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Journal of Clinical Oncology, Vol 22, No 15 (August 1), 2004: pp. 3053-3060 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.05.178 Phase II Study of Neoadjuvant Carboplatin and Paclitaxel Followed by Radiotherapy and Concurrent Cisplatin in Patients With Locoregionally Advanced Nasopharyngeal Carcinoma: Therapeutic Monitoring With Plasma Epstein-Barr Virus DNAFrom the Departments of Clinical Oncology, Chemical Pathology, and Department of Diagnostic Radiology and Organ Imaging, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China Address reprint requests to Anthony T.C. Chan, MD, FRCP, Department of Clinical Oncology at the Sir Y.K. Pao Center for Cancer, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong Special Administrative Region, China; e-mail: anthonytcchan{at}cuhk.edu.hk
PURPOSE: To assess the efficacy of neoadjuvant paclitaxel and carboplatin (TC) followed by concurrent cisplatin and radiotherapy (RT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) and to monitor treatment response with plasma Epstein-Barr virus (EBV) DNA. PATIENTS AND METHODS: Thirty-one patients with International Union Against Cancer stages III and IV undifferentiated NPC had two cycles of paclitaxel (70 mg/m2 on days 1, 8, and 15) and carboplatin (area under the curve 6 mg/mL/min on day 1) on a 3-weekly cycle, followed by 6 to 8 weeks of cisplatin (40 mg/m2 weekly) and RT at 66 Gy in 2-Gy fractions. Plasma EBV DNA was measured serially using the real-time quantitative polymerase chain reaction method. RESULTS: All patients completed planned treatment. Response to neoadjuvant TC was as follows: 12 patients (39%) achieved partial response (PR) and 18 achieved (58%) complete response (CR) in regional nodes; five patients (16%) achieved PR and no patients achieved CR in nasopharynx. At 6 weeks after RT, one patient (3%) achieved PR and 30 patients (97%) achieved CR in regional nodes, and 31 patients (100%) achieved CR in nasopharynx; 29 patients (93%) had EBV DNA level of less than 500 copies/mL. Neoadjuvant TC was well tolerated, and the most common acute toxicity of cisplatin plus RT was grade 3 mucositis (55%). At median follow-up of 33.7 months (range, 7 to 39.3 months), six distant and three locoregional failures occurred. Plasma EBV DNA level increased significantly in eight of nine patients who experienced treatment failure but did not increase in those who did not. The 2-year overall and progression-free survival rates were 91.8% and 78.5%, respectively. CONCLUSION: This strategy was feasible and resulted in excellent local tumor control. Serial plasma EBV DNA provides a noninvasive method of monitoring response in NPC.
Undifferentiated and poorly differentiated nasopharyngeal carcinoma (NPC; WHO type II and III) is unique among head and neck malignancies in its association with the Epstein-Barr virus (EBV) and sensitivity to chemotherapy.1 EBV infection is ubiquitous in the tumor cells of undifferentiated NPC and may contribute to the pathogenesis of the disease.2-4 With the advent of real-time polymerase chain reaction (PCR) quantitative technology, circulating cell-free EBV DNA can be detected in more than 95% of patients with NPC.5 Studies have demonstrated an association between the level of circulating EBV DNA and disease stage, tumor recurrence, and patient survival after radical radiotherapy (RT).5-8 Tumor cells have been postulated to release EBV DNA directly into the circulation, such that the level of circulating EBV DNA reflects tumor load and microscopic residual disease after RT.8 With the reproducibility of the real-time PCR technique and circulating kinetics that closely reflect clinical response to RT, plasma EBV DNA analysis may be a valuable tool in monitoring response to neoadjuvant therapy and chemoradiotherapy in NPC. Incorporation of chemotherapy with standard RT has improved the therapeutic outcome of patients with locoregionally advanced NPC. This is supported by a meta-analysis of six randomized trials suggesting that when compared with RT alone, the addition of chemotherapy in any sequence increases disease-free survival by 35% at 2 to 4 years and overall survival by 20% at 3 to 4 years.9 A key question remains regarding the optimal sequencing of chemotherapy and RT. Three published