|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 24, No 25 (September 1), 2006: pp. 4202-4208 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.4980 Phase III Study of Craniospinal Radiation Therapy Followed by Adjuvant Chemotherapy for Newly Diagnosed Average-Risk Medulloblastoma
From the Divisions of Neurology, Pediatrics, Radiology, and Oncology, Children’s National Medical Center; Departments of Neurology, Pediatrics, and Radiology, The George Washington University, Washington, DC; Department of Oncology and Radiology, St Jude Research Hospital, Memphis, TN; Division of Neuropathology, Children’s Hospital of Philadelphia; Department of Pathology, University of Pennsylvania, Philadelphia, PA; Department of Pathology, Johns Hopkins University, Baltimore, MD; Department of Neurology, Pediatrics and Neurosurgery, University of Michigan, Ann Arbor, MI; Division of Pediatric Hematology-Oncology, Weill Medical College of Cornell University; Department of Radiation Oncology, New York University School of Medicine, New York; Department of Radiation Oncology, Maimonides Cancer Center, Brooklyn, NY; Department of Radiation Oncology, Children’s Memorial Hospital; Department of Radiation Oncology, Northwestern University, Chicago, IL; Children’s Hospital of Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles; and the Children’s Oncology Group, Arcadia, CA Address reprint requests to Roger J. Packer, MD, Department of Neurology, Children’s National Medical Center, 111 Michigan Ave, NW, Washington, DC 20010; e-mail: rpacker{at}cnmc.org
Purpose To determine the event-free survival (EFS) and overall survival of children with average-risk medulloblastoma and treated with reduced-dose craniospinal radiotherapy (CSRT) and one of two postradiotherapy chemotherapies. Methods Four hundred twenty-one patients between 3 years and 21 years of age with nondisseminated medulloblastoma (MB) were prospectively randomly assigned to treatment with 23.4 Gy of CSRT, 55.8 Gy of posterior fossa RT, plus one of two adjuvant chemotherapy regimens: lomustine (CCNU), cisplatin, and vincristine; or cyclophosphamide, cisplatin, and vincristine. Results Forty-two of 421 patients enrolled were excluded from analysis. Sixty-six of the remaining 379 patients had incompletely assessable postoperative studies. Five-year EFS and survival for the cohort of 379 patients was 81% ± 2.1% and 86% ± 9%, respectively (median follow-up over 5 years). EFS was unaffected by sex, race, age, treatment regimen, brainstem involvement, or excessive anaplasia. EFS was detrimentally affected by neuroradiographic unassessability. Patients with areas of frank dissemination had a 5-year EFS of 36% ± 15%. Sixty-seven percent of progressions had some component of dissemination. There were seven second malignancies. Infections occurred more frequently on the cyclophosphamide arm and electrolyte abnormalities were more common on the CCNU regimen. Conclusion This study discloses an encouraging EFS rate for children with nondisseminated MB treated with reduced-dose craniospinal radiation and chemotherapy. Additional, careful, step-wise reductions in CSRT in adequately staged patients may be possible.
Medulloblastoma, an embryonal tumor of the cerebellum, is the most common brain malignancy occurring in children, comprising 40% of all childhood posterior fossa tumors.1 Children older than 3 years of age at diagnosis with totally or near totally resected, nondisseminated disease (average risk) have a predicted 5-year progression-free survival of 50% to 65% after 36 Gy of craniospinal radiotherapy (CSRT), supplemented with 18 Gy to 20 Gy of radiotherapy to the posterior fossa.2,3 Higher survival rates for children with average-risk disease have been obtained with the addition of chemotherapy to radiation therapy.4-6 Children surviving medulloblastoma are at risk for neurologic, cognitive, and endocrinologic sequelae, believed to be due, in great part, to cranial irradiation, and there have been attempts to reduce the dose of CSRT for children without apparent disseminated disease.3,7,8,9 Treatment with reduced-dose CSRT (23.4 Gy) without chemotherapy has resulted in a higher likelihood of early isolated neuroaxis relapse.2 Children who have received preradiation chemotherapy and reduced-dose CSRT had a significantly poorer event-free survival (EFS) than those treated with immediate postoperative radiotherapy.3,10 However, 80% 5-year survival rates, after treatment with reduced-dose radiotherapy and chemotherapy during and after radiotherapy, have been reported.11 A variety of different chemotherapeutic agents have been utilized either before or after radiotherapy, and encouraging results have been obtained with the use of vincristine during radiotherapy followed by cycles of lomustine (CCNU), cisplatin, and vincristine.5,6,11 Data supporting the activity of CCNU as an active agent in children with medulloblastoma are relatively scant4,5 and in xenograft models and phase II clinical trials, cyclophosphamide has been found to be an active agent.12,13 This study was undertaken to determine if a postradiotherapy cyclophosphamide arm would increase the rate of progression-free survival, compared with a CCNU-containing regimen, for children with average-risk medulloblastoma, and to determine the EFS and overall survival and pattern of relapse of children treated with reduced-dose (23.4 Gy) craniospinal radiation therapy.
