Peter H.K. Choi

Prospective Randomized Study of Intensity-Modulated Radiotherapy on Salivary Gland Function in Early-Stage Nasopharyngeal Carcinoma Patients

PURPOSE This randomized trial compared the rates of delayed xerostomia between two-dimensional radiation therapy (2DRT) and intensity-modulated radiation therapy (IMRT) in the treatment of early-stage nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS Between November 2001 and December 2003, 60 patients with T1-2bN0-1M0 NPC were randomly assigned to receive either IMRT or 2DRT. Primary end point was incidence of observer-rated severe xerostomia at 1 year after treatment based on Radiotherapy Oncology Group /European Organisation for the Research and Treatment of Cancer late radiation morbidity scoring criteria. Parallel assessment with patient-reported outcome, stimulated parotid flow rate (SPFR), and stimulated whole saliva flow rate (SWSFR) were also made. RESULTS At 1 year after treatment, patients in IMRT arm had lower incidence of observer-rated severe xerostomia than patients in the 2DRT arm (39.3% v 82.1%; P = .001), parallel with a higher fractional SPFR (0.90 v 0.05; P < .0001), and higher fractional SWSFR (0.41 v 0.20; P = .001). As for patients subjective feeling, although a trend of improvement in patient-reported outcome was observed after IMRT, recovery was incomplete and there was no significant difference in patient-reported outcome between the two arms. CONCLUSION IMRT is superior to 2DRT in preserving parotid function and results in less severe delayed xerostomia in the treatment of early-stage NPC. Incomplete improvement in patients subjective xerostomia with parotid-sparing IMRT reflects the need to enhance protection of other salivary glands.

A prospective randomized study of chemotherapy adjunctive to definitive radiotherapy in advanced nasopharyngeal carcinoma

PURPOSE A prospective randomized trial was conducted to compare chemoradiotherapy against radiotherapy alone in the treatment of locoregionally advanced nasopharyngeal carcinoma. METHODS AND MATERIALS Eighty-two patients with histologically proven nasopharyngeal carcinoma who had either Hos N3 staging or any N stage with a nodal diameter of > or = 4 cm were entered. Seventy-seven patients were evaluated for tumor response and survival. The patients were randomized to receive two cycles of cisplatin 100 mg/m2 Day 1,5-fluorouracil 1000 mg/m2 24-h infusion Days 2, 3, and 4 before radical radiotherapy, and four cycles of postradiotherapy chemotherapy (37 patients) or radiotherapy alone (40 patients). All patients received radical radiotherapy to the nasopharynx and neck. The nasopharynx and upper neck were treated to 66 Gy by conventional fractionation and the lower neck to 58 Gy. Booster radiotherapy (7.5 Gy/two fractions/week) was given to any residual nodes after standard radiotherapy. RESULTS The patient characteristics, including staging, were similar in both arms. The overall response rate to neoadjuvant chemotherapy was 81% (19% complete response, 62% partial response). The rates of radiotherapy for boosting parapharyngeal disease or residual lymph nodes were not significantly different in the two arms. The overall complete response rate to chemoradiotherapy was 100%, and to radiotherapy alone, 95%. Toxicities in the chemoradiotherapy arm were mainly myelosuppression, nephrotoxicity, and nausea and vomiting. The degree of mucositis was not significantly different in the two arms. There was no treatment-related death. The median follow up was 28.5 months. The 2-year overall survival was 80% in the chemoradiotherapy arm and 80.5% in the radiotherapy arm. The 2-year disease-free survival was 68% in the chemoradiotherapy arm and 72% in the radiotherapy arm, without significant difference between the two arms. The locoregional relapse rate, distant metastatic rate, and median time to relapse were also not significantly different between the two arms. CONCLUSION Despite promising tumor response rates from Phase II trials, this prospective randomized trial has demonstrated no benefit from adjunctive chemotherapy to radiotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma.