randomized trials of concurrent chemoradiotherapy have demonstrated a progression-free (PFS) and/or overall survival (OS) benefit over RT alone,10-12 yet the merits of adjuvant and neoadjuvant chemotherapy remain unproven. In the United States Intergroup study published by Al-Sarraf et al, 12 patient compliance to adjuvant chemotherapy was problematic, and it is difficult to ascertain whether the adjuvant therapy contributed to the reported OS benefit. In this regard, neoadjuvant chemotherapy may have better tolerability, and moreover, impressive tumor response rates have been reported in phase II studies.1 Despite the failure of randomized trials in demonstrating a survival advantage of this approach over RT alone,13-17 two large trials have shown significant improvement in PFS in subgroups of patients with stage III and IV NPC.14,15 The purpose of this study was twofold: to assess the toxicity and tumor response of two cycles of neoadjuvant paclitaxel and carboplatin (TC) followed by concurrent cisplatin and RT (cisplatin-RT) in the treatment of stage III to IV NPC and to monitor treatment response with serial plasma EBV DNA. This sequential design was based on the assumption that a short course of intensive chemotherapy administered at weekly intervals before and during RT may improve patient tolerability and minimize the theoretical problem of tumor repopulation occurring after neoadjuvant chemotherapy and before commencing RT.18 Paclitaxel at a dose of 135 to 175 mg/m2 in combination with carboplatin area under the curve of 6 mg/mL/min is feasible and active in metastatic NPC.19,20 Furthermore, paclitaxel up to 230 mg/m2 can be given safely with growth factor support.21 On the basis of the feasibility of weekly paclitaxel in the treatment of metastatic breast cancer,22 a total paclitaxel dose of 210 mg/m2 per cycle given as three divided doses every week was combined with carboplatin in this study. An outpatient schedule of weekly concurrent cisplatin and RT was adopted from that described in our published phase III study.11
Eligibility Eligible patients had untreated, histologically proven WHO type II or III NPC23 and International Union Against Cancer stage classification III or IV disease (any T stage, N stage 2 to 3).24 Other criteria included age greater than 18 years, the presence of measurable disease, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Pretreatment organ function and hematologic reserve included absolute neutrophil count of greater than 1.5 x 109/L, platelet count greater than 100 x 109/L, serum creatinine of less than 1.5 times the upper limit of normal or a 24-hour creatinine clearance (CrCl) of greater than 50 mL/min, normal serum bilirubin, ALT and alkaline phosphatase levels of less than two times the upper limit of normal. The study was approved by the Clinical Research Ethics Committee of the Chinese University of Hong Kong, and written informed consent was obtained from all patients before trial entry.
Evaluation and Follow-Up Throughout the treatment period, patients underwent weekly physical examination and toxicity assessment. Biochemical blood tests and 24-hour CrCl were performed every 3 weeks; CBC count was performed on days 1, 8, and 15 of each cycle of neoadjuvant chemotherapy and weekly during cisplatin-RT. Three milliliters of blood for EBV DNA analysis was drawn at baseline, weekly during neoadjuvant TC and cisplatin-RT, 4 to 6 weeks post-RT, and then every 8 weeks for 1 year. Tumor response was evaluated at the end of neoadjuvant TC and again at 4 to 6 weeks after completion of cisplatin-RT. These included a CT scan of NP (including the retropharyngeal nodes) and nasopharyngoscopy to assess the primary tumor, in addition to clinical measurement of neck lymph nodes. A repeat complete physical examination, nasopharyngoscopy, chest radiograph, biochemical, and hematologic blood tests were performed 4 to 6 weeks after the end of cisplatin-RT. Patients were followed up clinically every 8 weeks during the first year, every 12 weeks for 2 years, and every 24 weeks thereafter. Patients who developed signs or symptoms suggestive of disease recurrence were investigated with nasopharyngoscopy and imaging (CT, magnetic resonance imaging [MRI], or ultrasound). Endoscopic NP biopsy would be taken if residual disease were suspected.
