EBV-associated primary CNS lymphoma occurring after immunosuppression is a distinct immunobiological entity.

Primary central nervous system lymphoma (PCNSL) is confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. Rarely, PCNSL occurs in the context of immunosuppression (eg, posttransplant lymphoproliferative disorders or HIV [AIDS-related PCNSL]). These cases are poorly characterized, have dismal outcome, and are typically Epstein-Barr virus (EBV)-associated (ie, tissue-positive). We used targeted sequencing and digital multiplex gene expression to compare the genetic landscape and tumor microenvironment (TME) of 91 PCNSL tissues all with diffuse large B-cell lymphoma histology. Forty-seven were EBV tissue-negative: 45 EBV- HIV- PCNSL and 2 EBV- HIV+ PCNSL; and 44 were EBV tissue-positive: 23 EBV+ HIV+ PCNSL and 21 EBV+ HIV- PCNSL. As with prior studies, EBV- HIV- PCNSL had frequent MYD88, CD79B, and PIM1 mutations, and enrichment for the activated B-cell (ABC) cell-of-origin subtype. In contrast, these mutations were absent in all EBV tissue-positive cases and ABC frequency was low. Furthermore, copy number loss in HLA class I/II and antigen-presenting/processing genes were rarely observed, indicating retained antigen presentation. To counter this, EBV+ HIV- PCNSL had a tolerogenic TME with elevated macrophage and immune-checkpoint gene expression, whereas AIDS-related PCNSL had low CD4 gene counts. EBV-associated PCNSL in the immunosuppressed is immunobiologically distinct from EBV- HIV- PCNSL, and, despite expressing an immunogenic virus, retains the ability to present EBV antigens. Results provide a framework for targeted treatment.

Dendritic cells, T cells and their interaction in rheumatoid arthritis.

Dendritic cells (DCs) are the key professional antigen-presenting cells which bridge innate and adaptive immune responses, inducing the priming and differentiation of naive to effector CD4+ T cells, the cross-priming of CD8+ T cells and the promotion of B cell antibody responses. DCs also play a critical role in the maintenance of immune homeostasis and tolerance. DC-T cell interactions underpin the generation of an autoimmune response in rheumatoid arthritis (RA). Here we describe the function of DCs and review evidence for DC and T cell involvement in RA pathogenesis, in particular through the presentation of self-peptide by DCs that triggers differentiation and activation of autoreactive T cells. Finally, we discuss the emerging field of targeting the DC-T cell interaction for antigen-specific immunotherapy of RA.

Cancer survival in Hong Kong SAR, China, 1996-2001.

The Hong Kong cancer registry was established in 1963, and cancer registration is done by passive and active methods. The registry contributed data on 45 cancer sites or types registered during 1996-2001 for this survival study. Follow-up has been carried out by passive methods with median follow-up ranging from 4-60 months. The proportion of cases with histologically verified cancer diagnosis ranged from 38-100%; death certificates only (DCOs) ranged from 0-11%; 83-99% of total registered cases were included for survival analysis. The 5-year age-standardized relative survival exceeded 100% for lip and non-melanoma skin followed by thyroid (94%) and testicular (92%) cancers. The corresponding survival for common cancers were breast (90%), colon (61%), liver and Lung (22%), nasopharynx (70%), rectum (59%) and stomach (39%). The 5-year relative survival by age group showed a decreasing trend with increasing agegroups for most cancers. A decreasing survival with increasing clinical extent of disease was noted.

Carcinoma showing thymus-like element (CASTLE) of thyroid: combined modality treatment in 3 patients with locally advanced disease.

