W. H. Kwan

Concurrent Chemotherapy-Radiotherapy Compared With Radiotherapy Alone in Locoregionally Advanced Nasopharyngeal Carcinoma: Progression-Free Survival Analysis of a Phase III Randomized Trial

PURPOSE Nasopharyngeal carcinoma (NPC) is highly sensitive to both radiotherapy (RT) and chemotherapy. This randomized phase III trial compared concurrent cisplatin-RT (CRT) with RT alone in patients with locoregionally advanced NPC. PATIENTS AND METHODS Patients with Hos N2 or N3 stage or N1 stage with nodal size > or = 4 cm were randomized to receive cisplatin 40 mg/m(2) weekly up to 8 weeks concurrently with radical RT (CRT) or RT alone. The primary end point was progression-free survival (PFS). RESULTS Three hundred fifty eligible patients were randomized. Baseline patient characteristics were comparable in both arms. There were significantly more toxicities, including mucositis, myelosuppression, and weight loss in the CRT arm. There were no treatment-related deaths in the CRT arm, and one patient died during treatment in the RT-alone arm. At a median follow-up of 2.71 years, the 2-year PFS was 76% in the CRT arm and 69% in the RT-alone arm (P =.10) with a hazards ratio of 1.367 (95% confidence interval [CI], 0.93 to 2.00). The treatment effect had a significant covariate interaction with tumor stage, and a subgroup analysis demonstrated a highly significant difference in favor of the CRT arm in Hos stage T3 (P =.0075) with a hazards ratio of 2.328 (95% CI, 1.26 to 4.28). For T3 stage, the time to first distant failure was statistically significantly different in favor of the CRT arm (P =.016). CONCLUSION Concurrent CRT is well tolerated in patients with advanced NPC in endemic areas. Although PFS was not significantly different between the concurrent CRT arm and the RT-alone arm in the overall comparison, PFS was significantly prolonged in patients with advanced tumor and node stages.

Significant prognosticators after primary radiotherapy in 903 nondisseminated nasopharyngeal carcinoma evaluated by computer tomography

PURPOSE To evaluate the significant prognosticators in nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS From 1984 to 1989, 903 treatment-naive nondisseminated (MO) NPC were given primary radical radiotherapy to 60-62.5 Gy in 6 weeks. All patients had computed tomographic (CT) and endoscopic evaluation of the primary tumor. Potentially significant parameters (the patients age and sex, the anatomical structures infiltrated by the primary lesion, the cervical nodal characteristics, the tumor histological subtypes, and various treatment variables were analyzed by both monovariate and multivariate methods for each of the five clinical endpoints: actuarial survival, disease-free survival, free from distant metastasis, free from local failure, and free from regional failure. RESULTS The significant prognosticators predicting for an increased risk of distant metastases and poorer survival included male sex, skull base and cranial nerve(s) involvement, advanced Hos N level, and presence of fixed or partially fixed nodes or nodes contralateral to the side of the bulk of the nasopharyngeal primary. Advanced patient age led to significantly worse survival and poorer local tumor control. Local and regional failures were both increased by tumor infiltrating the skull base and/or the cranial nerves. In addition, regional failure was increased significantly by advancing Hos N level. Parapharyngeal tumor involvement was the strongest independent prognosticator that determined distant metastasis and survival rates in the absence of the overriding prognosticators of skull base infiltration, cranial nerve(s) palsy, and cervical nodal metastasis. CONCLUSIONS The significant prognosticators are delineated after the advent of CT and these should form the foundation of the modern stage classification for NPC.

Prognosticators determining survival subsequent to distant metastasis from nasopharyngeal carcinoma

Distant metastases are common in patients with nasopharyngeal carcinoma (NPC), and their presence is the most important factor in limiting survival. We aimed to study the prognosticators determining survival subsequent to distant metastasis from NPC.

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 DNA

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.

A Retrospective Study of the Role of Intracavitary Brachytherapy and Prognotic Factors Determining Local Tumour Control After Primary Radical Radiotherapy in 903 Non-Disseminated Nasopharyngeal Carcinoma Patients

The aims of this retrospective study were to determine the role of intracavitary brachytherapy given shortly after external beam radiotherapy in the primary radical treatment of non-metastatic nasopharyngeal (NPC) cancer patients, and the prognostic factors governing local tumour control. From 1984 to 1989, 903 patients with non-disseminated NPC who had had no previous treatment were managed at the Prince of Wales Hospital, where investigation and treatment methods had been standardized according to a departmental protocol. The external radiotherapy dose of 60.0-62.5 Gy in 6 weeks was given to all patients. Parapharyngeal booster radiotherapy with a single photon beam to 20 Gy in 2 weeks was given to those with parapharyngeal tumour extension. Computed tomography of the nasopharynx and skull base, and pretreatment nasopharyngoscopy and biopsy were performed in all patients. Nasopharyngoscopy was repeated at 4 weeks after the last day of external irradiation. Local persistence in 99 patients was treated additionally by intracavitary brachytherapy to 24 Gy in three fractions over 15 days. Fifty-one patients with early stage primary disease (Ho Stage T1 and T2n (nasal)) who responded completely to external radiotherapy were given adjuvant intracavitary brachytherapy to 18 Gy in three fractions over 15 days. Intracavitary therapy was an inadequate salvage treatment for the locally persisting T3, T20 (oropharyngeal) and T2p (parapharyngeal) disease, but there was a trend towards improved local control after intracavitary brachytherapy for the locally persisting T1 tumours. Adjuvant brachytherapy did not enhance local tumour control for the early T-stage tumours that completely responded to external radiotherapy. Both forms of intracavitary brachytherapy were safe with few and acceptable complications. In the 903 non-disseminated NPCs, the patients age and tumour involvement of the skull base and cranial nerves were significant independent prognostic factors governing local tumour control. In the 358 patients with Ho T3 disease, tumour involvement of the orbits and the laryngopharynx significantly worsened local tumour control. The presence of local persistence at 4 weeks after external radiotherapy, for which therapeutic brachytherapy was given, was marginally significant as a prognostic factor in addition to the presence of cranial nerve palsy.