Tumor response evaluation was based on the Eastern Cooperative Oncology Group Solid Tumor Response Criteria. Toxicity was graded according to National Cancer Institute Common Toxicity Criteria version 2.0. Plasma EBV DNA reduction to
Chemotherapy
Radiation Therapy External-beam RT (ERT) was administered according to the techniques described by Ho.25 The NP, adjacent muscles, and bones were treated to 66 Gy in 33 fractions per 6.5 weeks by a shrinking-field technique (two lateral faciocervical 6-MV photon fields to 40 Gy in 20 fractions per 4 weeks, followed by a three-field treatment to 26 Gy in 13 fractions per 2.5 weeks). In the presence of parapharyngeal disease, the anterior facial fields of the three-field treatment phase technique were enlarged to adequately cover the tumor target, and a parapharyngeal boost of 20 Gy in 10 fractions was given at 2 weeks after the ERT. Any palpable residual nodes after ERT were boosted to 7.5 Gy in two fractions in 2 days at the 90% isodose level with an electron field (8 to 10 MV). Patients with persistent NP disease were given intracavitary brachytherapy using iridium-192 sources, delivering a dose of 18 Gy in four fractions in 15 days. Those with histologically proven residual neck nodes were referred for radical neck dissection.
Dose Modification for Chemotherapy-Related Toxicity and Supportive Care
Real-Time Quantitative PCR for EBV DNA
Statistical Methods
Patient Characteristics Thirty-one Chinese patients with exclusively WHO type III NPC were enrolled between May 2000 and August 2001 at the Prince of Wales Hospital, the Chinese University of Hong Kong. Their characteristics are listed in Table 1. All 31 patients completed the planned treatment without protocol violations, and all were assessable for response and toxicity.
Response and Survival After 6 weeks of neoadjuvant TC, 12 patients (39%) achieved a partial response (PR) and 18 patients (58%) achieved a complete response (CR) in the regional nodes, and five patients (16%; 95% CI, 7% to 31%) achieved a PR and no patient achieved CR in the NP. The overall response rate (PR and CR) to neoadjuvant chemotherapy was 16%. At the end of cisplatin-RT, 30 patients (97%) achieved CR at both NP and regional nodes, and one patient had persistent neck nodal disease. With a median follow-up of 33.7 months (range, 7 to 39.3 months), a total of nine patients experienced distant or locoregional failure after RT. Six patients developed distant metastases to bone, liver, and/or lung and were treated with palliative chemotherapy. Three patients developed locoregional failure only; one patient who developed locoregional failure in the regional nodes refused radical neck dissection, whereas another patient experienced relapse in both regional nodes and NP and was treated with chemotherapy because salvage surgery was not feasible. The third patient with persistent neck nodal disease went into CR after salvage neck dissection. Four patients have died at the time of data analysis (which took place on December 24, 2003), and median survival has not been reached. The 1- and 2-year overall survival rates were 95.4% and 91.8%, respectively, and the 1- and 2-year PFS rates were 88.4% and 78.5%, respectively (Fig 2).
Plasma EBV DNA Level The mean pretreatment EBV DNA level was 28,938 copies/mL (range, 5.75 to 407,154 copies/mL). After 6 weeks of neoadjuvant TC, 24 patients (77%; 95% CI, 61% to 88%) achieved an EBV DNA level of  500 copies/mL. At the end of cisplatin-RT, 29 patients (94%; 95% CI, 80% to 99%) achieved an EBV DNA level of 500 copies/mL, and the level was undetectable in 23 patients (74%; Tables 2 and 3). Of the 22 patients who achieved CR after cisplatin-RT and remained disease-free, their plasma EBV DNA level decreased to and stayed at 500 copies/mL after cisplatin-RT right up to the date of data analysis (Fig 3). In the nine patients who experienced treatment failure, the EBV DNA level decreased to 500 copies/mL toward the end of cisplatin-RT (Table 4) and started to increase to greater than 500 copies/mL in eight patients (one patient had persistently low levels, identified as PW006) at approximately 2 to 16 months before any clinically suggestive evidence of disease progression.
Treatment Delivery All 31 patients completed two cycles of neoadjuvant TC. Twenty-three patients (74%) completed 80% or more of the planned paclitaxel dose, and all completed the planned carboplatin dose. Twenty-two patients completed  six doses of concurrent cisplatin at a weekly schedule during RT, and there was no delay during RT.