OBJECTIVES: To examine the value of chemotherapy, radiotherapy and surgery for treatment of locally advanced carcinoma showing thymus-like element (CASTLE) of the thyroid. METHODS: Retrospective analysis of 3 Chinese patients in a tertiary referral center in Hong Kong. RESULTS: CASTLE is a rare thyroid malignancy with a frequency of only 0.15% (3/2033 patients) in our center. Three patients (M:F=2:1) aged 43, 49 and 62 years were studied. All 3 patients had advanced T4 disease with extensive tracheal infiltration and airway compression. None had lymph node or distant metastasis. Total thyroidectomy, combined with chemotherapy and radiotherapy, was effective in local control and symptom relief. Etoposide and carboplatin were tried in 2 patients with positive response. Neoadjuvant chemotherapy shrank the tumor rapidly and relieved symptoms of airway compression. All 3 patients had external radiotherapy resulting in good local control. In a patient with inoperable disease, chemotherapy and radiotherapy rendered the disease operable. All 3 patients were symptom-free and alive at 6, 2.5 and 1.8 years after diagnosis. CONCLUSIONS: CASTLE is locally infiltrative and presents at advanced T stage in this small series. Chemotherapy and radiotherapy, apart from surgery, are effective treatment modalities. In cases of inoperable disease or advanced local disease, they can be employed in combination with surgery. Organ preservation of larynx and trachea may be achieved. Chemotherapy can be very useful for rapid relief of symptoms, especially in shrinking tumor to prevent airway obstruction.

Medullary thyroid carcinoma in Hong Kong Chinese patients.

OBJECTIVE: To study the clinical parameters and treatment outcome of medullary thyroid carcinoma in Hong Kong Chinese patients. DESIGN: Retrospective study. SETTING: Regional oncology unit, Hong Kong. PATIENTS: Patients with medullary thyroid carcinoma who were identified among 1656 patients with thyroid malignancies seen in a single institute in Hong Kong from January 1960 to June 2003. MAIN OUTCOME MEASURES: Ten-year cause-specific survival, locoregional failure-free survival, and distant metastasis failure-free survival. RESULTS: Twenty-two (1.3%) patients with medullary thyroid carcinoma were identified. The mean age at diagnosis was 43.7 (standard deviation, 16.5) years. The sex ratio was 1:1. The 10-year cause-specific survival, locoregional failure-free survival, and distant metastasis failure-free survival were 75.4%, 82.0%, and 62.4%, respectively. Lymph node metastasis was present in seven (31.8%) patients at diagnosis. Distant metastasis developed in nine (40.9%) patients: lung, 3 (13.6%); bone, 5 (22.7%); liver, 2 (9.1%); mediastinum, 4 (18.2%). Seven (31.8%) patients died of distant metastasis. Mediastinal (n=3) and bone metastases (n=3) were important causes of death. Genetic study confirmed multiple endocrine neoplasia type 2A in 3 (25.0%) of 12 patients who all had bilateral and multifocal diseases. Younger age (<45 years) was associated with better survival, better locoregional control, and less distant metastasis. Patients with pT1N0 disease (n=3) had an excellent prognosis: all were disease-free following total thyroidectomy. Among eight patients who received external radiation therapy, seven achieved good locoregional control. In seven patients with lymph node metastasis, external radiation therapy gave 100% (4/4) locoregional control compared with 33.3% (1/3) in those without external radiation therapy. Chemotherapy using dacarbazine and 5-fluorouracil was tried in three patients with poor response. CONCLUSIONS: Early stage (T1N0) medullary thyroid carcinoma is associated with a very good prognosis. Postoperative external radiation therapy can achieve good locoregional control in patients with lymph node metastasis or locally advanced disease.

Staging of nasopharyngeal carcinoma: suggestions for improving the current UICC/AJCC Staging System.

