Philip W.K. Kwong

Concurrent and Adjuvant Chemotherapy for Nasopharyngeal Carcinoma: A Factorial Study

PURPOSE To study the efficacy of concurrent chemoradiotherapy (CRT) and adjuvant chemotherapy (AC) for nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS Patients with Hos stage T3 or N2/N3 NPC or neck node > or = 4 cm were eligible. Patients were randomly assigned to have radiotherapy (RT) or CRT with uracil and tegafur and to have AC or no AC after RT/CRT. AC comprised alternating cisplatin, fluorouracil, vincristine, bleomycin, and methotrexate for six cycles. There were four treatment groups: A, RT; B, CRT; C, RT and AC; D, CRT and AC. For CRT versus RT, groups B and D were compared with groups A and C. For AC versus no AC, groups C and D were compared with groups A and B. RESULTS Three-year failure-free survival (FFS) and overall survival (OS) for CRT versus RT were 69.3% versus 57.8% and 86.5% versus 76.8%, respectively (P =.14 and.06; n = 110 v 109). Distant metastases rate (DMR) was significantly reduced with CRT (14.8% v 29.4%; P =.026). Locoregional failure rates (LRFR) were similar (20% v 27.6%; P =.39). Three-year FFS and OS for AC versus no AC were 62.5% versus 65% and 80.4% versus 83.1%, respectively (P =.83 and.69; n = 111 v 108). DMR and LRFR were not reduced with AC (P =.34 and.15, respectively). Cox model showed CRT to be a favorable prognostic factor for OS (hazard ratio, 0.42; P =.009). CONCLUSION An improvement in OS with CRT was observed but did not achieve statistical significance. The improvement seemed to be associated with a significant reduction in DMR. AC did not improve outcome.

Linear accelerator-based stereotactic radiosurgery for limited, locally persistent, and recurrent nasopharyngeal carcinoma: Efficacy and complications

PURPOSE To evaluate the efficacy and complication of linear accelerator-based stereotactic radiosurgery (SRS) when used as salvage treatment for early-stage persistent and recurrent nasopharyngeal carcinoma (NPC) after primary radiotherapy (RT). MATERIALS AND METHODS Between March 1998 and June 2001, 18 patients (15 men and 3 women; median age 46 years, range 32-84) with locally persistent or recurrent NPC confined to the nasopharynx (rT1) or with limited extension to the nasal fossa or parapharyngeal space (rT2) were treated by SRS. Thirteen patients had rT1 disease and 5 had rT2 disease. Most patients had disease not amenable to surgery or brachytherapy. All patients had undergone previous radical RT. Persistent disease was defined as tumor relapse within 4 months of completion of primary RT, and recurrence as tumor relapse beyond 4 months. Seven patients were treated for persistent disease, eight for a first recurrence, and three for a second recurrence. SRS was performed using multiple noncoplanar arcs of photons delivered to the target volume, which was defined by axial CT at a 3 mm thickness, supplemented by MRI in selected patients (67%). The median target volume was 5.3 cm(3) (range 2.2-16.9). The median SRS dose was 12.5 Gy (range 11-14) delivered to the 80% isodose line. All patients underwent serial nasopharyngoscopy and imaging after SRS. The median follow-up was 26 months (range 11-48). RESULTS After SRS, 16 (89%) of 18 patients had complete regression of tumor as assessed by nasopharyngoscopy and biopsy. Four patients with an initial complete response to SRS subsequently developed local relapse again, with one recurrence developing outside the target volume 8 months after SRS and three within the target volume at 6-26 months after SRS. Two patients with local disease controlled by SRS developed relapse in other sites (neck node and liver metastases). The actuarial 2-year local control rate after SRS was 72%. Patients treated for persistent disease had a better local control rate (100%; 7 of 7) than those treated for recurrent disease (46%; 5 of 11). Patients with rT1 disease also had a better outcome after SRS compared with those with rT2 disease, with a control rate of 77% (10 of 13) for rT1 disease and 40% (2 of 5) for rT2 disease. Treatments were well tolerated, with no acute side effects. One patient had radiologic evidence of temporal lobe necrosis, although the right temporal lobe had already received a high dose during prior RT. That patient also developed additional local recurrence and liver metastases and died. The actuarial 2-year survival rate was 86%. CONCLUSIONS Our preliminary results indicate that SRS is an effective treatment modality for persistent and recurrent early-stage NPC, with early control rates comparable to other salvage treatments such as brachytherapy and nasopharyngectomy. A modest SRS dose at 12.5 Gy also appears to be effective and is associated with minimal morbidities. More clinical experience and longer follow-up are needed to validate our results and to address fully the role of SRS in salvaging local failures of NPC.