Eligibility Patients with a histologically confirmed medulloblastoma, between the ages of 3 years and 21 years at the time of diagnosis, were eligible for study. Patients were to have no evidence of disseminated disease on magnetic resonance imaging of the entire brain and spine performed pre- or postoperatively or on cytologic examination of lumbar CSF, performed between 5 days after surgery and the time of radiation. Ventricular CSF could be substituted in only rare instances when lumbar puncture was medically contraindicated. Patients were to have less than 1.5cm2 of residual tumor on postoperative neuroimaging performed within 21 days, preferably within 72 hours, of surgery. Patients with brainstem involvement were eligible. Patients were not allowed to have received any previous radiotherapy or chemotherapy, other than corticosteroids, and treatment must have been begun within 31 days of definitive surgery. All institutions participating in the study had received approval from their institutional review boards and age-appropriate informed consent/assent was obtained by each patient/parent/guardian.
Radiotherapy
Chemotherapy
For grade 3 or grade 4 vincristine neurotoxicity, the vincristine was to be held for one dose and restarted at full dosage when symptoms resolved. If symptoms recurred, a reduction in dose of vincristine was allowed. For those on regimen A, if the absolute neutrophil count was below 750 and/or the platelet count of less than 75,000, the cycle of chemotherapy would be delayed. For patients on regimen B, each cycle of chemotherapy had to begin when the absolute neutrophil count was greater than 1,000, with platelets greater than 100,000. Patients were not to receive cisplatin if creatinine clearances was less than 50% of baseline value. If the creatinine clearance was less than 75% of baseline value, then the cisplatin was reduced by 50%. Audiograms were required before each cycle of chemotherapy. For a decrease in auditory acuity of greater than 30 decibels at 4,000 hz to 8,000 hz, a 50% in cisplatin was mandated. For a greater than 20 decibels loss at 500 hz to 3,000 hz, at 50% reduction in cisplatin dosage was made. For grade 4 ototoxicity, cisplatin was held and not restarted unless follow-up audiograms returned to at least no more than grade 2 ototoxicity.
Staging Review
Pathology Review
Statistical Considerations Nonparametric EFS and survival curves were computed using the product-limit (Kaplan-Meier) estimates, with SE via the Greenwood formula.15 Follow-up probabilities were also estimated using the product-limit estimate by censoring patients experiencing treatment failure events. Cumulative toxicity rates are also computed actuarially.
Between December 1996 and December 2000, 421 patients were enrolled on this study. Forty-two of these patients were excluded from the analysis after central review (Table 2). The remaining 379 patients include 66 patients who, on central review, had no clear evidence of excess residual or metastatic disease, but whose studies could not be fully evaluated because of poor quality or incompleteness of submission. Patient characteristics are in Table 3. Median follow-up (last patient enrolled 57 months ago) is just more than 5 years, with all patients having been observed at least 3 years, 81% at least 4 years, and 57% at least 5 years.
Treatment Toxicity Table 4 shows the cumulative rate of key toxicities over the entire course of therapy. Virtually all patients experienced grade 3 or 4 hematologic toxicity sometime during therapy. Grade 4 hematologic toxicity and infections occurred significantly more frequently in patients treated with regimen B. Electrolyte toxicity and poor performance score occurred more frequently in patients treated with regimen A.
