W.Y. Lee

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.

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.

ENHANCEMENT OF LOCAL CONTROL IN LOCALLY ADVANCED NODE-POSITIVE NASOPHARYNGEAL CARCINOMA BY ADJUNCTIVE CHEMOTHERAPY

PURPOSE To determine the efficacy of chemotherapy adjunctive to radical radiotherapy (neoadjuvant +/- adjuvant) in patients with node-positive nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS All the node-positive patients given adjunctive chemotherapy between 1984-1989 (n = 209, CHEMO) were compared with all the node-positive patients treated by radical radiotherapy alone during the same period (n = 409, NCHEMO). The CHEMO group had significantly more bulky nodes, lower cervical/supraclavicular nodes, and more advanced overall stages than the NCHEMO group because nodal size (> or =24 cm) was used as a selection criterion for chemotherapy (1984-1988 departmental protocol and 1988-1989 prospective randomized trial). The chemotherapy consisted of two courses of neoadjuvant cisplatin (100 mg/m2 D1) and 5-fluorouracil (5-FU) (1 gm/m2 D1-D3) in 191 patients. In addition to the two courses of neoadjuvant, four courses of adjuvant chemotherapy, of the same combination, were given after radical radiotherapy in a further 18 patients. Radical radiotherapy delivered a nasopharyngeal dose of 60-62.5 Gy. In addition, parapharyngeal booster external radiotherapy (20 Gy) was given in the presence of parapharyngeal involvement, and intracavitary brachytherapy (24 Gy) was used to treat any local residual tumor diagnosed at 4-6 weeks after external radiotherapy. Both crude and actuarial rates were compared (survival, distant metastases, and local failures) between CHEMO and NCHEMO for all patients, for individual Hos overall stage, for patients with nodes of different sizes (< or =3 cm, >3-< or =6 cm, >6 cm), for individual T-stage and individual N-stage, and for patients belonging to different gender and different age groups (<40 years, > or =40 years). Multivariate analyses using the Cox Regression Model were performed to identify significant prognostic factors. RESULTS With a median follow-up of 5.5 years (range 0.7 to 10 years), CHEMO had significantly less local failures overall than NCHEMO; this was especially true for patients with advanced stages (III + IV). Additionally, in all nodal-size subgroups, in all node-positive T3, and in node-positive T3-Stage IV, there was a significant reduction in local failures after chemotherapy. There was a trend toward fewer local failures in favor of chemotherapy in Stage III, Stage IV, and T3-Stage III (0.05<p< or =0.1). There was no difference in local failures between CHEMO and NCHEMO in Stage II or in T1 and T2. The multivariate analyses identified the administration of adjunctive chemotherapy to be of independent significance in determining the local failure rate for all patients, the T3 (node-positive), and the advanced overall stages (III and IV combined). There was no difference in overall survival, relapse-free survival, and distant metastasis rates between CHEMO and NCHEMO among patients belonging to Stages III and IV despite the presence of more advanced nodal diseases in CHEMO. There were very few late local relapses in patients given adjunctive chemotherapy, in contradistinction to the well-known predisposition of NPC to late local relapses after radical radiotherapy. CONCLUSION Adjunctive chemotherapy enhanced local control in node-positive NPC in general, and node positive-T3 and -T3-Stage IV in particular with reduction of late local relapses. The enhancement in local control of the locally advanced NPC could be explained by the significant shrinkage of the primary tumor by the neoadjuvant chemotherapy, leading to an increased safety margin between the tumor volume and the radiation volume. We recommend that adjunctive chemotherapy (neoadjuvant +/- adjuvant) should become an integral part of the multimodality curative treatment for patients with node-positive T3 NPC.

The prognostic significance of parapharyngeal tumour involvement in nasopharyngeal carcinoma

From 1984 to 1989, 903 treatment-naive non-disseminated nasopharyngeal carcinomas (NPCs) were given primary radical radiotherapy. All patients had computed tomographic and endoscopic evaluation of the primary tumour. Potentially significant parameters were analysed by both univariate and multivariate methods for independent significance. In the whole group of patients, the male sex, skull base and cranial nerves(s) involvement, advanced Ho N-level, presence of fixed or partially fixed nodes and nodes contralateral to the side of the bulk of the nasopharyngeal primary, significantly determined survival and distant metastasis rates, whereas skull base and cranial nerve involvement, advanced age and male sex significantly worsened local control. However in the Ho T2No subgroup, parapharyngeal tumour involvement was the most significant 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. The local tumour control of the Ho T2No was adversely affected by the presence of oropharyngeal tumour extension. The administration of booster radiotherapy (20 Gy) after conventional radiotherapy (60-62.5 Gy) in tumours with parapharyngeal involvement has led to an improvement in local control, short of statistical significance.

