaskovich MA, Knowles D, et al: Antitumor efficacy of a novel class of non-thiol-containing peptidomimetic inhibitors of farnesyltransferase and geranylgeranyltransferase I: Combination therapy with the cytotoxic agents cisplatin, Taxol, and gemcitabine. Cancer Res 59:4919–4926, 1999
35. Brognard J, Clark AS, Ni Y, et al: Akt/Protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res 61:3986–3997, 2001
36. Zinda MJ, Johnson MA, Paul JD, et al: AKT-1, -2, and -3 are expressed in both normal and tumor tissues of the lung, breast, prostate, and colon. Clin Cancer Res 7:2475–2479, 2001
37. Massion PP, Kuo W-L, Stokoe D, et al. Genomic copy number analysis of non-small cell lung cancer using array comparative genomic hybridization: implications of the phosphatidylinositol 3-kinase pathway. Cancer Res 62:3636–3640, 2002 Submitted September 16, 2002; accepted January 29, 2003.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
