|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2001 American Society for Clinical Oncology Clinical Impact of 18F Fluorodeoxyglucose Positron Emission Tomography in Patients With Non–Small-Cell Lung Cancer: A Prospective StudyFrom the Department of Nuclear Medicine, Alfred Hospital, Prahran, and Departments of Diagnostic Imaging and Radiation Oncology, Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia. Address reprint to Rod Hicks, MD, FRACP, Director of Diagnostic Imaging, PET Center, Peter MacCallum Cancer Institute, 12 Cathedral Place, East Melbourne VIC 3002, Australia; email rhicks@ petermac.unimelb.edu.au.
PURPOSE: To prospectively study the impact of 18F fluorodeoxyglucose (FDG) positron emission tomography (PET) on clinical management of patients with non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: One hundred five consecutive patients with NSCLC undergoing 18F FDG PET were analyzed. Before PET, referring physicians recorded scan indication, conventional clinical stage, and proposed treatment plan. PET scan results were reported in conjunction with available clinical and imaging data, including results of computed tomography (CT). Subsequent management and appropriateness of PET-induced changes were assessed by follow-up for at least 6 months or until the patient’s death. RESULTS: Indications for PET were primary staging (n = 59), restaging (n = 34), and suspected malignancy subsequently proven to be NSCLC (n = 12). In 27 (26%) of 105 of cases, PET results led to a change from curative to palliative therapy by upstaging disease extent. Validity of the PET result was established in all but one case. PET appropriately downstaged 10 of 16 patients initially planned for palliative therapy, allowing either potentially curative treatment (four patients) or no treatment (six patients). PET influenced the radiation delivery in 22 (65%) of 34 patients who subsequently received radical radiotherapy. Twelve patients considered probably inoperable on conventional imaging studies were downstaged by PET and underwent potentially curative surgery. PET missed only one primary tumor (5-mm scar carcinoma). CT and PET understaged three of 20 surgical patients (two with N1 lesions < 5 mm and one with unrecognized atrial involvement), and PET missed one small intrapulmonary metastasis apparent on CT. No pathological N2 disease was missed on PET. CONCLUSION: FDG PET scanning changed or influenced management decisions in 70 patients (67%) with NSCLC. Patients were frequently spared unnecessary treatment, and management was more appropriately targeted.
IT HAS RECENTLY been suggested that positron emission tomography (PET) using 18F fluorodeoxyglucose (FDG) should be routinely incorporated into conventional staging algorithms used to determine the most appropriate treatment for potentially curable patients with non–small-cell lung cancer (NSCLC).1-3 This is as a direct result of formal comparison studies clearly demonstrating the superiority of PET over conventional computed tomography (CT).4-11 These studies have uniformly shown improvements in sensitivity and specificity for staging of individual patients ranging from approximately 60% to more than 85%, particularly if the PET scans were read in conjunction with the CT scans.4,6,12,13 As more accurate staging should lead to more appropriate therapy, PET may lead to both an improvement in patient quality of life and health-care cost savings.14 This study builds on the foundation of these earlier studies by prospectively examining the clinical impact of this new imaging modality on the management of patients with NSCLC. Initial management plans were designated by treating physicians using clinical and imaging information available before the PET scan. These plans were compared with the management actually delivered. The validity of management changes was assessed by outcome analysis.
Eligibility Consecutive patients referred to the Peter MacCallum Cancer Institute PET center for FDG scanning for proven or suspected NSCLC Between August 1997 and December 1998 were entered into this study. At this institute, all such patients routinely undergo a chest x-ray and contrast-enhanced CT scan from the neck to the upper abdomen to include the liver and adrenal glands in the field of view. In addition, patients with musculoskeletal symptoms that are suggestive of skeletal metastases, or those who are found to have at least stage II disease, undergo additional whole-body bone scintigraphy. A contrast CT scan of the brain is performed if there is clinical suspicion of cerebral involvement. To be included in analysis, patients were required to have histologically or cytologically proven disease diagnosed before or after PET scanning and no proven metastatic disease. PET scans were performed as part of usual clinical practice for patients managed at our institution. Specific subgroups entered onto clinical trials gave informed consent, and the study protocols were approved by the institutional ethics committee. At our center, PET is used for clinical evaluation of NSCLC for (a) routine staging of medically or surgically inoperable patients who are candidates for radical chemoradiotherapy or radiotherapy, (b) patients with suspected but unproven recurrence of NSCLC after surgery or radiation therapy if active treatment is considered appropriate, and (c) patients who are candidates for potentially curative surgery.
