Randomized trial of radiotherapy plus concurrent-adjuvant chemotherapy vs radiotherapy alone for regionally advanced nasopharyngeal carcinoma.

BACKGROUND: Current practice of adding concurrent-adjuvant chemotherapy to radiotherapy (CRT) for treating advanced nasopharyngeal carcinoma is based on the Intergroup-0099 Study published in 1998. However, the outcome for the radiotherapy-alone (RT) group in that trial was substantially poorer than those in other trials, and there were no data on late toxicities. Verification of the long-term therapeutic index of this regimen is needed. METHODS: Patients with nonkeratinizing nasopharyngeal carcinoma staged T1-4N2-3M0 were randomly assigned to RT (176 patients) or to CRT (172 patients) using cisplatin (100 mg/m(2)) every 3 weeks for three cycles in concurrence with radiotherapy, followed by cisplatin (80 mg/m(2)) plus fluorouracil (1000 mg per m(2) per day for 4 days) every 4 weeks for three cycles. Primary endpoints included overall failure-free rate (FFR) (the time to first failure at any site) and progression-free survival. Secondary endpoints included overall survival, locoregional FFR, distant FFR, and acute and late toxicity rates. All statistical tests were two-sided. RESULTS: The two treatment groups were well balanced in all patient characteristics, tumor factors, and radiotherapy parameters. Adding chemotherapy statistically significantly improved the 5-year FFR (CRT vs RT: 67% vs 55%; P = .014) and 5-year progression-free survival (CRT vs RT: 62% vs 53%; P = .035). Cumulative incidence of acute toxicity increased with chemotherapy by 30% (CRT vs RT: 83% vs 53%; P < .001), but the 5-year late toxicity rate did not increase statistically significantly (CRT vs RT: 30% vs 24%; P = .30). Deaths because of disease progression were reduced statistically significantly by 14% (CRT vs RT: 38% vs 24%; P = .008), but 5-year overall survival was similar (CRT vs RT: 68% vs 64%; P = .22; hazard ratio of CRT = 0.81, 95% confidence interval = 0.58 to 1.13) because deaths due to toxicity or incidental causes increased by 7% (CRT vs RT: 1.7% vs 0, and 8.1% vs 3.4%, respectively; P = .015). CONCLUSIONS: Adding concurrent-adjuvant chemotherapy statistically significantly reduced failure and cancer-specific deaths when compared with radiotherapy alone. Although there was no statistically significant increase in major late toxicity, increase in noncancer deaths narrowed the resultant gain in overall survival.

Bisphosphonates for advanced prostate cancer.