Toxicity
This phase II study demonstrates that combining neoadjuvant carboplatin-paclitaxel and concurrent cisplatin-RT in a sequential approach is feasible and results in CR in more than 97% of patients after chemoradiotherapy. This study also evaluated plasma EBV DNA as a tool in monitoring treatment response and showed that in the majority of patients, changes in the level of plasma EBV DNA reflect tumor response as defined by clinical, radiologic, and/or endoscopic criteria. Seventy-eight percent and 93% of patients achieved plasma EBV DNA levels of 500 copies/mL after neoadjuvant TC and cisplatin-RT, respectively (Table 2). Eight of the nine patients who subsequently experienced treatment failure at distant or locoregional sites had increasing plasma levels of EBV DNA that predated clinical evidence of progression, whereas all of the disease-free patients had low to undetectable levels after cisplatin-RT (Table 4). In this study, we described tumor response in the NP and regional nodes separately. The high response rate to neoadjuvant TC in the regional nodes (97%) is consistent with that reported in metastatic disease (58% to 73%).19,20 However, response rate in the NP was inferior (16%) by comparison. This apparently differential response may suggest differences between the tumor clones deriving from the primary tumor and metastases in terms of susceptibility to chemotherapy or differences in drug delivery.27 A more likely explanation lies in the inadequacy of endoscopic and CT examination in evaluating the NP. Our institutional practice was to use clinical and CT examination in assessing treatment response for patients with NPC. Although CT scan is good in assessing bony structures of the head and neck and most nodal groups in the neck, it does not surpass MRI in assessing the retropharyngeal nodes or the soft tissue structures around the NP (especially parapharyngeal disease).28-31 Another challenging problem common to endoscopic, CT, or MRI examination is assessment of the NP during the immediate post-RT period, where the anatomy of the inflamed NP is often distorted, rendering interpretation difficult.31 Although positron emission tomography may be superior compared with CT in this setting,28,32 it, too, may produce false-positive and false-negative results in the first 6 months after RT, and moreover, its broader application is limited by availability and expense. Consequently, the pursuit of a circulating molecular marker such as EBV DNA for the monitoring of treatment response in NPC stems from a need to overcome these limitations of conventional assessment.
Elevated plasma EBV DNA levels measured before and at 6 weeks after radical RT are significant predictors of disease recurrence and inferior survival in patients with locoregionally advanced NPC.6,8 A post-RT level exceeding 500 copies/mL represents a more powerful predictor of inferior PFS (risk ratio, 11) than a pre-RT level of more than 4,000 copies/mL (risk ratio, 2.5).8 Kinetics studies performed during RT or nasopharyngectomy showed that plasma EBV DNA clearance in most patients occurs rapidly and early during treatment and that any subsequent increase invariably represents subclinical disease relapse.33,34 The above findings are confirmed in this study, where EBV DNA was used as a marker of patients’ response to neoadjuvant chemotherapy and cisplatin-RT. The high mean pretreatment EBV DNA level (28,938 copies/mL; range, 5.75 to 407,154 copies/mL) is consistent with the advanced disease stage of the cohort.5 A decreasing trend in the plasma EBV DNA level was observed in nearly all patients (except one patient; Fig 3) during neoadjuvant TC and in all who completed cisplatin-RT. Lastly, the plasma EBV DNA measured at 6 weeks after RT, when 29 patients (93%) achieved a level of The caveat of plasma EBV DNA monitoring is its relatively low negative predictive value for local recurrence as opposed to distant recurrence.35 As noted in a previous study, elevated posttreatment EBV DNA level (using a cutoff of 500 copies/mL) has a positive and negative predictive value for NPC recurrence of 87% and 83%, respectively.8 Among the nine patients who had