The time course of histologic remission after treatment of patients with nasopharyngeal carcinoma

The objective of this study was to define the time course of histologic remission and to evaluate the prognostic significance of delayed histologic remission of patients with nasopharyngeal carcinoma (NPC).

Stereotactic radiosurgery as a salvage treatment for locally persistent and recurrent nasopharyngeal carcinoma

The purpose of this work was to study the efficacy of stereotactic radiosurgery as a salvage treatment in patients with locally persistent and recurrent nasopharyngeal carcinoma (NPC).

Sunitinib in metastatic renal cell carcinoma: An ethnic Asian subpopulation analysis for safety and efficacy

We evaluated and compared the safety and efficacy of sunitinib in Asian and non‐Asian patients with metastatic renal cell carcinoma enrolled in a previously reported global expanded access program.

Patterns of failure after induction chemotherapy and radiotherapy for locoregionally advanced nasopharyngeal carcinoma: the Queen Mary Hospital experience

PURPOSE Our center contributed 183 patients to the Asian-Oceanian Clinical Oncology Association (AOCOA) multicenter randomized trial comparing induction chemotherapy (CT) followed by radiotherapy (RT) vs. RT alone in patients with locoregionally advanced undifferentiated nasopharyngeal carcinoma (NPC). In a preliminary report no difference in terms of overall survival or relapse-free survival was found between the 2 treatment arms. To study the long-term outcome and patterns of failure after CT for NPC, we analyzed our own center data for which a uniform radiation treatment protocol was adopted and a longer follow-up time was available. METHODS AND MATERIALS Between September 1989 and August 1993, a total of 183 patients were recruited into the AOCOA randomized study from our center. Patients with newly diagnosed NPC of Hos T3 disease, N2-N3 disease, or with neck node size of at least 3 cm were eligible. Stratification was made according to the nodal size (< or = 3 cm, >3- 6 cm, > 6 cm). Patients were randomized to receive 2-3 cycles of CT with cisplatin 60 mg/m(2) and epirubicin 110 mg/m(2) D1 followed by RT or RT alone. Four patients were excluded from the current analysis (2 died before treatment, 2 received treatment elsewhere). The remaining 179 patients were randomized to the two treatment arms, with 92 to the CT arm and 87 to the RT arm. Two patients in the CT arm had RT only, and all patients completed radiation treatment. Overall survival (OAS), relapse-free survival (RFS), local relapse-free survival (LRFS), nodal relapse-free survival (NRFS), and distant metastases-free survival (DMFS) were analyzed using Kaplan--Meier method and significance of survival curve differences calculated using log--rank test. Analysis was performed based on the intent-to-treat. RESULTS The median follow-up was 70 months. At the time of analysis, 50% of patients in the CT arm and 61% in the RT arm had relapse, while 32% in the CT arm and 36% in the RT arm had died of the disease. The median RFS was 83 months in the CT arm and 37 months in the RT arm. The median OAS has not yet been reached for both arms. No significant differences were found for the various endpoints, although there was a trend suggesting better nodal control in the CT arm. The 5-year rates for the various endpoints in the CT arm vs. the RT arm were: 53% vs. 42% for RFS (p = 0.13), 70% vs. 67% for OAS (p = 0.68), 80% vs. 77% for LRFS (p = 0.73), 89% vs. 80% for NRFS (p = 0.079), and 70% vs. 68% for DMFS (p = 0.59). There was also no significant difference in the patterns of failure between both arms: in the CT arm, 28% of failures were local only, 13% regional only, 4% locoregional, 44% distant, and 11% mixed locoregional and distant. In the RT arm, 23% of failures were local only, 13% regional only, 11% locoregional, 43% distant, and 9% mixed locoregional and distant. CONCLUSION Induction chemotherapy with the regimen used in the current study did not improve the treatment outcome or alter the failure patterns in patients with locoregionally advanced NPC, although there was a trend suggesting better nodal control in the combined modality arm. Alternative strategies of combining chemotherapy and radiotherapy should be tested and employed instead.