Intensity-modulated radiotherapy in nasopharyngeal carcinoma: dosimetric advantage over conventional plans and feasibility of dose escalation

PURPOSE To compare intensity-modulated radiotherapy (IMRT) with two-dimensional RT (2D-RT) and three-dimensional conformal radiotherapy (3D-CRT) treatment plans in different stages of nasopharyngeal carcinoma and to explore the feasibility of dose escalation in locally advanced disease. MATERIALS AND METHODS Three patients with different stages (T1N0M0, T2bN2M0 with retrostyloid extension, and T4N2M0) were selected, and 2D-RT, 3D-CRT, and IMRT treatment plans (66 Gy) were made for each of them and compared with respect to target coverage, normal tissue sparing, and tumor control probability/normal tissue complication probability values. In the Stage T2b and T4 patients, the IMRT 66-Gy plan was combined with a 3D-CRT 14-Gy boost plan using a 3-mm micromultileaf collimator, and the dose-volume histograms of the summed plans were compared with their corresponding 66-Gy 2D-RT plans. RESULTS In the dosimetric comparison of 2D-RT, 3D-CRT, and IMRT treatment plans, the T1N0M0 patient had better sparing of the parotid glands and temporomandibular joints with IMRT (dose to 50% parotid volume, 57 Gy, 50 Gy, and 31 Gy, respectively). In the T2bN2M0 patient, the dose to 95% volume of the planning target volume improved from 57.5 Gy in 2D-RT to 64.8 Gy in 3D-CRT and 68 Gy in IMRT. In the T4N2M0 patient, improvement in both target coverage and brainstem/temporal lobe sparing was seen with IMRT planning. In the dose-escalation study for locally advanced disease, IMRT 66 Gy plus 14 Gy 3D-CRT boost achieved an improvement in the therapeutic ratio by delivering a higher dose to the target while keeping the normal organs below the maximal tolerance dose. CONCLUSIONS IMRT is useful in treating all stages of nonmetastatic nasopharyngeal carcinoma because of its dosimetric advantages. In early-stage disease, it provides better parotid gland sparing. In locally advanced disease, IMRT offers better tumor coverage and normal organ sparing and allows room for dose escalation.

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.

Detection of recurrent chromosomal gains and losses in primary nasopharyngeal carcinoma by comparative genomic hybridisation

Nasopharyngeal carcinoma (NPC) is a common cancer in Southern China but rare in Western countries. To search for genetic alterations in NPC, we examined a series of 20 primary tumours with comparative genomic hybridisation. The identified common chromosomal alterations included gain of chromosomes 1q, 8, 12, 19 and 20 as well as loss of chromosomes 1p, 3p, 9p, 9q, 11q, 13q, 14q and 16q. In concordance with our previous loss of heterozygosity studies in primary NPC, a high incidence of loss was detected on chromosomes 3p (75%), 11q (70%) and 14q (65%). Losses of 9q (60%), 13q (50%) and 16q (40%) were also identified. Novel chromosomal gains were observed on chromosome 12, with a high frequency (70%). Current analysis has revealed a comprehensive profile of the chromosomal regions showing losses and gains in primary NPC. Our findings may provide an entry point for conducting further investigations to locate the putative tumour‐suppresser genes and oncogenes that may be involved in the tumourigenesis of NPC. Int. J. Cancer 82:498–503, 1999.

Final report of a randomized trial on altered-fractionated radiotherapy in nasopharyngeal carcinoma prematurely terminated by significant increase in neurologic complications.

PURPOSE The aim of the present study was to compare the survival, local control and complications of conventional/accelerated-hyperfractionated radiotherapy and conventional radiotherapy in nonmetastatic nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS From February 1993 to October 1995, 159 patients with newly diagnosed nonmetastatic (M0) NPC with N0 or 4 cm or less N1 disease (Hos N-stage classification, 1978) were randomized to receive either conventional radiotherapy (Arm I, n = 82) or conventional/accelerated-hyperfractionated radiotherapy (Arm II, n = 77). Stratification was according to the T stage. The biologic effective dose (10 Grays) 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. RESULTS With comparable distribution among the T stages between the two arms, the free from local failure rate at 5 years after radiotherapy was not significantly different between the two arms (85.3%; 95% confidence interval, 77.2-93.4% for Arm I; and 88.9%; 95% confidence interval, 81.7-96.2% for Arm II). The two arms were also comparable in overall survival, relapse-free survival, and rates of distant metastasis and regional relapse. Conventional/accelerated-hyperfractionated radiotherapy was associated with significantly increased radiation-induced damage to the central nervous system (including temporal lobe, cranial nerves, optic nerve/chiasma, and brainstem/spinal cord) in Arm II. Although insignificant, radiation-induced cranial nerve(s) palsy (typically involving VIII-XII), trismus, neck soft tissue fibrosis, and hypopituiturism and hypothyroidism occurred more often in Arm II. In addition, the complications occurred at significantly shorter intervals after radiotherapy in Arm II. CONCLUSION Accelerated hyperfractionation when used in conjunction with a two-dimensional radiotherapy planning technique, in this case the Hos technique, resulted in increased radiation damage to the central nervous system without significant improvement in efficacy.