BACKGROUND: Prostate cancer is the most common cancer in men in many western countries. It is characterized by its propensity for bone metastases which occur in more than 80% of patients with advanced disease. Patients are at risk of complications including pain, hypercalcaemia, bone fracture and spinal cord compression. Hormonal treatment is the mainstay of treatment for these patients but most of them will then become hormone refractory. Bisphosphonates act by inhibiting osteoclast activities and are a potential therapeutic option for metastatic prostate cancer. In addition, they have been shown to reduce pain in patients with bone metastases as a consequence of multiple myeloma. Early uncontrolled studies of bisphosphonates in metastatic prostate cancer patients have shown encouraging results. OBJECTIVES: The objective of this review was to determine the effectiveness of bisphosphonates in relieving pain in patients with bone metastases from prostate cancer. SEARCH STRATEGY: Studies were identified by electronic search of bibliographic databases including MEDLINE, EMBASE, CancerLit and the Cochrane Controlled Trials Register. Handsearching included Proceedings of American Society of Clinical Oncology and reference lists of all eligible trials identified. SELECTION CRITERIA: Randomised controlled studies comparing the effectiveness of bisphosphonates with placebo or open control for pain relief in patients with bone metastases from prostate cancer. DATA COLLECTION AND ANALYSIS: Data were extracted from eligible studies and included study design, participants, interventions and outcomes. Comparable data were pooled together for meta-analysis with intention-to-treat principle. Outcomes included pain response, analgesic consumption, skeletal events (including pathological fractures, spinal cord compression, bone radiotherapy, bone surgery), prostate cancer death, disease progression, radiological response, PSA response, adverse events, performance status, quality of life and comparisons between different routes, doses and types of bisphosphonates. MAIN RESULTS: One thousand nine hundred and fifty-five patients from ten studies were included in this review. The pain response rates were 27.9% and 21.1% for the treatment group and the control group, respectively, with an absolute risk difference of 6.8%. The OR for pain response was 1.54 (95% CI 0.97 to 2.44, P = 0.07), showing a trend of improved pain relief in the bisphosphonate group, although this was not statistically significant. The rates for skeletal events were 37.8% and 43.0% for the treatment group and the control group, respectively, with an absolute risk difference of 5.2%. The OR for skeletal events was 0.79 (95% CI 0.62 to 1.00, P = 0.05). A significant increase in nausea was observed in patients who received bisphosphonates compared to placebo. No increase in other adverse events was observed. There was no statistically significant difference between the bisphosphonate group and the control group in terms of prostate cancer death, disease progression, radiological response and PSA response. There are insufficient data to guide the choice of bisphosphonates or the dose and the route of administration . AUTHORS' CONCLUSIONS: Bisphosphonates should be considered for patients with metastatic prostate cancer for the treatment of refractory bone pain and prevention of skeletal events. More research is needed to guide the choice of bisphosphonates, optimal treatment schedule as well as cost-benefit comparisons. Combining results from different studies is difficult because different tools were used to assess pain, and also, bisphosphonates vary considerably in potency. This review highlights the need for standardisation and co-ordination among researchers in cancer pain studies.

Preliminary results of a randomized study on therapeutic gain by concurrent chemotherapy for regionally-advanced nasopharyngeal carcinoma: NPC-9901 Trial by the Hong Kong Nasopharyngeal Cancer Study Group.

PURPOSE: This randomized study compared the results achieved by concurrent chemoradiotherapy (CRT) versus radiotherapy (RT) alone for nasopharyngeal carcinoma (NPC) with advanced nodal disease. PATIENTS AND METHODS: Patients with nonkeratinizing/undifferentiated NPC staged T1-4N2-3M0 were randomized to CRT or RT. Both arms were treated with the same RT technique and dose fractionation. The CRT patients were given cisplatin 100 mg/m2 on days 1, 22, and 43, followed by cisplatin 80 mg/m2 and fluorouracil 1,000 mg/m2/d for 96 hours starting on days 71, 99, and 127. RESULTS: From 1999 to January 2004, 348 eligible patients were randomly assigned; the median follow-up was 2.3 years. The two arms were well-balanced in all prognostic factors and RT parameters. The CRT arm achieved significantly higher failure-free survival (72% v 62% at 3-year, P = .027), mostly as a result of an improvement in locoregional control (92% v 82%, P = .005). However, distant control did not improve significantly (76% v 73%, P = .47), and the overall survival rates were almost identical (78% v 78%, P = .97). In addition, the CRT arm had significantly more acute toxicities (84% v 53%, P < .001) and late toxicities (28% v 13% at 3-year, P = .024). CONCLUSION: Preliminary results confirmed that CRT could significantly improve tumor control, particularly at locoregional sites. However, there was significant increase in the risk of toxicities and no early gain in overall survival. Longer follow-up is needed to confirm the ultimate therapeutic ratio.

Treatment of stage IV(A-B) nasopharyngeal carcinoma by induction-concurrent chemoradiotherapy and accelerated fractionation.

