Affiliations of authors: Department of Clinical Oncology, Sir Y. K. Pao Center for Cancer, Prince of Wales Hospital, Chinese University of Hong Kong (ATCC, SFL, PMLT, WHK, EPH, WY, KHY, KWC, TSKM, FKFM, MMPL, BBYM, MKMM, TWTL, PJJ, PHKC, BCYZ); Department of Clinical Oncology, Queen Elizabeth Hospital (RKCN, WHL, HYY, FYC, DTC, SY, KTY); Centre for Clinical Trials, School of Public Health, Chinese University of Hong Kong (BCYZ)
Correspondence to: Anthony Tak Cheung Chan, MD, Department of Clinical Oncology, Prince of Wales Hospital, Shatin, N.T. Hong Kong (e-mail: anthonytcchan{at}cuhk.edu.hk).
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ABSTRACT |
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This is an updated final report on OS of the previously published progression-free survival (PFS) analysis of a phase III randomized study addressing whether adding cisplatin concurrently to radiotherapy improves survival compared with radiotherapy alone in locally advanced NPC (10). Patients with Ho's N2- or N3-stage or N1-stage with node size of at least 4 cm (11) were eligible for this trial, and patients were also classified according to the 1997 International Union Against Cancer (UICC) staging system (12) (Table 1). The protocol was approved by the institutional review boards of Prince of Wales Hospital (PWH) and Queen Elizabeth Hospital (QEH), and all patients gave written informed consent. Patients were stratified by center and randomly assigned to concurrent cisplatinradiotherapy or radiotherapy alone. The external radiotherapy technique (ERT) of the two institutions has been published previously (10). The nasopharynx was treated to 66 Gy in 33 fractions per 6.5 weeks; parapharyngeal boost was given to patients with parapharyngeal involvement to 20 Gy in 10 fractions in 2 weeks (PWH) and 10 Gy in five fractions in 1 week (QEH). Patients with any palpable residual nodes after ERT were treated with 7.5 Gy in two fractions in 4 days. Patients with biopsy-proven persistent local disease were given intracavitary brachytherapy using iridium-192 sources to 24 Gy in three fractions in 15 days (PWH) and 21 Gy in three fractions in 15 days (QEH). The parapharyngeal boost and brachytherapy doses reflect the standard local practice of PWH and QEH, with no published data of impact on treatment outcome. Patients randomly assigned to the chemotherapyradiotherapy arm received cisplatin 40 mg/m2 in 1 L of normal saline over 2 hours weekly during ERT (10). Patients were seen every 8 weeks in the first year, every 12 weeks in the second and third years, and every 1624 weeks thereafter. At each follow-up visit, patients would undergo history and physical examination, routine mirror or endoscopic examination of the nasopharynx, and tests for distant failure if clinical suspicion existed.
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Eight patients who were randomly assigned to the chemotherapyradiotherapy arm who received no chemotherapy were included in the analysis according to the intention-to-treat principle (Fig. 1). All patients were evaluated for treatment toxicity, disease control, and PFS. Ten patients were lost to follow-up and were censored in the OS analysis. The treatment details and response, toxicity, and PFS analysis after 108 events had occurred have been published previously. Although systemic toxicity was more frequent in the CRT arm, 78% of patients completed at least four cycles of concurrent cisplatin during radiotherapy, and there were no treatment-related deaths (10). At the time of this analysis, 156 tumors had progressed. The unadjusted analysis showed that there was no statistically significant difference between the two arms with respect to PFS (P = .16). The 5-year PFS was 52.1% for the radiotherapy arm and 60.2% for the CRT arm. The difference in PFS reached borderline statistical significance in the Cox regression analysis adjusted for T stage and overall stage (HR = 0.74 [95% confidence interval {CI} = 0.54 to 1.0], P = .06, Supplementary Fig. 1, which can be viewed at http://jncicancerspectrum.oupjournals.org/jnci/content/vol97/issue7). Subgroup analysis demonstrated that there was no statistically significant difference in PFS between the arms for T1/T2 stage (HR = 0.99 [95% CI= 0.66 to 1.5], P = .97), whereas there was a statistically significant difference between the arms for T3/T4 stage (HR = 0.53 [95% CI = 0.33 to 0.88], P = .012, Supplementary Fig. 2, which can be viewed at http://jncicancerspectrum.oupjournals.org/jnci/content/vol97/issue7) favoring the CRT arm. At the time of this analysis, 133 deaths had been reported. The unadjusted analysis shows a borderline statistically significant difference in OS in favor of the concurrent arm (P = .065). The 5-year OS was 58.6% (95% CI = 50.9% to 66.2%) for RT and 70.3% (95% CI = 63.4% to 77.3%) for CRT. In the Cox regression analysis, the difference in OS was statistically significantly in favor of CRT after adjusting for T stage, age, and overall stage (HR = 0.71 [95% CI = 0.5 to 1.0]; P = .049, Fig. 2). Subgroup analysis demonstrated that there was no difference between OS in the arms for T1/T2 stage (HR = 0.93 [95% CI = 0.59 to 1.4]; P = .74), whereas there was a difference between the arms for T3/T4 stage (HR = 0.51 [95% CI = 0.3 to 0.88]; P = .013, Fig. 3), favoring the CRT arm. No statistically significant difference in locoregional recurrence between the arms was observed, although there was a clear trend favoring the CRT arm for the T3/T4 stage subgroup (HR = 0.45 [95% CI = 0.21 to 1.0]; P = .051, Supplementary Fig. 3, which can be viewed at http://jncicancerspectrum.oupjournals.org/jnci/content/vol97/issue7. No statistically significant difference in occurrence of distant metastases was observed between the arms (HR = 0.65 [95% CI = 0.37 to 1.2]; P = .15, Supplementary Fig. 4, which can be viewed at http://jncicancerspectrum.oupjournals.org/jnci/content/vol97/issue7).
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Manuscript received October 6, 2004; revised January 18, 2005; accepted February 1, 2005.
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