Loss of heterozygosity on the short arm of chromosome 3 in nasopharyngeal carcinoma

A consistent loss of constitutional heterozygosity within a specific chromosome locus in a tumor type is suggestive of a tumor suppressor gene important in the genesis of that tumor. We studied whether such genetic alterations are involved, in the development of nasopharyngeal carcinoma (NPC). Tumor and matched blood leukocytes DNA from eleven Hong Kong Chinese patients with primary NPC stages I to IV were subjected to restriction fragment length polymorphism (RFLP) analysis using chromosome 3-specific polymorphic probes. Such probes are assigned to chromosomal region 3p25 (RAF-1), 3p24-22.1 (ERBA beta), 3p21 (DNF15S2), 3p14 (D3S3), and 3q12 (D3S1). The breakpoint varied among tumors, ranging in extent from 3p21-14. However, 100% frequency of complete loss of heterozygosity was observed at two chromosomal loci: RAF-1 locus (ten of ten cases at 3p25) and D3S3 locus (nine of nine cases at 3p14), in all evaluable NPC patients, suggesting the presence of putative tumor suppressor gene(s) within or close to these defined regions. The observed consistent deletion of alleles on the short arm of chromosome 3 in the NPC cases, which is in line with our previously reported and present cytogenetic findings, may represent a critical event in the multistep genesis of NPC. The present report also identifies defined loci for linkage studies on NPC families.

Two distinct regions of deletion on chromosome 13q in primary nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is rare in most parts of the world, but prevalent in Southern China. Although this disease poses a serious health problem in our population, the genetic alterations that lead to the development of NPC have yet to be defined. In a comparative genomic hybridization (CGH) study on NPC by our group, loss of the long arm of chromosome 13 has been identified as a frequent event. To investigate further the involvement of this genetic alteration in NPC tumorigenesis, we examined 31 primary NPC tumours by LOH analysis with a panel of 13 microsatellite polymorphic markers distributed along the long arm of chromosome 13. It was found that 19/31 tumours (60%) showed LOH for markers on chromosome 13q. The highest frequency of LOH was found at loci D13S133 (53.6%) on 13q14.3 and D13S796 (38.5%) on 13q32‐34. Two distinct smallest deletion regions were delineated: the first region between D13S133 and D13S119 at 13q14.3‐22, and the second region between D13S317 and D13S285 at 13q31‐34. Our findings show that LOH of 13q is a common event in NPC and that at least 2 putative tumour‐suppressor loci may be present on 13q. Mapping of the critical regions of these loci suggests that some candidate tumour‐suppressor genes on 13q, other than Rb and BRCA2, may be involved in the development of NPC. Int. J. Cancer 83:305–308, 1999.

Multicenter phase II trial of mitoxantrone in patients with advanced nasopharyngeal carcinoma in Southeast Asia: an Asian-Oceanian Clinical Oncology Association Group study.

PURPOSE Patients with advanced nasopharyngeal carcinoma (NPC) have a high incidence of recurrence and often develop distant metastases despite local control. This prospective multicenter phase II trial was conducted to evaluate the safety and efficacy of Novantrone (mitoxantrone; Lederle Laboratories, Wayne, NJ) in the therapy of patients with advanced NPC. PATIENTS AND METHODS One hundred eight patients with advanced NPC, namely, those with recurrent or persistent disease following primary radiotherapy, or newly diagnosed metastatic disease, were treated with mitoxantrone. Mitoxantrone was administered intravenously at an initial dose of 12 mg/m2 and repeated every 3 weeks, with dose escalation to a maximum of 14 mg/m2. The distribution of histologic subtypes was representative of NPC, with the majority being (61%) undifferentiated (or anaplastic) carcinoma. RESULTS The overall response rate (complete response [CR] and partial response [PR]) was 25% (95% confidence interval, 17% to 33%). The median response duration, time to treatment failure, and survival duration were 140, 82, and 394 days, respectively. Histology (poorly differentiated squamous cell) was found to be the only important factor in predicting response (P = .04) based on a multivariate analysis of nine pretreatment characteristics. The major dose-limiting toxicity was leukopenia. The incidences of nausea/vomiting, alopecia, and stomatitis/mucositis were 34%, 6%, and 3%, respectively. None were severe. Two patients had asymptomatic, moderate Alexander-grade cardiotoxicity. CONCLUSION This study represents a large, controlled multicenter trial of single-agent mitoxantrone in the treatment of advanced NPC. Mitoxantrone was well tolerated and produced an overall response rate comparable to that of other single-agent therapies used in the treatment of advanced head and neck cancer. Combination trials with mitoxantrone for advanced disease should be considered.