Treatment Failures Seventy-three patients have experienced a treatment failure event, as defined by their treating institution, and 54 have died. On central neuroradiographic analysis, the reviewers believed that the area considered by the institution to demonstrate tumor progression was equivocal in two, and in five others, represented gliosis (two patients), cerebellar treatment-related demyelination (one patient), lumbar nerve root enhancement (one patient), or a vein on dorsum of the conus (one patient). However, for analysis, all these patients are considered treatment failures. Three of these patients remain alive, after various forms of retreatment, for longer than 5 years after relapse, and four patients died of progressive disease. One patient suffered an aortic hemorrhage during radiotherapy (of unclear etiology), and another succumbed due to extensive brainstem necrosis. Seven patients experienced second malignant neoplasms as a first event, an average of 59 months from study enrollment and three patients died. Details are summarized in Table 5. The remaining 64 patients experienced tumor progression or relapse, and 45 patients died. Sites of progression/recurrence are summarized in Table 6.
Overall Outcome and Treatment Effect Figure 1 shows EFS and survival for the entire patient cohort as determined by institutional review. Five-year EFS and survival probabilities are 81% ± 2.1% and 86% ± 1.9%, respectively. Figures 2 and 3 show EFS and survival, respectively, by randomized treatment assignment. Five-year EFS is 82% ± 2.8% and 80% ± 3.1% for regimens A and B, respectively. Five-year survival is 87% ± 2.6% and 85% ± 2.8.
Prognostic Factors Table 6 summarizes 3- and 5- year EFS within patient categories defined by sex, race, age, brainstem involvement, and whether the tumor displayed features of excessive anaplasia. None of these factors was a statistically significant predictor of EFS. Patients whose tumors displayed features of excessive anaplasia had nominally worse outcome at 5 years: EFS 83% ± 2.3% versus 73% ± 6.4% (P = .087); and significantly worse survival: 89% ± 1.9% versus 75% ± 6.4% (P = .005). No difference in EFS could be detected depending on whether severe anaplasia was focal or diffuse (P = .89; Fig 4), nor did the pattern of failure or relapse differ in patients with anaplastic versus nonanaplastic tumors.
Comparison Based on Assessability A comparison of EFS in the 313 fully assessable patients, the 66 patients who were incompletely assessable, and the 15 patients who were considered ineligible because of unequivocal excess residual or disseminated disease on review is shown in Figure 5 and Table 7. Five-year EFS was 83% ± 2.2% versus 73% ± 5.8% versus 75% ± 13% versus 36% ± 15% in these four groups, respectively (logrank P < .005). There was no detectable difference in the pattern of relapse between these patient groups.
The results of this study, the largest prospective randomized trial ever performed for children with medulloblastoma, discloses an encouraging 81% ± 2% 5-year EFS rate for children older than 3 years of age with nondisseminated disease, which is essentially identical to the EFS obtained in previous prospective studies which utilized either 36 Gy or 24 Gy of CSRT and regimen A used in the study.5,6,11 The EFS rate compares favorably with results obtained after treatment with radiotherapy alone, including a contemporary prospective trial which found a 64.8% EFS rate for nondisseminated patients treated with 36 Gy of CSRT and supports the use of chemotherapy for all children with medulloblastoma.3,17 The results of our trial also are as good, if not better, than the highest reported survival rates in studies using higher doses of CSRT with more intensive chemotherapy regimens.18,19 It is conceivable that as imaging techniques have improved, more patients who are now considered average risk may have been classified as poor risk in past studies, possibly artificially improving comparative outcomes. The incorporation of molecular parameters into stratification may make comparisons to older studies difficult, however, molecularly based stratification might also identify patients who will be amenable to treatment with even less aggressive therapy.20-31 The pattern of relapse seen in this series raises the issue of whether reduced (23.4 Gy) craniospinal radiotherapy is adequate to prevent distant disease relapse. Posterior fossa relapse alone occurred in 20 (32%) of 63 assessable patients, with 43 patients having either disseminated relapse alone (40%) or posterior fossa and distant relapse (25%). In a study which utilized 36 Gy of CSRT therapy, isolated posterior fossa relapse occurred in 11 (34.4%) of 32 patients, essentially identical to that seen in our study.17 It is likely that a subset of initially nondisseminated medulloblastomas are likely to relapse outside the primary tumor site, independent of the dose of CSRT, due to not fully defined biologic predispositions.25 The presence of anaplastic histologic features has