PURPOSE: To explore a more effective strategy for treating nasopharyngeal carcinoma with extensive locoregional disease. METHODS AND MATERIALS: Between October 1998 and January 2003, 49 patients with Stage IV(A-B) disease infiltrating or abutting neurologic structures were treated with induction-concurrent chemotherapy and accelerated radiotherapy (RT). A combination of cisplatin and 5-fluorouracil was used in the induction phase and single-agent cisplatin in the concurrent phase. All patients were irradiated with conformal techniques at 2 Gy/fraction, six daily fractions weekly, to a total dose of 70 Gy. RESULTS: Although 92% of patients had one or more acute toxicities Grade 3 or worse, 96% completed the whole course of RT, and 92% had five or more cycles of chemotherapy. The great majority of toxicities were uneventful, but 1 patient died of neutropenic sepsis. With a median follow-up of 3.1 years, 20 patients had failure at one or more sites and 15 patients died. The 3-year locoregional and distant failure-free rate was 77% and 75%, respectively, and the overall survival rate was 71%. At last follow-up, 27% of patients had developed late Grade 3 or worse toxicity (24% were hearing impairments), but none had radiation-induced neurologic damage. CONCLUSION: The current strategy achieved encouraging results for this poor prognostic group, and confirmation of the therapeutic gain by a prospective randomized trial is warranted.

Treatment results for nasopharyngeal carcinoma in the modern era: the Hong Kong experience.

PURPOSE: To analyze the treatment results achievable for nasopharyngeal carcinoma in the modern era to identify the key failures for future improvement and to provide an updated baseline for future trials. METHODS AND MATERIALS: The results of 2687 consecutive patients treated at all public oncology centers in Hong Kong during 1996-2000 were retrospectively analyzed. The stage distribution (by American Joint Committee on Cancer and International Union Against Cancer staging system, 1997) was 7% Stage I, 41% Stage II, 25% Stage III, and 28% Stage IVA-B. All patients were irradiated with 6-MV photons and the median total dose was 66 Gy. Only 23% of patients had additional treatment with chemotherapy. RESULTS: The 5-year local, nodal, and distant failure-free rates were 85%, 94%, and 81%, respectively; patients with local failure had significantly higher risk of nodal and distant failures. The 5-year progression-free, overall, and cancer-specific survival rates were 63%, 75%, and 80%, respectively. The presenting stage was the most important prognostic factor for all endpoints: with overall survival decreasing from 90% for Stage I to 58% for Stage IVA-B. The results achieved by the 2070 patients treated by radiotherapy alone were almost identical to that of the whole series, the distant failure-free rate among patients with locoregional control was 89% for Stage I-II and 75% for Stage III-IVB. The 860 patients (32%) staged with magnetic resonance imaging achieved significantly better results than those staged by computed tomography, the overall survival being 93% vs. 83% for Stages I-II, and 72% vs. 63% for Stages III-IVB (p = 0.001). CONCLUSIONS: Treatment results for nasopharyngeal carcinoma have substantially improved in the modern era; future trials should be based on updated baseline results. Further reduction of distant failure is important for future breakthrough, particularly for patients with 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.

Post-mastectomy radiotherapy after immediate autologous breast reconstruction in primary treatment of breast cancers.

AIM: To assess the clinical outcome of breast cancer patients with immediate autologous breast reconstruction and post-mastectomy radiotherapy (PMRT) as primary treatment. MATERIALS AND METHODS: Twenty-five women with breast cancer treated with immediate autologous breast reconstruction and post-mastectomy radiotherapy as primary treatment between 1995 and 2001 in Pamela Youde Nethersole Eastern Hospital of Hong Kong were retrospectively studied. Radiation doses of 50 Gy (in 2 Gy daily fraction) were given to the reconstructed breasts, except one who was given 45 Gy (in 1.8 Gy daily fraction). Nine women (36%) were treated without bolus, whereas the other 16 women (64%) were treated with 0.5 cm thick bolus on alternate days. The main outcome measures include local control, treatment complications and cosmetic outcome. RESULTS: Median follow-up was 3.7 years (range: 1.0-6.6 years). Two women (8%), who were treated without bolus, developed chest wall recurrences. The overall 5-year, actuarial, local failure-free rate and disease-specific survival rate were 89.8% and 77.9%, respectively. Apart from mild acute skin reactions, no significant acute radiotherapy side-effects were observed. No flap necrosis or flap loss was seen. The cosmesis of the reconstructed breasts were rated as good to excellent in 85% of the surviving patients. There was no observed adverse effect on cosmesis by adding bolus on alternate days. CONCLUSION: PMRT after immediate autologous tissue-flap breast reconstruction is well tolerated and is not associated with increased incidence of complications. Adding 0.5 cm bolus on alternate days might improve local control without causing adverse cosmetic effect. The concern of adverse effects of radiotherapy should not exclude the choice of immediate breast reconstruction in suitable patients.