Patient Population The remaining 105 patients with histologically or cytologically proven NSCLC formed the basis of this study. Of these, 59 patients (56%) were undergoing primary staging, 34 (32%) were being restaged for suspected recurrence, and 12 (12%) had suspected but unconfirmed primary lung malignancy. These latter patients had all undergone CT staging and, unless contraindicated, attempted cytologic diagnosis, which was either negative or equivocal. The mean (± SD) patient age was 64 ± 9 years (range, 39 to 80 years), and 44 patients (42%) were female. The histologic classification of the tumors was available in all cases before treatment was instituted ( Table 1).
Pre-Scan Clinical Information On the clinical request form, referring physicians were required to state the indication for the PET scan, the histologic diagnosis, if known, the current clinical stage, and the results of the most recent structural imaging tests. Tumor-node-metastasis status and formal stage groupings were assigned for the 59 patients undergoing primary staging. The 1997 revision of the international system for staging lung cancer was used.15 For patients being planned for therapy at our institution, imaging studies not performed in-house were reviewed and repeated only if technically inadequate. In cases in which the structural imaging abnormalities were considered equivocal, patients were allocated to the most favorable stage grouping. Referring physicians were required to state their proposed management plan. If the request forms were incomplete, the referring physicians were contacted to obtain the missing information before the release of the PET scan findings. For eight patients, the referring clinician refused to commit to a treatment plan without access to the PET information.
PET Scan Procedure Image data sets were obtained using iterative reconstruction (the ordered subset expectation maximization method).17 Attenuation correction was performed using previously described methods.18 Data sets with and without measured attenuation correction were reported from the screen using an interactive display program that allows multiple orthogonal images to be displayed simultaneously. Rotating count–rendered images were also reviewed.
PET Scan Interpretation
Follow-Up: Influence of the PET Scan
Outcome of Patients in Whom PET Scanning Induced Management Changes Statistics Where appropriate, 95% confidence intervals (CIs) are reported that have been calculated using StatXact 4.0.1 software (Cytel Software Corp, Cambridge, MA).
The impact of PET was analyzed for each of the three scan indication groupings. Overall, PET altered treatment intent, modality, or delivery in 62 (64%; 95% CI, 54% to 73%) of 97 patients with a prospectively defined pre-PET treatment plan and determined treatment in the remaining eight patients without a pre-PET plan.
Impact of PET in Primary Staging
Among the 56 patients whose physicians were able to prospectively determine a treatment plan before PET scanning ( Table 3), the PET results changed the treatment modality (three patients) or intent (23 patients) in 46%. For 17 of the 50 patients initially planned for curative therapy, the treatment intent was changed to palliative therapy (39% of radical radiotherapy candidates and 26% of surgical candidates). Due to downstaging, three of six patients initially thought suitable only for palliative therapy were recommended for treatment with curative intent.
The radiotherapy plan was altered for 10 (53%) of 19 patients for whom radical radiotherapy was the proposed treatment before PET and remained so after PET. Further, of 26 patients who actually received radical radiotherapy after primary staging using PET, 17 (65%) had the treatment volume or radiation dose influenced by the result of PET. In summary, PET influenced treatment intent, modality, or delivery in 36 (64%) of 56 patients compared with a prospectively recorded pre-PET plan and determined treatment in three patients who did not have a pre-PET plan. As would be expected, the predominant effect of PET was to identify those with more extensive disease than previously suspected, leading to less aggressive treatment than planned in 23 (41%) of 56 patients but also to more intensive treatment for five patients (9%).
Impact of PET in Restaging In summary, for patients who underwent restaging, PET altered treatment intent, modality, or delivery in 21 (72%) of 29 patients with a prospectively defined pre-PET treatment plan and determined management in the five patients without a defined pre-PET plan.