distant or locoregional failure in this study, only three patients had post-RT level exceeding 500 copies/mL. Furthermore, one patient (identified as PW006) who developed locoregional failure had a persistently low plasma EBV DNA level after diagnosis of relapse. One possible explanation is that there is impaired release of EBV DNA from the primary tumor into circulation after RT-induced damage to the stromal vasculature, though the exact mechanism of EBV DNA release from tumors remains to be elucidated. The benefit of concurrent chemoradiotherapy in treating locoregionally advanced NPC is well established in three published randomized trials showing OS benefit,10,11,12 but the role of neoadjuvant chemotherapy is debatable. Recently, promising 4- to 5-year OS rates exceeding 75% have been reported in studies from Australia and North America using sequential neoadjuvant chemotherapy and chemoradiotherapy. Rischin et al36 used three cycles of the cisplatin, epirubicin, and infusional fluorouracil (ECF) followed by concomitant RT at 60 Gy in 2-Gy fractions and cisplatin (administered daily for 5 days in week 1 and 6). In another study, three cycles of cisplatin/fluorouracil/leucovorin and interferon-alfa 2b were given before RT and concurrent hydroxyurea and fluorouracil.37 The current study confirms the feasibility of combining neoadjuvant TC with chemoradiotherapy in treating patients with NPC living in an endemic area. In this study, the incidence of grade 3 to 4 neutropenia (52%) and mucositis within the RT field (55%) were higher than that reported in Rischin et al’s study, in which a 19% rate of grade 3 to 4 neutropenia was reported with neoadjuvant ECF, compared with a 31% rate of mucositis and 23% dermatitis during cisplatin-RT. However, patient tolerability and compliance to neoadjuvant TC was good, and there were no treatment-related deaths. The outpatient administration of TC also avoids the need for hospital admission or indwelling catheters associated with the ECF regimen. In summary, neoadjuvant carboplatin and paclitaxel followed by concurrent cisplatin-RT results in excellent tumor control and manageable toxicity. Serial plasma EBV DNA provides a noninvasive method to monitor tumor response and may contribute to the early detection of distant or locoregional failure after treatment. The management of patients with persistent or increasing plasma EBV DNA after RT without any clinical/radiologic evidence of disease is a subject of ongoing research. Other unanswered questions include the optimal duration and number of chemotherapeutic agents and whether neoadjuvant chemotherapy contributes to the survival benefit associated with concurrent chemoradiotherapy in the treatment of NPC. To address some of these questions, we are conducting a randomized study comparing chemoradiotherapy with or without neoadjuvant chemotherapy.
The authors indicated no potential conflicts of interest.
Supported in part by a central allocation fund of the Research Grants Council of Hong Kong, the Institute of Molecular Oncology at the Chinese University of Hong Kong, and a research grant from Bristol-Myers Squibb. Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002. Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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2. Pathmanathan R, Prasad U, Sadler R, et al: Clonal proliferations of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma. N Engl J Med 333:693-698, 1995 3. Pathmanathan R, Prasad U, Chandrika G, et al: Undifferentiated, nonkeratinizing, and squamous cell carcinoma of the nasopharynx: Variants of Epstein-Barr virus-infected neoplasia. Am J Pathol 146:1355-1367, 1995[Abstract]
4. Tune CE, Liavaag PG, Freeman JL, et al: Nasopharyngeal brush biopsies and detection of nasopharyngeal cancer in a high-risk population. J Natl Cancer Inst 91:796-800, 1999
5. Lo YM, Chan LY, Lo KW, et al: Quantitative analysis of cell-free Epstein-Barr virus DNA in plasma of patients with nasopharyngeal carcinoma. Cancer Res 59:1188-1191, 1999
6. Lo YM, Chan AT, Chan LY, et al: Molecular prognostication of nasopharyngeal carcinoma by quantitative analysis of circulating Epstein-Barr virus DNA. Cancer Res 60:6878-6881, 2000