AIMS: To evaluate the current UICC/AJCC Staging System for nasopharyngeal carcinoma and to search for ways of improving the system. MATERIALS AND METHODS: This is a retrospective analysis of 2687 consecutive patients treated in five public centres in Hong Kong during the period 1996-2000. All patients were staged by computed tomography, magnetic resonance imaging, or both. The prognostic significance of the current stage assignment on various aspects of tumour control was evaluated. RESULTS: T-category, N-category and stage-group were all significant prognostic factors for major end points (P < 0.01). However, the distinction of prognosis between Stage I and II was insignificant (5-year cancer-specific survival being 92% vs 95%; P = 0.13). Multivariate analyses (corrected for age and sex) revealed lack of significance between T2a and T1 in hazards of local and distant failures, N3a and N2 in distant failure and subgroups of T1-2N0 in cancer-specific deaths. Corresponding down-staging of T2a to T1, N3a to N2, and subgroup T2N0 to stage I, resulted in more even and orderly increase in the hazard ratio of cancer-specific deaths (from 1 for stage I to 1.98 for II, 3.5 for III, 6.08 for IVA and 8.62 for IVB), better hazard consistency among subgroups of the same stage and more balanced stage distribution. CONCLUSIONS: The current UICC/AJCC Staging System could be further improved by the modifications suggested; validation of the current proposal by external data is urgently awaited.

Changes in clinical presentation, management and outcome in 1348 patients with differentiated thyroid carcinoma: experience in a single institute in Hong Kong, 1960-2000.

The clinical features, management and outcome of 1348 patients diagnosed with differentiated thyroid carcinoma in Queen Elizabeth Hospital, Hong Kong, were analysed according to the period of diagnosis: A (before 1980), B (1981-1990) and C (1991-2000). As time advanced, ratio of papillary carcinoma (PTC) to follicular carcinoma (FTC) increased (A:B:C = 1.6: 3.1: 7.2). The mean size of the primary tumour decreased (A:B:C = 3.5 cm: 2.8 cm: 2.5 cm), with a greater percentage of microcarcinoma of 1 cm or less (A:B:C = 5.1%: 16.1%: 21.7%). At presentation, the incidence of lymph-node metastasis decreased (A:B:C = 32.7%: 31.6%: 24.8%) and that of distant metastasis decreased (A:B:C = 9%: 6.1%: 5.3%). Bilateral surgical resection was more commonly used (A:B:C = 62.8%: 89.1%: 94.8%) than lobectomy (A:B:C = 26.3%: 2.8%: 1.8%). Radiation treatment, radioactive iodine (131I; RAI) and external radiotherapy (EXT), was more commonly used (A:B:C = 53.2%: 74.7%: 85.1%). RAI was used in 84.3% (A:B:C = 50%: 71.2%: 84.3%) and EXT in 14.5% of patients in the past decade (A:B:C = 10.9%: 8.7%: 14.5%). The proportion of patients who adopted a bilateral surgery and RAI treatment increased gradually with time (A:B:C = 33%: 68%: 83.8%). The 5-year cause-specific survival (A:B:C = 90.2%: 93.7%: 95.7%), locoregional failure-free survival (A:B:C = 72.6%: 82.9%: 91.6%) and distant metastasis failure-free survival (A:B:C = 84.5%: 89.1%: 92.6%) were improved. However, the period of diagnosis was not found to be an important explanatory variable (i.e. P > 0.05) in Cox regression after adjusting for other factors, indicating that the improvement was probably related to the temporal trend of other factors: presentation at earlier stage, increased ratio of PTC:FTC and more aggressive management by bilateral surgery and radiation therapy.

Diffuse sclerosing variant of papillary thyroid carcinoma--clinical features and outcome.