Nasopharyngeal carcinoma with metastatic disease to mediastinal and hilar lymph nodes: An indication for more aggressive treatment

Nasopharyngeal carcinoma (NPC) is a highly chemo- and radiosensitive tumour, distinctive from other head and neck squamous cell carcinomas. Distant metastatic rates correlate directly with T and N stages. The prognosis of metastatic NPC is grave and long term survivors are anecdotal. We encountered an 18-year-old man with locoregionally advanced NPC, who was initially treated with neoadjuvant chemotherapy and radiotherapy, but subsequently relapsed 6 months later in the superior mediastinal and right hilar nodal regions. Further chemotherapy and consolidation radiotherapy resulted in complete remission. He is currently alive and free of disease 5 years and 6 months after the completion of salvage treatment. We recommend aggressive treatment of NPC with isolated intrathoracic nodal relapse and imaging of the mediastinum for non-metastatic Hos Stage N3 NPC patients.

Early tumour response and treatment toxicity after hyperfractionated radiotherapy in nasopharyngeal carcinoma

The aim of the present study was to undertake a planned interim analysis of a prospective randomized trial comparing the tumour response and the acute and subacute complications of hyperfractionated radiotherapy and conventional radiotherapy in non-metastatic nasopharyngeal carcinoma (NPC). 100 patients with newly diagnosed non-metastatic NPC were randomized to receive either conventional radiotherapy (Arm I) or hyperfractionated radiotherapy (Arm II). Stratification was done according to the T-Stage (modified Hos T-Stage classification). The biological effective dose (10 Gy) to the primary and the upper cervical lymphatics were 75.0 and 73.1 for Arm I and 84.4 and 77.2 for Arm II, respectively. Hyperfractionated radiotherapy was associated with significant mucositis which is of higher grade than conventional radiotherapy (p = 0.0001), but the duration of mucositis was similar between the two Arms and all study patients completed radiotherapy on schedule without interruption of radiotherapy. Early survival and tumour recurrence rates were comparable between the Arms. The preliminary results indicate that the hyperfractionated radiotherapy has excellent patient compliance in Chinese patients, with acceptable acute and subacute toxicities and the local and regional complete tumour response rates being comparable with conventional radiotherapy. The significance of the time required after start of radiotherapy to achieve a complete tumour response is discussed.

The significance of keratinizing squamous cell histology in chinese patients with nasopharyngeal carcinoma

Six hundred and ninety-three Chinese patients with non-metastatic nasopharyngeal carcinoma (NPC) were treated at one institution under a uniform protocol between 1984 and 1989. The tumour histology of these patients was subjected to a standardized review and classified into two distinct groups of World Health Organization (WHO) type I (keratinizing squamous cell carcinoma) (n = 13) or WHO types II and III (non-keratinizing carcinoma and undifferentiated carcinoma) (n = 662). The differentiation between the two groups was uncertain in 18 patients. The patient characteristics and clinical outcome after a uniform treatment policy of the two groups were not statistically significantly different. The low incidence of WHO type I NPC may account for the lack of prognostic significance of this histological subtype in Chinese populations.

A retrospective study of the use of cisplatinum-5-fluorouracil neoadjuvant chemotherapy in cervical-node-positive nasopharyngeal carcinoma (NPC)

A retrospective study on 422 nasopharyngeal carcinoma (NPC) patients with cervical nodal metastases treated between 1984 and 1987 was performed. 169 received neoadjuvant chemotherapy (CHEMO) with cisplatinum and 5-fluorouracil for two or three courses prior to definitive radiotherapy and 253 were treated by radical radiotherapy alone (NCHEMO). While the primary tumour (T-stage) prognosticators had been comparable between the two groups, CHEMO had significantly more advanced cervical nodal metastases with bulkier nodes and more low-cervical and supraclavicular nodes (P < 0.05) which could account for its overall worse survival, poorer regional tumour control and a trend towards worse systemic tumour control. The worse regional control in CHEMO for Hos N1 could be the result of more bulky nodes and more tumours infiltrating the skull base and/or causing cranial nerve(s) palsy. There was no statistical or apparent difference between CHEMO and NCHEMO for the same Hos overall stages of NPC with comparable nodal and primary tumour characteristics for the clinical endpoints of actuarial survival rate (ASR), disease-free survival rate (DFS), free of local failure survival rate (FLF), and free from distant metastases survival rate (FDM), despite the presence of significantly more fixed nodes and bulky nodes. This suggests a possible beneficial effect of the neoadjuvant chemotherapy. However, multivariate analysis has not shown the administration of the neoadjuvant chemotherapy to be of prognostic significance. Even though the chemotherapy was well tolerated with little toxicity, we recommend against the routine use of neoadjuvant chemotherapy in cervical-node-positive NPC outside the context of a prospective randomised clinical trial.

Perineal Paget's Disease: Effective Treatment with Fractionated High Dose Rate Brachytherapy

A patient with perineal extramammary Pagets disease is described. He was treated successfully with fractionated high dose rate brachytherapy.