Y.F. Poon

Retrospective analysis of 5037 patients with nasopharyngeal carcinoma treated during 1976-1985: overall survival and patterns of failure.

This is a retrospective analysis of 5037 patients with squamous cell carcinoma of the nasopharynx treated during the years 1976-1985. The stage distribution according to Hos classification was 9% Stage I, 13% II, 50% III, 22% IV, and 6% Stage V. Only 4488 (89%) patients had a full course of megavoltage radiation therapy. The median equivalent dose to the nasopharyngeal region was 65 Gy and cervical region in node-positive patients 53 Gy. Seventy percent (906/1290) of the node-negative patients had no prophylactic neck irradiation. The overall actuarial 10-year survival rate was 43%, and the corresponding failure-free survival 34%. Altogether, 4157 (83%) patients achieved complete remission lasting more than 6 months, but 53% (2205/4157) of them relapsed after a median interval of 1.4 years. The 10-year actuarial local, regional, and distant failure-free rates were 61%, 64%, and 59%, respectively. Thirty-eight percent (338/891) of all patients with local recurrence achieved second local remission. The local complete remission rate with aggressive re-irradiation alone was 47% (333/706). But 37% (124/338) of the responders recurred the second time. The incidence of distant failure correlated significantly with both the N-stage and the T-stage, with the highest (57%) occurring in patients with N3 disease. The incidence of nodal relapse in node-negative patients was 11% (44/384) among those given prophylactic neck irradiation, but 40% (362/906) among those without. Therapeutic irradiation achieved a complete regional remission rate of 90% (306/339). However, despite successful salvage, these patients had a significantly higher distant failure rate than those without nodal relapse, even if they remained local-failure-free (21% vs 6%). Patients treated during 1981-1985 achieved significantly better treatment results than those treated during 1976-1980, especially in terms of the overall survival (57% vs 47% at 5-year), the overall failure-free survival (42% vs 35% at 5-year), and the local failure-free rate (70% vs 63% at 5-year). The possible contributing factors are discussed.

Reirradiation for recurrent nasopharyngeal carcinoma: Factors affecting the therapeutic ratio and ways for improvement

PURPOSE To identify factors for maximizing local salvage and minimizing damages by reirradiation for recurrent nasopharyngeal carcinoma. METHODS AND MATERIALS 654 patients with recurrent nasopharyngeal carcinoma treated by reirradiation during 1976-1992 were retrospectively analyzed. Various fractionation schedules had been used during primary treatment with the total dose ranging from 45.6-70 Gy, fractional dose (at different phases) 1.5-4.2 Gy, and overall time 36-101 days. The gap between the two courses ranged from 0.5-10.6 years. Eighty-two percent of patients were reirradiated with teletherapy, 6% brachytherapy, and 12% with both. For those treated with teletherapy alone, the total dose ranged from 7.5-70 Gy, fractional dose 1.8-5 Gy, and overall time 3-89 days. RESULTS The 5-year actuarial local salvage and complication-free rates were 23% and 52%, respectively. Multivariate analyses showed that the extensiveness of local recurrence was the most significant factor affecting local salvage, while T-stage of primary tumor also influenced prognosis. Choice of method for reirradiation and fractional effect during both courses affected the risk of late complications. For patients treated by teletherapy alone, the hazard of local failure decreased by 1.7% per Biological Effective Dose (assuming alpha/beta ratio = 10) of the second course, while radiation factors during primary radiotherapy had no significant effect. On the other hand, the risk of late complications was predominantly affected by the primary treatment: the hazard increased by 4.2% per Biological Effective Dose (assuming alpha/beta ratio = 3) of the first course, while the corresponding impact of reirradiation failed to reach statistical significance. Length of the gap between the two courses did not affect the outcome. CONCLUSION Early detection of local recurrence and adequate total dose by reirradiation are crucial for improving the chance of local salvage. Combination of teletherapy and brachytherapy should be considered whenever feasible and large fractional dose avoided to minimize late complications. Optimization of biological dose during primary treatment is important.