AIM: Diffuse sclerosing variant of papillary thyroid carcinoma (DSPC) is rare and occurs in young patients. This is a single institute retrospective analysis to report the clinical features and outcome of DSPC. METHOD: DSPC constituted 8 (0.74%) of 1086 papillary thyroid carcinomas (PTC) referred to the department of Clinical Oncology, Queen Elizabeth Hospital Hong Kong from 1960 to 2000. RESULTS: The mean follow-up was 8 years (range: 1.4 to 15.2 years). Six were females and two were males, with age ranging from 11 to 48 years. All were ethnic Chinese. Compared with the whole cohort of PTC followed in the same period, these patients showed younger age at presentation (mean 27.4 vs 45.3 years), larger tumor size (mean 6.9 cm vs 2.4 cm), higher incidence of lymph node metastasis (100% vs 32.4%), and more frequent presence of serum anti-thyroglobulin autoantibody (75% vs 11.3%). The patients were managed as for differentiated thyroid carcinoma according to the institute's protocol, including total thyroidectomy followed by radioiodine (RAI) treatment. External radiotherapy was given to two patients as primary treatment and one patient after regional relapse. One patient had distant metastases at presentation and she was successfully treated by surgery followed by RAI, remaining in complete remission at 12.1 years. One patient had lymph node recurrence after primary total thyroidectomy and RAI treatment and was successfully salvaged by surgery and external radiotherapy. At last follow-up, all eight patients were alive with no evidence of disease. CONCLUSIONS: Although DSPC is associated with some unfavourable features at presentation (such as large tumor size, extensive lymph node metastasis), the prognosis appears to be as good as classical PTC. After aggressive treatment by radical surgery, RAI ablation and/or external radiotherapy, the outcome and survival was excellent.

Cognitive function of patients with nasopharyngeal carcinoma with and without temporal lobe radionecrosis.

BACKGROUND: Radiotherapy is the primary treatment for nasopharyngeal carcinoma, and temporal lobe necrosis is observed in about 7% of patients after radiotherapy. Although some studies reported that these patients demonstrated cognitive impairment after radiotherapy, it is still unclear if the cognitive deficits are related to the radiation exposure or the radiation-induced necrosis. OBJECTIVE: To compare the cognitive function of patients with and without temporal lobe necrosis after radiotherapy for nasopharyngeal carcinoma. METHODS: A comprehensive neuropsychological battery was administered to 53 patients with nasopharyngeal carcinoma who had completed their radiotherapy at least 1 year previously. As evidenced by magnetic resonance imaging, 31 patients developed necrosis after treatment. Thirty-one age- and education-matched individuals were recruited as normal control subjects. RESULTS: Whereas the performance of patients without temporal lobe necrosis was similar to that of normal control subjects, patients with temporal lobe necrosis demonstrated significant impairment on tests of verbal (P<.001) and visual memory (range, P<.001 to P =.03), language (range, P<.001 to P =.01), motor ability (P =.02), planning (P =.02), cognitive ability (P =.007), and abstract thinking (range, P =.009 to P =.04). However, the performance of patients with necrosis on tests of general intelligence (range, P =.08 to P =.15), attention (range, P =.06 to P =.55), and visual abilities (range, P =.06 to P =.47) was not significantly different from that of normal control subjects and patients without necrosis. CONCLUSIONS: Radiotherapy for nasopharyngeal carcinoma seemed to have adverse but insignificant effects on the cognitive functions of the patients. However, for patients who developed temporal lobe necrosis after radiotherapy, memory, language, motor ability, and executive functions were significantly impaired, although their general intelligence remained relatively intact.

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).

Recurrent nasopharyngeal carcinoma: the puzzles of long latency.

PURPOSE: To study the peculiar characteristics of relapses with long latency following radical treatment for nasopharyngeal carcinoma. METHODS AND MATERIALS: 847 patients with nasopharyngeal recurrence were retrospectively studied, focusing on the independent effects of latency on different outcome aspects and its relationship with other prognostic factors. RESULTS: The proportion of recurrence with latency <2 years (Group A), 2-<5 years (Group B), and 25 years (Group C) were 52%, 39%, and 9%, respectively. A higher proportion of Group C originated from patients with node-negative early primary, but fewer of them were still confined within the nasopharynx at detection of recurrence. There was no significant difference in the choice of salvage modality, but among those reirradiated, more of Group C were treated with external beams to a higher dose. The difference in local salvage rate was not statistically significant, but the 5-year distant failure-free rates of the 3 groups were 57%, 67%, and 83%, respectively; and the corresponding disease-specific survival (DSS) were 14%, 20%, and 35%. Multivariate analysis confirmed the independent significance of latency in predicting distant failure (hazard ratio = 0.81 per year, p < 0.01) and cancer deaths (hazard ratio = 0.90 per year, p < 0.01). CONCLUSIONS: Nasopharyngeal recurrence with long latency showed different natural behavior: the prognosis was significantly better due to lower risk of distant failure.