Accuracy of nasopharyngeal carcinoma staging by magnetic resonance imaging.

To audit the accuracy of magnetic resonance (MR) staging of nasopharyngeal carcinoma (NPC) in daily reporting, the MR images of 101 adult patients with newly diagnosed NPC reported between December 1996 and February 2002 were reviewed retrospectively. Based on the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) TNM staging criteria (1997), the tumour staging obtained from the MR reports and the MR films was compared by two experienced head and neck radiologists. The number of patients being upstaged, downstaged or unchanged was noted. In all stages, the NPC staging obtained from the MR reports revealed 18 (17.8%) understaged, eight (7.9%) overstaged and 75 (74.2%) the same stage when compared to the staging obtained from the MR films based on the AJCC/UICC criteria. The percentage of patients being understaged or overstaged, in decreasing order of frequency, were stages II, III, IV and I. Magnetic resonance of NPC should be reported by radiologists who are not only familiar with the pathology of this condition and its pattern of spread but who should also base their reports on the AICC/UICC staging criteria. The necessity to improve our MR staging accuracy is largely because it determines the type of therapy to be given and this has to be appropriate and adequate for a successful treatment.

Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy--a systematic review of randomised trials.

Recent randomised studies have reported that single fraction radiotherapy is as effective as multifraction radiotherapy in relieving pain caused by bone metastasis. However, there are concerns about the higher re-treatment rates and the efficacy of preventing future complications, such as pathological fracture and spinal cord compression, by single fraction radiotherapy. A systematic review of randomised studies, examining the effectiveness of single fraction radiotherapy versus multiple fraction radiotherapy for metastatic bone pain relief and prevention of bone complications, was conducted to help answer this controversy. Randomised studies comparing single fraction radiotherapy with multifraction radiotherapy on metastatic bone pain were identified. The analyses were performed using intention-to-treat principle. The results were pooled using meta-analysis to estimate the effect of treatment on pain response, re-treatment rate, pathological fracture rate and spinal cord compression rate. Twelve trials involving 3621 sites were included in the meta-analysis. The overall pain-response rates for single fraction radiotherapy and multifraction radiotherapy were 60% (1080/1814) and 59% (1060/1807), respectively, giving an odds ratio (OR) of 1.03 (95% confidence interval [CI] 0.90-1.19), indicating no difference between the two radiotherapy schedules. There was also no difference in complete pain response rates for single fraction radiotherapy (34% [508/1476]) and multifraction radiotherapy (32% [475/1473]), with an OR of 1.10 (950% CI 0.94-1.30). Patients treated by single fraction radiotherapy had a higher re-treatment rate, with 21.5% (267/1240) requiring re-treatment compared with 7.4% (91/1236) of patients in the multifraction radiotherapy arm (OR 3.44 [95% CI 2.67-4.43]). The pathological fracture rate was also higher in single fraction radiotherapy arm patients. Three per cent (37/1240) of patients treated by single fraction radiotherapy developed pathological fracture compared with 1.6% (20/1236) for those treated by multifraction radiotherapy (OR 1.82 [95% CI 1.06-3.11]). The spinal cord compression rates were similar for both arms (OR 1.41 [95% CI 0.72-2.75]). Single fraction radiotherapy was as effective as multifraction radiotherapy in relieving metastatic bone pain. However, the re-treatment rate and pathological fracture rate were higher after single fraction radiotherapy. Studies with quality of life and health economic end points are warranted to find out the optimal treatment option.

Changing epidemiology of nasopharyngeal carcinoma in Hong Kong over a 20-year period (1980-99): an encouraging reduction in both incidence and mortality.