Impact of PET in Unproven but Later Confirmed NSCLC
Patient Outcomes When PET Information Was Used in Treatment Planning Conversely, in eight patients, treatment plans were changed to observation rather than active treatment after negative PET findings at sites of suspicious structural imaging abnormalities. A further four patients whose treating physicians were unwilling to commit to treatment plans before clarification of equivocal structural imaging abnormalities were assigned to observation only after a negative PET finding (Table 3). Only one of these patients later showed evidence of malignancy in the site of concern after at least 9 months of follow-up (a 5-mm scar carcinoma). Of the 22 patients whose management plans remained or became curative surgery after PET (Table 3), two patients refused surgery. In 18 (90%) of 20 patients, PET correctly staged the mediastinum. Two patients with small-volume N1 disease (one abutting the primary tumor) were understaged. In no case was confirmed N2 disease missed by PET. The tumor stage was incorrect in two patients (one patient who had unrecognized direct atrial involvement that could not have been predicted by PET and one patient with a bronchoalveolar carcinoma had a 5-mm, CT-defined satellite lung metastasis that was PET-negative but that did not compromise operability). One or more abnormalities suspected of being metastatic disease were present on conventional staging in 12 of 20 patients who subsequently underwent curative surgery. These abnormalities included borderline enlarged intrathoracic lymph nodes (six patients), possible lung metastases (five patients) or pleural thickening (one patient) on CT scans, bone scan abnormality (one patient), and abnormal results of liver function tests (two patients). In all 12 cases, surgery was performed only after results of a PET scan encompassing the area of concern were negative. There was no progression in any of these sites at a minimum follow-up of 6 months, and only the patient with bronchoalveolar tumor and a 5-mm satellite lesion appears to have been incorrectly assessed. PET results altered or defined treatment delivery in 22 (65%) of the 34 patients who went on to receive radical radiotherapy (Table 3). In six of these 34 patients, the PET information was disregarded ( Fig 1). These patients are discussed in more detail below. The remaining 28 patients were suitable for radical radiotherapy according to PET criteria and included 17 patients in whom the final treatment volume incorporated all suspected disease on both conventional and PET staging. In the remaining 11 patients, the radiation target volume did not include all abnormalities defined by conventional staging but encompassed all PET-defined disease.
Of the 17 patients with radiation treatment planned to encompass all imaging abnormalities, eight patients underwent radical radiotherapy as initially planned, five patients had the radiation treatment volume increased to incorporate PET-positive but nonenlarged nodes, three patients had their treatment plans changed from surgery after demonstration of unrecognized mediastinal nodal involvement, and one patient without a predefined plan had the treatment volume defined by PET. Only two of these patients had evidence of progression outside the radiation treatment volume within 12 months of the PET scan. One patient developed a cerebral metastasis (not in the imaging field on baseline PET), and one patient had documented evidence of both local and distant treatment failure. Despite the reduction in radiation treatment volumes in 11 patients, no disease progression was demonstrated at a site excluded from treatment after at least 9 months of follow-up. Three patients experienced disease progression within the treatment volume, and one patient died of respiratory failure during treatment, despite reduced radiation volume.