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 < or =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.

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.

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 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 (Ho's 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.

T1 nasopharyngeal carcinoma: the effect of waiting time on tumor control.

PURPOSE: To study the effect of unperturbed tumor growth on the control of nasopharyngeal carcinoma. METHODS AND MATERIALS: This is a retrospective analysis of 290 patients with T1N0-3M0 disease (Ho's classification) treated by the same technique and dose schedule to the nasopharyngeal region. The median interval from diagnosis to commencement of irradiation was 26 days (range: 8-68 days). Cox proportional hazards analyses were performed to study the independent effect of waiting time on the probability of failure at various sites. Actuarial failure-free survival of patients with delay < 22 days, 22-28 days and > 28 days were also compared to illustrate the clinical observation. RESULTS: Both tests showed that waiting time had no significant impact on local failure: The N-stage stratified hazard ratio was 0.985 per day, and the 10-year local failure-free survival for the three groups was 76%, 80%, and 82%, respectively. A similar result was obtained for nodal control in patients with our scheduled neck irradiation. Although the p value of all tests failed to reach statistical significance, the N-stage stratified hazard ratio for distant failure was 1.020 per day, and the corresponding metastasis-free survival in patients with N2-3 disease was 70%, 65%, and 52%, respectively. For node-negative patients without elective neck irradiation, the hazard ratio was 1.019 per day, with the corresponding regional failure-free rates at 57%, 62%, and 33%, respectively. CONCLUSION: Delay in initiation of treatment to the primary target (within the range observed) did not affect the control rate at irradiated sites, but there was a trend (though statistically insignificant) towards increase in failures at untreated sites that were clinically too serious to be ignored.

Retrospective analysis of patients with nasopharyngeal carcinoma treated during 1976-1985: survival after local recurrence.

PURPOSE: To study the value of re-irradiation, the overall survival and pattern of failures for patients with nasopharyngeal recurrence. METHODS AND MATERIALS: All the 891 patients with local recurrence following radiotherapy for nasopharyngeal carcinoma during 1976-1981 were retrospectively analyzed. Only 70% of them had local failure alone at the time of detection, and the T-stage distribution (by Ho's system) was 31% rT1, 16% rT2, 51% rT3, and 1% rT?. Seven hundred and six (79%) patients had been re-irradiated with various techniques and doses. Among those who failed, 50 had further irradiation. RESULTS: The overall 5- and 10-year actuarial cancer-specific survival rates were 14% and 9%, respectively. Patients with rT3 disease had the worst prognosis. Successful local salvage was achieved in 32% of those re-irradiated (26% of the whole series). The highest control rate was achieved by those treated with external radiotherapy to 60 Gy (equivalent) or above. Only 8/50 patients responded to the third course of radiotherapy. The cumulative incidence of late post-re-irradiation sequelae was 24%, and the treatment mortality rate 1.8%. Besides local failure, 54% had regional relapse and/or distant metastasis. Thus, only 16% of recurrent patients were totally disease-free at final assessment. CONCLUSION: The overall prognosis for patients with nasopharyngeal recurrence was grave. High dose re-irradiation could achieve successful local salvage in a substantial number of patients with early recurrence, but late complications did occur. Furthermore, high incidence of failure at other sites was observed.

Nasopharyngeal carcinoma: local control by megavoltage irradiation.