7. Lo YM: Quantitative analysis of Epstein-Barr virus DNA in plasma and serum: Applications to tumor detection and monitoring. Ann N Y Acad Sci 945:68-72, 2001
8. Chan AT, Lo YM, Zee B, et al: Plasma Epstein-Barr Virus DNA and residual disease after radiotherapy for undifferentiated nasopharyngeal carcinoma. J Natl Cancer Inst 94:1614-1619, 2002 9. Huncharek M, Kupelnick B: Combined chemoradiation versus radiation therapy alone in locally advanced nasopharyngeal carcinoma: Results of a meta-analysis of 1,528 patients from six randomized trials. Am J Clin Oncol 25:219-223, 2002[CrossRef][Medline]
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19. Tan EH, Khoo KS, Wee J, et al: Phase II trial of a paclitaxel and carboplatin combination in Asian patients with metastatic nasopharyngeal carcinoma. Ann Oncol 10:235-237, 1999 20. Yeo W, Leung TW, Chan AT, et al: A phase II study of combination paclitaxel and carboplatin in advanced nasopharyngeal carcinoma. Eur J Cancer 34:2027-2031, 1998 21. Creaven P, Raghavan D, Pendyala L, et al: Phase I study of paclitaxel and carboplatin: Implications for trials in head and neck cancer. Semin Oncol 22:13-16, 1995 (suppl 12) 22. Seidman AD: One-hour paclitaxel via weekly infusion: Dose-density with enhanced therapeutic index. Oncology (Huntingt) 12:19-22, 1998 23. WHO: International Classification of Tumors: Histological Typing of Upper Respiratory Tract Tumors. Geneva, Switzerland, World Health Organization, 1991 24. American Joint Committee on Cancer: Head and Neck Sites, Manual for Staging of Cancer (ed 5). Philadelphia, PA, Lippincott, 1997, pp 37-38 25. Ho JH: An epidemiological and clinical study of nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 4:182-198, 1978[Medline] 26. Simon R: Optimal two-stage designs. Control Clin Trials 10:1-10, 1989[Medline] 27. Abe I, Hori K, Saito S, et al: Some aspects of size-dependent differential drug response in primary and metastatic tumors. Cancer Metastasis Rev 4:27-39, 1985[CrossRef][Medline] 28. Kao CH, Hsieh JF, Tsai SC, et al: Comparison of 18-fluoro-2-deoxyglucose positron emission tomography and computed tomography in detection of cervical lymph node metastases of nasopharyngeal carcinoma. Ann Otol Rhinol Laryngol 109:1130-1134, 2000[Medline] 29. Sievers KW, Greess H, Baum U, et al: Paranasal sinuses and nasopharynx CT and MRI. Eur J Radiol 33:185-202, 2000[CrossRef][Medline] 30. King AD, Teo P, Lam WW, et al: Paranasopharyngeal space involvement in nasopharyngeal cancer: Detection by CT and MRI. Clin Oncol (R Coll Radiol) 12:397-402, 2000 31. Olmi P, Fallai C, Colagrande S, et al: Staging and follow-up of nasopharyngeal carcinoma: Magnetic resonance imaging versus computerized tomography. Int J Radiat Oncol Biol Phys 32:795-800, 1995[CrossRef][Medline] 32. Peng N, Yen S, Liu W, et al: Evaluation of the effect of radiation therapy to nasopharyngeal carcinoma by positron emission tomography with 2-[F-18]fluoro-2-deoxy-D-glucose. Clin Positron Imaging 3:51-56, 2000[CrossRef][Medline]
33. To E, Chan KC, Leung SF, et al: Rapid clearance of plasma Epstein-Barr virus DNA after surgical treatment of nasopharyngeal carcinoma. Clin Cancer Res 9:3254-3259, 2003
34. Lo YM, Leung SF, Chan LY, et al: Kinetics of plasma Epstein-Barr virus DNA during radiation therapy for nasopharyngeal carcinoma. Cancer Res 60:2351-2355, 2000
35. Leung SF, Chan ATC, To KF, et al: Disparity of sensitivities in detection of radiation-naïve and postirradiation recurrent nasopharyngeal carcinoma of the undifferentiated type by quantitative analysis of circulating Epstein-Barr Virus DNA 1,2. Clin Cancer Res 9:3431-3434, 2003
36. Rischin D, Corry J, Smith J, et al: Excellent disease control and survival in patients with advanced nasopharyngeal cancer treated with chemoradiation. J Clin Oncol 20:1845-1852, 2002
37. Oh J, Vokes E, Kies MS, et al: Induction chemotherapy followed by concomitant chemoradiotherapy for advanced nasopharyngeal cancer. Ann Oncol 14:564-569, 2003 Submitted May 28, 2003; accepted May 6, 2004. This article has been cited by other articles:
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