Epidemiological data from the Hong Kong Cancer Registry for the period 1980-99 were analyzed. Altogether 21,768 new cases of nasopharyngeal carcinoma (NPC) and 8,664 related deaths were registered. In both genders, the peak incidence occurred in the 50-59 years age group, and this age distribution pattern remained similar throughout. The age-standardized incidence rate steadily decreased from 28.5 in 1980-84 to 20.2 in 1995-99 per 100,000 males, and from 11.2-7.8 per 100,000 females, resulting in a total decrease of 29% for males and 30% for females over this 20-year period. The magnitude of total decrease in NPC mortality amounted to 43% and 50%, respectively, as the age-standardized mortality rate steadily decreased from 13.7 in 1980-84 to 7.8 in 1995-99 per 100,000 males, and from 4.5-2.2 per 100,000 females. The age-standardized mortality/incidence ratio also decreased from the peak of 0.48 in 1980-84 to 0.39 in 1995-99 for males, and from 0.40-0.29 for females. Females had significantly lower age-standardized incidence (male/female ratio 2.5-2.6, p < 0.01) and mortality (male/female ratio 3.0-3.5, p< 0.01) throughout the whole period. Furthermore, females had consistently lower mortality/incidence ratio: 0.29 vs. 0.39 in 1995-99. These data are highly suggestive of significant improvement in prevention and control of NPC in Hong Kong. Closer scrutiny of the differences in intrinsic and extrinsic factors between the genders might help to show important factors affecting oncogenesis and prognosis. Possible ways for further reduction of incidence and mortality are discussed.

Breast conservation treatment in Hong Kong-early results of 203 patients: retrospective study.

OBJECTIVE: To study the clinical outcomes of patients with invasive or non-invasive breast cancer after breast conservation treatment. DESIGN: Retrospective study. SETTING: Clinical oncology department of a public hospital, Hong Kong. PATIENTS: Two hundred and three patients who received postlumpectomy radiotherapy at the Pamela Youde Nethersole Eastern Hospital between January 1994 and June 1999. INTERVENTIONS: Adjuvant radiotherapy with or without systemic adjuvant treatment. MAIN OUTCOME MEASURES: Actuarial local control rate, progression-free survival rate, disease-specific survival rate, and cosmetic score. RESULTS: The median follow-up was 3.5 years. Two of the 25 patients with carcinoma in situ only developed local recurrence; the 5-year actuarial local control rate was 91.3%. Among the 178 patients with invasive cancer, seven had a local recurrence and 12 developed distant metastases without local failure. The 5-year actuarial local control, progression-free survival, and disease-specific survival rates for patients with invasive cancer were 95.5%, 85.8%, and 95.2%, respectively. The risk of local recurrence was significantly increased for younger patients (age <40 years) and those with positive final margins. Cosmetic scores were rated good to excellent by 95.6% of patients. CONCLUSIONS: The early clinical outcomes of these patients are comparable to those in large overseas trials, which have demonstrated the equivalence of mastectomy and breast conservation treatment in terms of survival. In addition to mastectomy, with or without breast reconstruction, breast conservation treatment should be offered as an alternative to suitable Chinese women. To maximise local control, further excision or mastectomy is recommended for patients with positive final margins.

Lymphoepithelioma-like carcinoma of oral cavity: report of three cases and literature review.

Lymphoepithelioma-like carcinoma is a rare tumour in the oral cavity and is characterized histologically by non-keratinizing, undifferentiated squamous cell carcinoma with lymphocytic infiltration. Three consecutive cases of intraoral lymphoepithelioma-like carcinoma are reported. A review of the literature reveals a similar biological behaviour to that of nasopharyngeal lymphoepithelioma: a high incidence of cervical nodal spread and remarkable radiosensitivity. Chemotherapy should be considered when nodal or distant metastases are present. The association of the Epstein-Barr virus with this tumour remains unclear but our experience suggests a positive correlation in Chinese individuals.

Retrospective analysis on treating nasopharyngeal carcinoma with accelerated fractionation (6 fractions per week) in comparison with conventional fractionation (5 fractions per week): report on 3-year tumor control and normal tissue toxicity.