Patient Outcomes When PET Information Was Ignored in Treatment Planning
This prospective study confirms in routine clinical practice the previously predicted benefits of the superior sensitivity and specificity of FDG over conventional imaging for the staging, restaging and diagnosis of patients with NSCLC.1-3 Over a broad range of clinical indications, PET changed or influenced therapy planning for 70 of 105 patients (67%; 95% CI, 57% to 76%). PET prevented aggressive therapy in 27 (35%) of 78 patients initially planned for treatment with curative intent by identifying more advanced disease than previously suspected. In 26 of 27 patients, this disease was confirmed within 6 months. By demonstrating less extensive disease than suspected on conventional staging, PET allowed four (25%) of 16 patients initially only considered for palliative therapy to be offered potentially curative treatment. In other series of patients being staged for newly diagnosed NSCLC,5,9,19 PET was shown to identify patients unsuitable for surgery due to mediastinal lymph node or systemic metastasis. Our study suggests that PET also has an important role in identifying suitable radical radiotherapy candidates and in tailoring radiation treatment fields more closely to gross disease. The potential for PET to alter radiotherapy plans was recently described by Kiffer et al20 in a retrospective analysis. In our own prospective study, PET influenced the radiation treatment volume for 22 (65%) of 34 patients who received radical radiotherapy. Our study also confirms previous evidence21 that PET can be used to determine whether new or residual structural imaging abnormalities in patients previously treated for lung cancer represent recurrent disease or the effects of treatment, particularly radiation fibrosis. PET had a high negative predictive value in our series, with no patient showing progressive disease at a site negative on PET scanning. In 25 patients enrolled onto this study without histologic confirmation of lung cancer before PET, 11 of 12 metabolically active lesions were caused by NSCLC and one was caused by active tuberculosis. Only one of 13 PET-negative lesions was demonstrated to be malignant on follow-up. This is in keeping with PET’s established role in assessing solitary pulmonary nodules.22,23 As in other series, PET also identified undetected disease, which subsequently had an impact on treatment planning. A somewhat higher overall percentage of our patients with a prospectively defined pre-PET treatment plan had management altered after PET (ie, 62 of 97 patients, or 64%; 95% CI, 54% to 73%), compared with previous series (up to 40%).2,9,19,24 This may reflect the significant number of radiotherapy candidates in our series compared with other primarily surgical series. Nevertheless, when changes in radiation treatment delivery were excluded from analyses, PET results still caused changes in treatment modality or intent in 48 (49%; 95% CI, 39% to 60%) of the 97 patients for whom the referring clinician was prepared to prospectively commit to a treatment plan. Our study again demonstrates the ability of PET to detect metastatic disease unrecognized by conventional staging algorithms. Unsuspected distant disease was identified in 18 (17%; 95% CI, 10% to 25%) of 105 patients, which is within the range of results (11% to 18%) found in other series.5,9,19 Although FDG uptake is not specific for tumor,2,3,25 in the eligible patients, there were only two documented false-positive results (a postradiotherapy pleural reaction and a thyroid nodule). We now recognize the pattern of postradiotherapy pleural reaction and do not report it as a positive scan result. One patient ineligible for the study also had a false-positive study related to active tuberculosis. Therefore, when the clinical scenario raises doubt regarding the nature of PET abnormalities, correlative imaging and biopsy of the suspicious area is recommended.2,3,5 The limited structural definition and spatial resolution provided by PET compromises accurate T-stage assignment, and therefore PET cannot replace structural imaging for this purpose. As demonstrated in this series by the patient with atrial involvement, even combined use of CT and PET will fail in some cases. Correlating CT/magnetic resonance imaging data with the PET data has the added advantage of improving detection of small-volume metastases by allowing the reader to cognitively correct PET lesion intensity for partial volume effects.4,13 The accuracy for correct pathologic node stage (90%) in our surgically staged patients is in keeping with larger surgical series5,9,19,24 and support the value of this technique for noninvasive node staging. We recognize that PET has limitations in detecting brain metastases because of high normal cortical uptake19,26 and therefore use structural imaging rather than PET to exclude brain metastases in high-risk or symptomatic patients. Although FDG is reported to have a somewhat lower sensitivity for bronchoalveolar cancer,27 both patients with this histologic diagnosis in our series had good uptake in the primary lesion. One small intrapulmonary metastasis was missed, but this may have been related to small lesion size rather than low intrinsic FDG uptake. The results obtained in our facility were achieved in our routine clinical practice using equipment that is significantly less expensive