been found in retrospective reviews of patients, treated in a variety of ways, to be related to poorer outcome.32 In our study, excessive anaplasia, be it diffuse or focal, was identified in 49 patients (15%) and was related to poorer overall survival. Parameters such as marked nuclear atypia, cytological pleomorphism, numerous mitosis, and apoptotic bodies are used to determine the degree of anaplasia. Some degree of anaplasia occurs in the majority of medulloblastomas and it was left to the subjective impressions of the two senior review neuropathologists if anaplasia was excessive.32 Other factors, such as sex, race, age at diagnosis, or brainstem involvement were not predictive of EFS. In a recent international study, overall survival and EFS were detrimentally affected if radiotherapy was completed in longer than 50 days.17 In our study, unlike the international study which treated patients with preirradiation chemotherapy, none had prolongation or delays in delivering radiotherapy. The major deviations in our series were due to targeting deviations and there was no significant impact on EFS or survival. As patients in this study received only chemotherapy during and after radiotherapy, no direct conclusions can be drawn concerning the relative merits of pre- versus postradiotherapy chemotherapy. In randomized studies addressing this issue, preirradiation chemotherapy has been associated with poorer disease control than chemotherapy after radiotherapy, especially when the dose of radiotherapy was reduced.2,10,18 A French Society of Pediatric Oncology study, treating a cohort of patients similar to ours with preirradiation chemotherapy and 25 Gy of CSRT after surgery, found a 5-year disease-free survival rate of approximately 65%, which seems inferior to our results.33 Our study demonstrates that both the CCNU and cyclophosphamide treatment arms result in similar progression-free and overall survival and that both arms have significant, but tolerable toxicity. In the newly-opened Children’s Oncology Group study for average-risk medulloblastoma, both drugs were incorporated. A major issue remains audiologic toxicity, thought predominantly due to cisplatin. Grade 3 or 4 toxicity was seen in nearly one quarter of the cohort, suggesting that stricter stopping rules needs to be utilized for cisplatin-associated hearing loss or alternatively, the cumulative dose of cisplatin be carefully reduced. A cautionary finding in this study was the results of central neuroradiographic review. Thirty of 409 reviewed patients had what was considered unequivocal evidence of residual or metastatic disease by the central reviewers and 66 had studies that were considered incomplete or of poor quality. Five-year EFS was poorer in patients with incompletely assessable studies, as compared with those with centrally reviewed adequate studies and was dismal, as could be expected, for those patients who, in retrospect, were inappropriately assigned to the study with disseminated disease. This shows the critical importance of adequate neuroimaging and interpretation, so as not to put patients who have disseminated medulloblastoma (see Fig 5) at undue risk. Another concerning finding was the disparity in seven patients between central review and institutional review in the determination of disease progression. Nonspecific nerve root enhancement, postsurgery gliosis, and post-treatment tissue damage can be difficult to separate from tumor recurrence. The presence of secondary tumors in seven patients, including three with malignant gliomas, with still a relatively short period of follow-up, is of concern. The neurocognitive, endocrinologic, and pulmonary outcome of patients treated on this study remains in analysis. In an ancillary study evaluating the acute postoperative neurologic status of patients entered on this trial, nearly one quarter of children were found to have postoperative delayed onset mutism, hypotonia, cerebellar deficits, supranuclear cranial nerve deficits, and extreme irritability and/or emotional lability (posterior fossa mutism syndrome).34,35 Approximately one half of affected patients had residual deficits 1 year later.35 This must be taken into account when assessing the long-term sequelae of treatment. From previous retrospective and prospective studies, it is likely that even after 23.4 Gy of craniopsinal irradiation therapy that children, especially those between 3 years and 7 years of age at diagnosis, will suffer significant learning and other associated cognitive complications.8 The results of our study raises the possibility that the dose of CSRT can be reduced even further, especially in meticulously staged patients without evidence of disseminated disease. This is the approach being utilized in the follow-up Children’s Oncology Group average-risk medulloblastoma study, randomly assigning children between 18 Gy and 23.4 Gy of CSRT. The EFS rate should be the basis of comparisons for future studies evaluating alternative means to treat this patient population.