BACKGROUND AND PURPOSE: To assess the therapeutic gain achieved by accelerated fractionation for non-keratinizing/undifferentiated nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: During January 1994 to October 1997, 325 patients were treated to a total dose of 66 Gy in 33-37 fractions: 167 (irradiated before mid-January 1996) with 5 daily fractions (CF) and subsequent 158 with 6 daily fractions (AF) per week. Their median treatment times were 46 and 39 days, respectively. Additional boost to parapharyngeal extension had been given to 181 and Cisplatin-based chemotherapy to 57 patients (24 concurrent with radiotherapy). RESULTS: The AF group had significantly higher progression-free rate than the CF group (74 vs. 63% at 3 years, P=0.02 by the log-rank test). However, the difference in disease-specific survival (86 vs. 80%, P=0.39) and overall survival (81 vs. 78%, P=0.9) did not reach statistical significance. Strongly significant improvement in local failure-free rate was achieved for patients with T3-4 tumors (87 vs. 62%, P<0.01). Multivariate analyses showed that fractionation was an independent significant factor for overall progression: hazard ratio=0.63, 95% confidence interval: 0.41-0.98, P=0.04. Among the 268 patients treated with radiotherapy alone, those treated by AF had significantly higher incidence of acute reaction grade > or=3 (72 vs. 13%, P<0.01). However, all patients completed the scheduled dose without excessive prolongation, and no significant increase in late complications was observed (20 vs. 15% at 3 years, P=0.19). CONCLUSIONS: The current analyses suggested that acceleration to 6 daily fractions per week could significantly improve the progression-free rate for NPC without excessive late toxicity. Improvement in local control was confined to T3-4 tumors.

MRI of the hypothalamus and pituitary gland in patients with hyperprolactinaemia following radiotherapy for nasopharyngeal carcinoma.

PURPOSE: Neuroendocrine dysfunction is a known complication of cranial radiation. While growth hormone deficiency is the most common laboratory finding, hyperprolactinaemia is one of the most common symptomatic dysfunction in adult female patients with nasopharyngeal carcinoma (NPC) following radiotherapy. This analysis aims to study the magnetic resonance imaging (MRI) features of the hypothalamus and the pituitary gland in affected patients. METHODS: MRI was performed in 24 patients NPC with hyperprolactinaemia detected 10-52 months following one course of radical radiotherapy. The region of study included the nasopharynx, the hypothalamus and the pituitary gland in 20 patients, while in the remaining four patients, this was limited to the pituitary gland. The estimated radiation dose to the hypothalamus and the pituitary gland was 66 Gy, and six patients also had adjuvant chemotherapy. There was no clinical evidence of tumour recurrence in all 24 patients when hyperprolactinaemia was detected. RESULTS: None of the 24 patients showed any MRI evidence of structural abnormality in the hypothalamic-pituitary region. CONCLUSION: MRI did not reveal any structural abnormality in the hypothalamic-pituitary region of patients who developed hyperprolactinaemia following radiotherapy for NPC.

Salvage radiation therapy for locally recurrent nasopharyngeal carcinoma.