Correlation of endoscopic and histologic findings before and after treatment for nasopharyngeal carcinoma

Background The endoscopic and histologic findings before and after radiotherapy (RT) for nasopharyngeal carcinoma (NPC) were correlated to study the sensitivity and specificity of endoscopic findings in predicting histologic results. The efficiacy of endoscopic examination and post-RT multiple site biopsies in detecting persistent disease was also evaluated. Methods Seven hundred forty-six patients were evaluated. Pre-RT, biopsies were taken from both sides of the nasopharynx to assess the extent of tumor. Four to 16 weeks after RT, routine six-site biopsy specimens were taken from both roofs, lateral, and posterior walls of the nasopharynx and repeated 2 weeks later. Endoscopic findings of exophytic growth, nodule, ulcer, and submucosal bulge were considered “residual tumor,” others were considered “no residual tumor.” Persistent disease was defined as positive histologic findings 12 weeks after RT. Results Before RT, sensitivity of endoscopic findings and biopsy specimens in detecting malignancy were 99.7% and 94.2%, respectively. After RT, sensitivity and specificity of endoscopic findings in predicting positive histologic findings were 29% and 85.8%, respectively, with a positive predictive value of 34.9% and a negative predictive value of 82.2%. Of positive histologic findings, 27.7% were missed in the first session of biopsies; 33.5% of those with positive histologic findings turned out to have persistent disease. For prediction of persistent disease, the sensitivity and specificity of endoscopic findings were 40.4% and 84.4%, with a positive predictive value of 16.3% and a negative predictive value of 95%, and that of histologic findings in the first session of biopsies were 59.6% and 88.3%, respectively, with a positive predictive value of 27.7% and a negative predictive value of 96.7%. Conclusions Endoscopic findings alone have low sensitivity in predicting persistent disease, multiple sites biopsy specimens are indicated. Because only 1.9% of patients with endoscopic findings of “no residual tumor” and negative histologic findings in first session of biopsies had persistent disease, this group can be spared second biopsies. Repeat biopsies are indicated for those with endoscopic findings of “residual tumor” or positive histologic findings in first session of biopsies to improve detection of persistent disease.

Randomized Phase II Study of the X-linked Inhibitor of Apoptosis (XIAP) Antisense AEG35156 in Combination with Sorafenib in Patients with Advanced Hepatocellular Carcinoma (HCC)

Objectives:This multicenter, randomized, open-label, phase II trial evaluated the efficacy and safety of AEG35156 in addition to sorafenib in patients with advanced hepatocellular carcinoma (HCC), as compared with sorafenib alone. Methods:Eligible patients were randomly assigned in a 2:1 ratio to receive AEG35156 (300 mg weekly intravenous infusion) in combination with sorafenib (400 mg twice daily orally) or sorafenib alone. The primary endpoint was progression-free survival (PFS). Other endpoints include overall survival (OS), objective response rates (ORR), and safety profile. Results:A total of 51 patients were enrolled; of them, 48 were evaluable. At a median follow-up of 16.2 months, the median PFS and OS were 4.0 months (95% CI, 1.2-4.1) and 6.5 months (95% CI, 3.9-11.5) for combination arm, and 2.6 (95% CI, 1.2-5.4) and 5.4 months (95% CI, 4.3-11.2) for sorafenib arm. Patients who had the study treatment interrupted or had dose modifications according to protocol did significantly better, in terms of PFS and OS, than those who had no dose reduction in combination arm and those in sorafenib arm. The ORR based on Choi and RECIST criteria were 16.1% and 9.7% in combination arm, respectively. The ORR was 0 in control arm. One drug-related serious adverse event of hypersensitivity occurred in the combination arm, whereas 2 gastrointestinal serious adverse events in the sorafenib arm. Conclusion:AEG35156 in combination with sorafenib showed additional activity in terms of ORR and was well tolerated. The benefit on PFS is moderate but more apparent in the dose-reduced subgroups.