This is a retrospective analysis of the long-term local control in 4128 patients with non-disseminated nasopharyngeal carcinoma treated solely by megavoltage irradiation during the years 1976-1985. The T-stage distribution according to Ho's classification was T1 37%, T2 14% and T3 49%. Different fractionation schedules had been employed at different periods, and the median dose to the primary target was equivalent to 65 Gy by time dose fractionation calculation. In 8% (344) of patients the tumour failed to regress completely after the basic course, but 89% (148/167) of those suitable for salvage with additional irradiation eventually attained complete local remission. The cumulative incidence of local failure was 24% (5% persistence, 19% recurrence). The 10-year actuarial local failure-free survival was 67%. While patients with T2 and T3a tumours achieved local control comparable to T1, those with T3c-d had the poorest control (with highest incidence of persistence and advanced recurrence). T-stage adjusted analyses suggested a significant trend of dose-response: the odds ratios for local failure were 1.16 and 1.86, respectively, when patients given 60-63 Gy and 55-59 Gy were compared with those given 64 Gy or above (p value = 0.0018). Patients treated during 1981-1985 achieved higher local failure-free survival than those treated during 1976-1980 (75% versus 70% at 5 years, p value = 0.0013). The possible attributes are studied, and ways for future optimization of treatment discussed.

Retrospective analysis of nasopharyngeal carcinoma treated during 1976-1985: late complications following megavoltage irradiation.

A retrospective analysis was undertaken of the late complications observed in 4527 patients with nasopharyngeal carcinoma treated by megavoltage radiotherapy during the years 1976-1985. Unconventional fractionation schedules were used because of serious resource limitations. The median equivalent doses were 65 Gy to the nasopharyngeal region and 53 Gy to the cervical region. 707 patients had reirradiation for local recurrences and 250 for regional relapses. The 10-year actuarial cancer-specific survival was 47%, and the corresponding all-complication-free and neurological-complication-free rates were 40% and 72%, respectively. Altogether, 1395 (31%) patients developed one or more late irradiation sequelae. The majority were mild soft-tissue damages, but 322 (7%) had significant functional disturbances, from which 62 (1%) died. Neurological damage that occurred in 450 (10%) patients constituted the major morbidity and accounted for all but three of the treatment mortalities. The cumulative incidence of the various complications is summarized, and the data recorded in the literature reviewed in order to give a proper perspective of the problem. Patients treated during 1981-1985 had a significantly higher actuarial encephalomyelopathy-free rate than those treated during 1976-1980, but the incidence-free rates for the other neurological complications remained unimproved, suggesting that the improvement could be mainly attributed to additional shielding for the brainstem rather than the reduction of dose from 3.8-4.2 Gy to 2.5 Gy per fraction.

6-[N,S-dimethyl-N'-cyanothioureidomethyl]-6,11-dihydro-5H- dibenz[b,e]azepine hydrochloride (Fran 12): a histamine and 5-hydroxytryptamine antagonist with pressor properties.

We have synthesized and examined some of the pharmacological properties of 6-[N,S-dimethyl-N'-cyanoisothioureidomethyl]-6,11-dihydro-5H- dibenz(b,e)azepine hydrochloride (Fran 12), a derivative of 6-methylaminomethyl-6,11-dihydro-5H- dibenz[b,e,]azepine. In the guinea-pig isolated ileum, Fran 12 (10(-7)-10(-5) M) caused parallel rightward shifts of the concentration-response curves to histamine. A Schild plot gave a pA2 of 7.48, with a slope not significantly different from -1.0. In the rat stomach fundus strip and in endothelium-denuded aortic rings, Fran 12 inhibited contractile responses to 5-hydroxytryptamine in a non-competitive manner. In both chloralose-anaesthetized and pithed rats, it inhibited pressor responses to 5-hydroxytryptamine. It had no effect on depressor responses to 5-hydroxytryptamine in anaesthetized rats. In pithed rats, Fran 12 (0.25-2 mg/kg, i.v.) produced dose-dependent increases in blood pressure. These were not inhibited by i.v. phentolamine, prazosin, yohimbine, propranolol, methysergide, pentolinium or atropine but were inhibited by verapamil. These results indicate that Fran 12 is a histamine and 5-hydroxytryptamine antagonist which also exerts pressor effects via a peripheral action. The pressor action does not appear to be mediated via effects on alpha 1- or alpha 2-adrenoceptors, muscarinic or nicotinic cholinoceptors or 5-hydroxytryptamine receptors, although calcium channel activation may play a role.