Effect of Time, Dose, and Fractionation on Temporal Lobe Necrosis Following Radiotherapy for Nasopharyngeal Carcinoma

PURPOSE To study the relative effects of different radiation factors on temporal lobe necrosis (TLN) and predictive accuracy of different biological equivalent models. METHODS AND MATERIALS Consecutive patients (1008) treated radically with four different fractionation schedules during 1976-1985 for T1 nasopharyngeal carcinoma were retrospectively analyzed. All were irradiated by megavoltage photons using the same technique. Their age ranged from 18-84 years, and 92% of patients had complete follow-up. The fractional dose to inferomedial parts of both temporal lobes ranged from 2.5-4.2 Gy, total dose 45.6-60 Gy, and overall time 38-75 days. RESULTS Despite a lower total dose of 50.4 Gy, the 621 patients irradiated with 4.2 Gy per fraction had a significantly higher incidence of temporal lobe necrosis than the 320 patients treated to 60 Gy with 2.5 Gy per fraction: the 10-year actuarial incidence being 18.6% vs. 4.6%, p < 0.001. Multivariate survival analysis showed that fractional effect (product of total dose and fractional dose) was the most significant factor: p = 0.0022, hazard ratio (HR) = 1.044 per Gy2. Overall time and age were both insignificant. The alpha/beta ratio calculated from our data was 2.9 Gy (95% CI: -1.8, 7.6 Gy). Biological effective dose (BED(Gy3)), neuret, and brain tolerance unit all showed strongly significant correlation with the necrotic rate (p < 0.001), and gave similar predictions. The hazard of TLN increased by 14% per Gy3, and it was estimated that 64 Gy (at conventional fractionation of 2 Gy daily) would lead to a 5% necrotic rate at 10 years. Not only did the nominal standard dose (NSD) show the lowest value in terms of log likelihood and standardized HR, but its predictions on TLN deviated markedly from clinically observed rates. CONCLUSION Fractional effect is the most significant factor affecting cerebral necrosis, and overall time has little protective effect. The BED formula, assuming an alpha/beta ratio of 3 Gy, is an appropriate model for predicting late effects on the temporal lobe, and NSD could give seriously misleading predictions.

Staging of nasopharyngeal carcinoma: From Ho's to the new UICC system †

The independent significance of different tumor factors in 4,514 patients with undifferentiated or non‐keratinizing carcinoma of the nasopharynx irradiated at the Queen Elizabeth Hospital during 1976–1985 were analyzed retrospectively. Multivariate analyses showed that the most significant primary factors included cranial nerve palsy, erosion of base of skull and oropharynx. For tumors within the nasopharynx, there was no difference in survival between those with involvement of 1 site vs. more than 1 sites. Patients with cranial nerve palsy had significantly worse prognosis than those with bony erosion alone. Although the nodal characteristics (size, level of extension, fixation, laterality and multiplicity) were inter‐related, their independent impact all reached statistical significance. However, the criteria used currently could be simplified: laterality should be revised to unilateral vs. bilateral, level to upper‐mid vs. lower neck, and size to ≤6 cm vs. >6 cm. Grouping of N2 together with N3 into Stage IV was inappropriate as the former had significantly better prognosis. Our findings, together with review of the publications, provided clinical data for developing the current UICC staging system for nasopharyngeal carcinoma. Such major revision resulted not only in better distinction of hazards, but also more even distribution of cases between different stages. Int. J. Cancer (Pred. Oncol.): 84:179–187, 1999.