The authors indicated no potential conflicts of interest.
Supported by a cooperative group grant to the Children’s Oncology Group (5UI0CA098543-02). Presented in part at the 33rd Annual Meeting of the Child Neurology Society in Ottawa, Canada, October 15, 2004, and the 11th International Symposium of Pediatric Neuro-Oncology in Boston, MA, on June 14, 2005. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. CBTRUS 1995-1999 Statistical Report: Primary Brain Tumors in the United States. Chicago, IL, Central Brain Tumor Registry of the United States, 2002 2. Zeltzer PM, Boyett JM, Finlay JL, et al: Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: Conclusions from the Children’s Cancer Group 921 randomized phase III study. J Clin Oncol 17:832-845, 1999 3. Thomas PR, Deutsch M, Kepner JL, et al: Low-stage medulloblastoma: Final analysis of trial comparing standard-dose with reduced-dose neuroaxis irradiation. J Clin Oncol 18:3004-3011, 2000 4. Packer RJ: Chemotherapy for medulloblastoma/primitive neuroectodermal tumors of the posterior fossa. Ann Neurol 28:823-828, 1990[CrossRef][Medline] 5. Packer RJ, Cogen P, Vezina G, et al: Medulloblastoma: Clinical and biologic aspects. Neuro Oncol 1:232-250, 1999[Abstract] 6. Packer RJ, Sutton LN, Elterman R, et al: Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J Neurosurg 81:690-698, 1994[Medline] 7. Packer RJ, Sutton LN, Atkins TE, et al: A prospective study of cognitive function in children receiving whole-brain radiotherapy and chemotherapy: 2-year results. J Neurosurg 70:707-713, 1989[Medline] 8. Ris MD, Packer R, Goldwein J, et al: Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: A Children’s Cancer Group study. J Clin Oncol 19:3470-3476, 2001 9. Packer RJ, Boyett JM, Janss AJ, et al: Growth hormone replacement therapy in children with medulloblastoma: Use and effect on tumor control. J Clin Oncol 19:480-487, 2001 10. Bailey CC, Gnekow A, Wellek S, et al: Prospective randomized trial of chemotherapy given before radiotherapy in childhood medulloblastoma: International Society of Paediatric Oncology (SIOP) and the (German) Society of Paediatric Oncology (GPO): SIOP II. Med Pediatr Oncol 25:166-178, 1995[Medline] 11. Packer RJ, Goldwein J, Nicholson HS, et al: Treatment of children with medulloblastomas with reduced-dose craniopsinal radiation therapy and adjuvant chemotherapy: A Children’s Cancer Group study. J Clin Oncol 17:2127-2136, 1999 12. Friedman HS, Schold SC: Rational approaches to the chemotherapy of medulloblastoma. Neurol Clin 3:843-854, 1985[Medline] 13. Allen JC, Helson L: High-dose cyclophosphamide chemotherapy for recurrent CNS tumors in children. J Neurosurg 55:749-756, 1981[Medline] 14. Sposto R: Cure model analysis in cancer: An application to data from the Children’s Cancer Group. Stat Med 21:293-312, 2002[CrossRef][Medline] 15. Kalbfleisch J, Prentice R: The Statistical Analysis of Failure Time Data. New York, NY, John Wiley and Sons, 1980 16. Sposto R, Sather HN: Determining the duration of comparative clinical trials while allowing for cure. Journal Chron Dis 38:683-690, 1985[CrossRef] 17. Taylor RE, Bailey CC, Robinson K, et al: Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: The International Society of Paediatric Oncology/United Kingdom Children’s Cancer study group PNET-3 study. J Clin Oncol 21:1581-1591, 2003 18. Kuhl J, Muller HL, Berthold F, et al: Preradiation chemotherapy of children and young adults with malignant brain tumors: Results of the German pilot trial HIT '88/’89. Klin Padiatr 210:227-233, 1998[Medline] 19. Kortmann RD, Kuhl J, Timmermann B, et al: Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: Results of the German prospective randomized trial HIT ’91. Int J Radiat Oncol Biol Phys 46:269-279, 2000[CrossRef][Medline] 20. Grotzer MA, Janss AJ, Fung K, et al: Trkc expression predicts good clinical outcome in primitive neuroectodermal brain tumors. J Clin Oncol 18:1027-1035, 2000 21. Pomeroy SL, Tamayo P, Gaasenbeek M, et al: Prediction of central nervous system embryonal tumor outcome based on gene expression. Nature 415:436-442, 2002[CrossRef][Medline] 22. Segal RA, Goumnerova LC, Kwon YK, et al: Expression of the neurotrophin receptor trkc is linked to a favorable outcome in medulloblastoma. Proc Natl Acad Sci U S A 91:12867-12871, 1994 23. MacDonald TJ, Rood BR, Santi MR, et al: Advances in the diagnosis, molecular genetics, and treatment of pediatric embryonal CNS tumors. Oncologist 8:174-186, 2003 24. Gilbertson RJ, Pearson AD, Perry RH, et al: Prognostic significance of the c-erbb-2 oncogene product in childhood medulloblastoma. Br J Cancer 71:473-477, 1995[Medline] 25. MacDonald TJ, Brown KM, LaFleur B, et al: Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease. Nat Genet 29:143-152, 2001[CrossRef][Medline] 26. Grotzer MA, Hogarty MD, Janss AJ, et al: Myc messenger RNA expression predicts survival outcome in childhood primitive neuroectodermal tumor/medulloblastoma. Clin Cancer Res 7:2425-2433, 2001 27. Rood BR, Zhang H, Weitman DM, et al: Hypermethylation of Hic-1 and 17p allelic loss in medulloblastoma. Cancer Res 62:3794-3797, 2002 28. Gajjar A, Hernan R, Kocak M, et al: Clinical, histopathologic, and molecular markers of prognosis: Toward a new disease risk stratification system for medulloblastoma. J Clin Oncol 22:984-993, 2004 29. Lamont JM, McManamy CS, Pearson AD, et al: Combined histopathological and molecular cytogenetic stratification of medulloblastoma patients. Clin Cancer Res 10:5482-5493, 2004 30. Herms J, Neidt I, Luscher B, et al: C-MYC expression in medulloblastoma and its prognostic value. Int J Cancer (Pred Oncol) 89:395-402, 2000[CrossRef][Medline] 31. Ray AM, Ho M, Ma J, et al: A clinicobiological model predicting survival in medulloblastoma. Clin Cancer Res 10:7613-7620, 2004 32. Eberhart CG, Kratz J, Wang Y, et al: Histopathological and molecular prognostic markers in medulloblastoma: C-myc, N-myc, TrkC, and Anaplasia. J Neuropathol Exp Neurol 63:441-449, 2004[Medline] 33. Oyharcabal-Bourden V, Kalifa C, Gentet JC, et al: Standard-risk medulloblastoma treated by adjuvant chemotherapy followed by reduced-dose craniopsinal radiation therapy: A French Society of Pediatric Oncology study. J Clin Oncol 22:4726-4734, 2005[CrossRef] 34. Pollack IF, Polinko P, Albright AL, et al: Mutism and pseudobulbar symptoms after resection of posterior fossa tumors in children: Incidence and pathophysiology. Neurosurgery 37:885-893, 1995[Medline] 35. Robertson PL, Murasko KM, Packer RJ, et al: Prospective study of the cerebellar mutism syndrome after posterior fossa surgery in two large cohorts of medulloblastoma. Ann Neurol 52:S115, 2002 (abstr 12)[CrossRef] Submitted March 8, 2006; accepted June 30, 2006.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