to purchase and operate than conventional dedicated PET scanners. Further, we did not use quantitative analysis or complex image coregistration algorithms. Nevertheless, we believe that attention to detail in each step of the staging process is critical to achieve such results. We plan and interpret the PET scan in combination with information derived from the patient and referring doctor, and we optimize image quality by routinely using iterative reconstruction techniques and attenuation correction. We have developed a model of PET practice optimized to clinical service provision.28 This, combined with improvements in technology and a larger installed base of PET scanning devices, should significantly lower the cost of this technique. Nevertheless, PET remains a relatively expensive imaging modality; therefore, in our institution it is used primarily in patients suitable for aggressive therapy, since prevention of futile local treatment in patients recognized to have widespread disease is likely to offset the cost of the PET procedure. It is also particularly useful in those patients for whom staging or restaging is difficult because of equivocal conventional imaging. In this group of patients, PET is used to determine whether the equivocal abnormality is likely to be benign or malignant and thus to determine the type and intent of therapy. Increasingly, PET is the first tool of investigation in patients suspected of having a symptomatic relapse. In a small number of cases in this subgroup, it has allowed the use of potentially curative therapy where it would not otherwise have been contemplated. For example, postage stamp radiotherapy can be used in patients in whom severe airways disease would otherwise preclude potentially curative standard-field radiotherapy. In conclusion, our study demonstrates that addition of PET to comprehensive conventional evaluation of NSCLC can have a significant impact on clinical management over a broad range of indications in patients presenting with a wide range of apparent disease extent. Where PET results provided discordant information in relation to conventional staging, patient outcome overwhelmingly confirmed the validity of the PET stage. More accurate staging spared a substantial number of patients the morbidity related to futile attempts at aggressive local control. PET staging also provided a chance of survival in a smaller but still significant number of patients who would have been denied potentially curative therapy based on false-positive structural imaging studies. Although not specifically addressed in this study, these changes also have the potential to provide significant cost savings to the community and improve outcomes.
Supported by a grant from the Consultative Committee on Diagnostic Imaging, under the auspices of the Australian Government Department of Health and Aged Care. We thank (a) the many referring physicians who provided their time and patients to allow this work to be completed; (b) the radiochemistry staff of the Austin and Repatriation Medical Center and Peter MacCallum Cancer Institute who prepared the FDG; (c) staff members of the Medical Records Department of the Peter MacCallum Cancer Institute who helped with data retrieval; (d) Jane Matthews, PhD, for her statistical advice and thoughtful comments during manuscript preparation; (e) the Alfred Hospital and its Whole Time Medical Specialist Fund, which cofunded V.K.’s sabbatical leave when this study was conceived and started, and (f) associate professor Michael J. Kelly of the Alfred Hospital, for his assistance in the manuscript review process.
1. Matin TA, Goldberg M: Surgical staging of lung cancer. Oncology 13: 679-685, 1999[Medline]
2.
Coleman RE: PET in lung cancer. J Nucl Med 40: 814-820, 1999 3. Chiti A, Schreiner FAG, Crippa F, et al: Nuclear medicine procedures in lung cancer. Eur J Nucl Med 26: 533-555, 1999[Medline]
4.
Wahl RL, Quint LE, Greenough RL, et al: Staging of mediastinal non-small cell lung cancer with FDG PET, CT and fusion images: Preliminary prospective evaluation. Radiology 191: 371-377, 1994
5.
Valk PE, Pounds TR, Hopkins DM, et al: Staging non-small cell lung cancer by whole body positron emission tomography. Ann Thorac Surg 60: 1573-1582, 1995
6.
Scott WJ, Gobar LS, Terry JD, et al: Mediastinal lymph node staging of non-small cell lung cancer: A prospective comparison of computed tomography and positron emission tomography. J Thorac Cardiovasc Surg 111: 642-648, 1996 7. Sasaki M, Ichiya Y, Kuwabara Y, et al: The usefulness of FDG positron emission tomography for the detection of mediastinal lymph node metastases in patients with non-small cell lung cancer: A comparative study with x-ray computed tomography. J Nucl Med 23: 741-747, 1996
8.
Steinert HC, Hauser M, Allemann F, et al: Non-small cell lung cancer: Nodal staging with FSDG PET versus CT with correlative lymph node mapping and sampling. Radiology 202: 441-446, 1997 9. Bury T, Dowlati A, Paulus P, et al: Whole-body 18-FDG positron emission tomography in the staging of non-small cell lung cancer. Eur Respir J 10: 2529-2534, 1997[Abstract]
10.
Marom EM, McAdams HP, Erasmus JJ, et al: Staging non-small cell lung cancer with whole-body PET. Radiology 212: 803-809, 1999 11. Kutlu CA, Pastorino U, Maisey MN, et al: Selective use of PET scan in the preoperative staging of NSCLC. Lung Cancer 21: 177-184, 1998[Medline]
12.