TREATMENT OF STAGE I NASOPHARYNGEAL CARCINOMA: ANALYSIS OF THE PATTERNS OF RELAPSE AND THE RESULTS OF WITHHOLDING ELECTIVE NECK IRRADIATION

This is a retrospective analysis of 196 patients with nasopharyngeal carcinoma Stage I (Hos classification) treated by megavoltage radiation during 1980-1984. The primary target volume included all potential sites of local invasion and the first station lymph nodes at retropharyngeal spaces. Two different dose schedules were used, both gave a total tumor dose biologically equivalent to 65 Gy by conventional fractionation, and both achieved a 5-year actuarial local-recurrence-free survival of 88%. Elective neck irradiation was withheld in all except seven patients. The overall 7-year actuarial survival was 85%, but the relapse-free survival was only 62%. The patterns of relapse, prognostic factors, and treatment complications were analyzed. Eighteen patients (9%) recurred locally. Radical retreatment with radiation achieved complete remission in seven out of fifteen cases. Distant failure occurred in 17 patients (9%). Although 57 (30%) of the 189 patients without elective neck irradiation subsequently showed lymph node involvement, none of the seven regionally-treated patients relapsed. The successful regional salvage rate was 81% overall (46 out of 57 patients), but 90% (44 of 49) for those properly treated with whole neck irradiation. However, the 7-year actuarial survival was lower in patients with nodal relapse than those without (70% versus 87%) because of the associated higher incidence of hematogenous dissemination. The various aspects of treatment, the value of elective neck irradiation in particular, are discussed.

Nasopharyngeal carcinoma in young patients

Seventy-one Chinese patients ranging in age from 9 to 20 years who had histologically verified nasopharyngeal carcinoma were reviewed. The presenting symptoms were often multiple, comprising nasal (77.5%) and ear (73.2%) symptoms, headache (60.6%), and neck swelling (63.4%). The median duration of these symptoms was 2 to 3 months, and 90.1% of the patients were Stage III or IV at presentation. All patients were treated primarily by radiotherapy. Forty-four of the 71 patients died of the disease; the median time to death was 18 months. Nasopharyngeal carcinoma in the young patients in Hong Kong does not appear to be different from that of the adult population in Hong Kong in terms of histology, pattern of relapse, and survival. Compared with the adult patients, however, the current series of young patients presented with more advanced-staged disease. The incidence of nasopharyngeal carcinoma in Hong Kong was compared with Chinese populations in other parts of the world, and the general pattern was comparable. The only postadolescent peak was found in the Chinese population of San Francisco.Seventy‐one Chinese patients ranging in age from 9 to 20 years who had histologically verified nasopharyngeal carcinoma were reviewed. The presenting symptoms were often multiple, comprising nasal (77.5%) and ear (73.2%) symptoms, headache (60.6%), and neck swelling (63.4%). The median duration of these symptoms was 2 to 3 months, and 90.1% of the patients were Stage III or IV at presentation. All patients were treated primarily by radiotherapy. Forty‐four of the 71 patients died of the disease; the median time to death was 18 months. Nasopharyngeal carcinoma in the young patients in Hong Kong does not appear to be different from that of the adult population in Hong Kong in terms of histology, pattern of relapse, and survival. Compared with the adult patients, however, the current series of young patients presented with more advanced‐staged disease. The incidence of nasopharyngeal carcinoma in Hong Kong was compared with Chinese populations in other parts of the world, and the general pattern was comparable. The only postadolescent peak was found in the Chinese population of San Francisco.

Remarkable Application of Serum EBV EBER-1 in Monitoring Response of Nasopharyngeal Cancer Patients to Salvage Chemotherapy