Three-dimensional dosimetric evaluation of a conventional radiotherapy technique for treatment of nasopharyngeal carcinoma

BACKGROUND AND PURPOSE The aim of this study is to evaluate and delineate the deficiencies in conventional two-dimensional (2-D) radiotherapy planning of nasopharyngeal carcinoma (NPC) treatment and to explore the means for improvement of the existing treatment technique aiming at enhancing local tumor control and reducing treatment complications. METHODS AND MATERIALS Ten patients with NPC sparing the skull base and without intracranial extension or cranial nerve(s) palsy were chosen in the present study. Two sets of CT images for Phases I and II of the radiotherapy treatment were taken with patient immobilized in the flexed-head and the extended-head positions, respectively. Based on the CT images and endoscopic findings, the gross tumor volume (GTV) was defined. The clinical target volume (CTV) circumscribing the GTV was defined according to Hos (Halnan, K.E. (ed.) Treatment of Cancer. London: Chapman and Hall, 1982. pp. 249-268) description of the organs at risk of tumor infiltration. The planning target volume (PTV) was defined by adding a margin to the CTV which catered for geometrical inaccuracies. The field borders and shields were set at standard distances from certain bony landmarks and were drawn on the simulator radiograph. Data on the beams and shield arrangements were then transferred to the planning computer via a digitizer. By applying 3-D volumetric dose calculation using a commercial three-dimensional (3D) treatment planning computer, the dose-volume-histograms (DVHs) of GTV, CTV, PTV and critical normal organs were generated for both phases of Hos treatment technique. The same patients were re-planned using a modified Hos technique which used 3-D beams-eye-view (BEV) in placing the shielding blocks and the same set of DVHs were generated and compared with those obtained from Hos technique. RESULTS The median volumes of GTV, CTV and PTV covered by the 95% isodose in Hos phase I treatment were around 60%. The dose coverage was unsatisfactory in the superior and inferior and the posterolateral regions. In phase II treatment, the median volume of GTV, CTV and PTV covered by the 95% isodose were 99, 96 and 72%, respectively. Even though the dose coverage of the PTV in both phases of treatment were unsatisfactory, radiotherapy with the original Hos technique had consistently produced good local control for NPC. However, there is potential room for enhancing the local control further because after modifying Hos technique by using 3-D BEV customization of the treatment portals, the median volume of the target covered by the 95% isodose was defined as V(95). The V(95) of the PTV during the Phase II treatment was improved by 13%. The 90% of the volume of temporo-mandibular joints and parotid glands were both irradiated to 53 Gy and 43.6 Gy of the total prescribed dose of 66 Gy, respectively, in phase I and II treatments. With the addition of a hypothalamus-pituitary shield to Hos technique, 50% of the volume of optic chiasma and temporal lobes received, respectively, 19.3 Gy and 4.5 Gy. However, small volume of the temporal lobes received a maximum dose (D(max)) of 62.8 Gy (95.2% of 66Gy). Most of the brainstem was shielded from the lateral portals but 5% of its volume received a dose ranging from 25.4 to 50.4Gy. The spinal cord (at C1/C2 level) received a D(max) of 40.8 Gy in phase I and of 4.8 Gy in phase II. After modifying Hos technique by 3-D BEV customization of the treatment portals, the D(max) to the brainstem, the optic chiasma and the temporal lobes could be reduced by 8, 12 and 5%, respectively. CONCLUSIONS Our study indicated that the dose-coverage of the PTV in Hos radiotherapy technique for the early T-stage NPC was less than satisfactory in the superior and inferior and the posterolateral regions. However, in view of the excellent historical local tumor control with Hos technique, we have to postulate that the present definition of CTV (and hence the PTV after adding margins to the CTV) lacks clinical significance and can be improved. It appears that the inclusion of the entire sphenoid sinus floor and both medial and lateral pterygoid muscles in the CTV is not necessary for maximal tumor control in the absence of clinical/radiological evidence of tumor infiltration of these organs. Hos technique can be improved by using 3-D BEV to customize the treatment portals with multileaf collimators or blocks.