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.

Afterloading radiotherapy for local persistence of nasopharyngeal carcinoma

71 patients suffering from local persistence of nasopharyngeal carcinoma after primary external radiotherapy were treated by afterloading intracavitary 192Ir. 66 (93.0%) had a complete response as evidenced by fibreoptic nasopharyngoscope examination and biopsy 4 weeks after the treatment. Significant prognosticators were studied by both monovariate and multivariate analysis. The early overall clinical stage at first presentation predicted a favourable survival. Local tumour control was adversely affected by advanced T-stage at first presentation, and by using a single 192Ir source, unilaterally applied to treat only one side of the nasopharynx. The intracavitary treatment was tolerated well and treatment complications were confined to the nasopharynx: chronic radiation ulceration (five patients) and diffuse telangiectasia (three patients).

Improved local control for early T-stage nasopharyngeal carcinoma - a tale of two hospitals

PURPOSE To study the efficacy of intracavitary brachytherapy (ICT) in early T-stage nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS All early T-stage (T1 and T2 nasal cavity tumour) NPC treated with a curative intent up to 1996 were analyzed (n=743), 163 from the Prince of Wales Hospital (PWH) and 25 from Tuen Mun Hospital (TMH) were given ICT after radical external radiotherapy (ERT; group A). They were compared with 555 patients treated with ERT alone (group B). The radiotherapy techniques were identical between the two hospitals. The ERT delivered the tumoricidal dose (uncorrected biological equivalent dose (BED)-10, > or = 75 Gy) to the primary tumour, and this did not differ in technique or dosage between the two groups. The ICT delivered a dose of 18-24 Gy in three fractions over 15 days to a point 1 cm perpendicular to the midpoint of the plane of the sources. RESULTS The local failure was significantly less (crude rates, 6.9 vs. 13.0%; 5-year actuarial rates, 5.8 vs. 11.7%) and the disease-specific mortality was significantly lower (crude rates, 13.8 vs. 18.9%; 5-year actuarial rates, 12.2 vs. 15.2%) in group A compared with group B. ICT was the only significant independent prognostic factor predictive of fewer local failures. When ICT was excluded from the Cox regression model, the total physical dose or the total BED-10 uncorrected for tumour repopulation became significant in predicting the ultimate local failure rate. The two groups were comparable in the rate of the chronic radiation complications. A significant dose-tumour-control relationship existed, plotting the local failure as a function of the total physical dose or the total BED. CONCLUSIONS Supplementing ERT, which delivered the tumoricidal dose (uncorrected BED-10, > or = 75 Gy), with ICT significantly enhanced ultimate local control in early T-stage (T1/T2 nasal infiltration) NPC. A significant dose-tumour-control relationship exists above the conventional tumoricidal dose level.

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.

Patterns of early treatment failure in non-metastatic nasopharyngeal carcinoma: a study based on CT scanning.

Six hundred and twenty-eight patients with non-metastatic nasopharyngeal carcinoma were staged by CT scanning and treated with radical locoregional radiotherapy. Parapharyngeal boost radiation for bulky parapharyngeal involvement, neoadjuvant chemotherapy for bulky nodal metastases, and intracavitary 192Ir treatment for local persistence of tumour after external radiotherapy were also used as appropriate. Forty-eight patients had Hos (1978) Stage I disease (7.6%), 167 Stage II (26.6%), 312 Stage III (49.7%) and 101 Stage IV (16.1%). At 2 years after treatment, 185 patients (29.5%) had developed recurrence; 112 had distant metastases (60.5%), and 75 had local failure (40.5%). Eighty-three patients had developed distant metastases alone, 73 patients locoregional failure alone and 29 patients had both locoregional and metastatic failure. The overall 2-year actuarial distant and local failure rates were 18.4% and 12.7% respectively. Distant metastasis is the major form of treatment failure which limits early survival. Seventy-four per cent of distant metastases were not associated with locoregional recurrence and had probably arisen from pre-existing occult foci. Our data also suggest that the advent of CT scanning has improved local tumour delineation and radiotherapy planning, and hence local control.