Abstract: Nineteen consecutive patients with metastatic or recurrent nasopharyngeal cancer (NPC) receiving combination chemotherapy were monitored for EBV DNA in their serum. EBV DNA (EBER‐1) concentration in serum was measured before, during, and after chemotherapy. Thirteen patients had additional multiple prechemotherapy readings. There was a significant lead time from first detection of serum EBER‐1 to clinical recurrence in 62% of patients by a mean of 17.4 weeks (range: 8–74.5 weeks; mean = 28.2 weeks if confined to the 8 patients with significant lead time). The median EBER‐1 concentration was significantly higher in those with distant metastasis as compared to those with loco‐regional recurrence only (17,468 vs. 684 pg/mL serum; p= 0.046, Mann‐Whitney U test). Among the 13 patients who responded to chemotherapy, 4 exhibited clinical complete remission (CR) who were only found in the group with EBER‐1 DNA drop to background level, while the magnitude of EBER‐1 drop did not discriminate partial remission (PR) and stable disease (SD) patients clearly. Subsequent profile of EBER‐1 DNA showed concordance with clinical course of either continuous remission or later progression. EBER‐1 DNA in serum can become a useful adjunctive surrogate marker to monitor chemotherapeutic response in NPC patients with distant metastasis or advanced local recurrence.

Total biological effect on late reactive tissues following reirradiation for recurrent nasopharyngeal carcinoma

PURPOSE To assess the additional damage of normal tissues attributable to reirradiation and the magnitude of partial recovery following the initial course. METHODS AND MATERIALS Symptomatic late complication rates (excluding xerostomia) in 3635 patients receiving one course (Group 1) and 487 patients receiving two courses of external radiotherapy (Group 2) for nasopharyngeal carcinoma were retrospectively analyzed and compared. RESULTS Group 2 had significantly lower actuarial complication-free survival rates than Group 1: 48% versus 81% at 5 years. The post-retreatment incidence was significantly affected by biologically effective dose (BED) (assuming an alpha/beta ratio of 3 Gy) of the first course: hazard ratio (HR) = 1.04 per Gy(3) (p = 0.01), but only marginally by that of the second course: HR = 1.01 per Gy(3) (p = 0.06). If the summated BED was taken as the dose unit, it was estimated that a total BED of 143 Gy(3) would induce a 20% incidence at 5 years, while the corresponding dose projected from Group 1 was 111 Gy(3). The gap effect was insignificant in the overall analyses, but a trend of decreasing risk with increasing interval was observed in patients with gap > or = 2 years: HR = 0.86 per year (p = 0.07). CONCLUSION The major determinant of post-retreatment complication is the severity of damage during the initial course. The sum of total doses tolerated is higher than that expected with a single-course treatment, suggesting occurrence of partial recovery (particularly in those reirradiated after an interval of 2 years or more).

Prognostic significance of DNA flow cytometric analysis in patients with nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is a prevalent malignant tumor among Southern Chinese. Previously, the authors described the prognostic significance of a serum antibody assay to a recombinant Epstein‐Barr virus Bam HI‐Z replication activator protein (ZEBRA) in NPC patients with long term follow‐up. In this study, the authors further reported the use of DNA flow cytometry (DNA‐FCM) as an additional technique for determining the prognosis of NPC patients in the same series.

Effect of time, dose and fractionation on local control of nasopharyngeal carcinoma

To study the effect of radiation factors on local control of nasopharyngeal carcinoma, 1008 patients with similarly staged T1N03M0 disease (Hos classification) were retrospectively analyzed. All patients were treated by megavoltage irradiation alone using the same technique. Four different fractionation schedules had been used sequentially during 1976-1985: with total dose ranging from 45.6 to 60 Gy and fractional dose from 2.5 to 4.2 Gy. The median overall time was 39 days (range = 38-75 days). Both for the whole series and 763 patients with nodal control, total dose was the most important radiation factor. The hazard of local failure decreased by 9% per additional Gy (p < 0.01). Biological equivalents expressed in terms of Biologically Effective Dose or Nominal Standard Dose also showed strong correlation. Fractional dose had no significant impact. The effect of overall treatment time was insignificant for the whole series, but almost reached statistical significance for those with nodal control (p = 0.06). Further study is required for elucidation, as 85% of patients completed treatment within a very narrow range (38-42 days), and the possible hazard is clinically too significant to be ignored.