Vansteenkiste JF, Stroobants SG, Deleyn PR, et al: Potential use of FDG-PET scan after induction chemotherapy in surgically staged IIIa-N2 non-small-cell lung cancer: A prospective pilot study—The Leuven Lung Cancer Group. Ann Oncol 9: 1193-1198, 1998 13. Vansteenkiste JF, Stroobants SG, Dupont PJ, et al: FDG- PET scan in potentially operable non-small cell lung cancer: Do anatometabolic PET fusion images improve the localisation of regional lymph node metastases? Eur J Nucl Med 25: 1495-1501, 1998[Medline]
14.
Scott WJ, Shepherd J, Gambhir S: Cost-effectiveness of FDG-PET for staging non-small cell lung cancer: A decision analysis. Ann Thorac Surg 66: 1876-1885, 1998 15. Mountain CF: Revisions to the international system for staging lung cancer. Chest 111: 1711-1717, 1997
16.
Karp JS, Muehllehner G, Mankoff DA, et al: Continuous-slice PENN-PET: A positron tomograph with volume imaging capability. J Nucl Med 31: 617-627, 1990 17. Fulham MJ, Meikle SR, Hooper PK, et al: Lesion detection in whole body FDG PET using simultaneous emission transmission acquisition and OSEM reconstruction (SET-OSEM) versus emission only (OE) and FBP reconstruction: An ROC study. J Nucl Med 5: 78P, 1997 (abstr) 18. Bénard F, Smith RJ, Hustinx R, et al: Clinical evaluation of processing techniques for attenuation correction with 137Cs in whole-body PET imaging. J Nucl Med 1999: 1257-1263, 1999
19.
Saunders CA, Dussek JE, O’Doherty MJ, et al: Evaluation of fluorine-18-fluorodeoxyglucose whole body positron emission tomography imaging in the staging of lung cancer. Ann Thorac Surg 67: 790-797, 1999 20. Kiffer JD, Berlangieri SU, Scott AM, et al: The contribution of 18F-fluoro-2-deoxy-glucose positron emission tomographic imaging to radiotherapy planning in lung cancer. Lung Cancer 19: 167-177, 1998[Medline]
21.
Patz EF, Lowe VJ, Hoffman JM, et al: Persistent or recurrent bronchogenic carcinoma: Detection with PET and 2[F-18]-2-deoxy-D-glucose. Radiology 191: 379-382, 1994
22.
Gupta NC, Frank AR, Dewan NA, et al: Solitary pulmonary nodules: Detection of malignancy with PET with 2-[F-18]-fluoro-2-deoxy-D-glucose. Radiology 184: 441-444, 1992 23. Lowe VJ, Fletcher JW, Gobar L, et al: Prospective investigation of positron emission tomography in lung nodules. J Clin Oncol 16: 1075-1084, 1998[Abstract] 24. Gupta NC, Graeber GM, Rogers JS, et al: Comparative efficacy of positron emission tomography with FDG and computed tomographic scanning in preoperative staging of non-small cell lung cancer. Ann Surg 229: 286-291, 1999[Medline] 25. Strauss LG: Fluorine-18 deoxyglucose and false-positive results: A major problem in the diagnosis of oncological patients. Eur J Nucl Med 23: 1409-1414, 1996[Medline] 26. Hellwig D, Leutz M, Rentz K, et al: Brain metastases of lung cancer: Diagnostic accuracy of positron emission tomography with fluorodeoxyglucose (FDG-PET). Med Klin 94: 224-227, 1999[Medline]
27.
Higashi K, Ueda Y, Seki H, et al: Fluorine-18-FDG PET imaging is negative in bronchoalveolar lung carcinoma. J Nucl Med 39: 1016-1020, 1998 28. Hicks RJ, Binns DS, Fawcett ME, et al: Positron emission tomography (PET): Experience with a large-field-of-view three-dimensional PET scanner. Med J Aust 171: 529-532 1999[Medline] Submitted December 29, 1999; accepted July 17, 2000.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