PURPOSE: To study the treatment outcome in patients with locally recurrent nasopharyngeal carcinoma (NPC) and to explore whether a combination of high-dose-rate (HDR) intracavitary brachytherapy and external beam radiation therapy (ERT) could improve the therapeutic ratio. METHODS AND MATERIALS: Ninety-one patients with nonmetastatic locally recurrent NPC who were treated with curative intent during the years 1990-1999 were retrospectively analyzed. Eighty-two patients had histologically proven carcinoma. The remaining 9 had clinical and imaging features suggestive of local recurrence. The Ho's T-stage distribution at recurrence (rT) was as follows: rT1-37, rT2-14, rT3-40. Total equivalent dose (TED) was calculated by the linear-quadratic formula without a time factor correction. For those treated by combined-modality treatment (CMT), the TED was taken as the summation of the equivalent dose by ERT and the absolute dose delivered to floor of the sphenoid by brachytherapy. Eight patients were treated solely with brachytherapy, all receiving 24-45 Gy in 3-10 sessions. Forty-one patients were treated with ERT alone receiving a median TED of 57.3 Gy (range, 49.8-62.5 Gy). Forty-two patients were treated by CMT with a median equivalent dose of 50 Gy (range, 40-60 Gy) given by ERT and 14.8 Gy by brachytherapy (range, 3-29.6 Gy). Multivariate analyses were performed using the Cox regression proportional hazards model. RESULTS: The 5-year actuarial overall survival rate, disease specific survival rate and local failure-free survival (LFFS) rate for the whole group were 30%, 33. 3% and 37.8%, respectively. The 3-year LFFS rates of rT1, rT2, and rT3 diseases were 64%, 61.5%, and 18.4%, respectively (p = 0.001). Of the 8 patients treated with brachytherapy alone, 4 failed locally. Further analyses were concentrated on the ERT (41 patients) and CMT (42 patients) groups. The 3-year LFFS rates of rT1, rT2, and rT3 diseases were 66.7%, 66.7%, and 18.4%, respectively (p = 0.0008). Better local control for patients who received a TED of 60 Gy or greater was shown. The corresponding 3-year LFFS rates were 29% and 60% (p = 0.0004). Subgroup analysis on the ERT and CMT groups showed a 3-year LFFS rate of 33.5% and 57% (p = 0.003). ERT group had an excess of patients with rT3 disease. Further analysis was performed on the rT1-2 patients showing a trend toward improvement in local control in favor of the CMT group (3-year LFFS rates: CMT, 71.7%; ERT, 54%; p = 0.13). Multivariate analyses showed that rT stage (p = 0.002) and TED (p = 0.01; HR, 0.93; 95% confidence interval, 0.88-0. 98) remained significant. The 5-year major and central nervous system (CNS) complication-free rates were 26.7% and 47.8%. The following factors were found to be significant on univariate analyses for both complications in the ERT and CMT groups: (1) Modality of treatment: more complications with ERT group; and (2) rT stage. Multivariate analyses showed that the rT stage was significant for predicting the occurrence of major (p = 0.004) and CNS complications (p = 0.04). CONCLUSION: For rT1-2 local recurrences, CMT with at least 60 Gy TED is recommended. The high incidence of major late complications is of serious concern. Ways of improving the local control of Ho's rT3 disease and reducing the risk of late complications should be explored.

Salvage brachytherapy for patients with locally persistent nasopharyngeal carcinoma.

PURPOSE: Locally persistent nasopharyngeal carcinoma (NPC) carries an increased risk of local failure if additional treatment is not given. This study was conducted to evaluate the outcomes of patients with locally persistent NPC as treated by high-dose-rate (HDR) intracavitary brachytherapy, and to explore whether routine brachytherapy boost could improve the local control. METHODS AND MATERIALS: Eighty-seven patients with locally persistent NPC treated during 1990-1998 with HDR intracavitary brachytherapy were retrospectively analyzed. Fibreoptic nasopharyngoscopy was performed 3-6 weeks after completion of the primary external radiation therapy (ERT). Biopsies were only taken from suspicious areas. Those with complete regression of local disease were put on observation. Eighty-seven patients were shown to have persistent viable disease at a median time of 6 weeks post-RT. The distribution according to Ho's staging system at initial diagnosis was as follows: Stage I-8, II-33, III-41, IV-5; T1-19, T2-48, T3-20; N0-32, N1-22, N2-28, N3-5. CT scan for restaging was not performed after the documentation of persistent disease. Our policy was to treat all patients with persistent disease with brachytherapy irrespective of the extent of disease just prior to brachytherapy. They were treated with HDR intracavitary brachytherapy, with either cobalt sources or an iridium source, giving 22.5-24 Gy in 3 weekly sessions in all but 4 patients. This dose was prescribed at a distance of 1.5 cm from the center of the surface as defined by the sources in the first six patients and subsequently reduced to 1 cm for the others. Twelve patients were treated with neoadjuvant chemotherapy. To compare the efficacy of brachytherapy, another 383 consecutive nonmetastatic patients, treated with curative intent by ERT, during the years 1990-1993, were evaluated. Multivariate analysis was performed using the Cox regression proportional hazards model. RESULTS: The 5-year actuarial local failure-free survival (LFFS) rates and disease-specific survival rates for the brachytherapy group and ERT group were 85% and 76.6% (p = 0.15), and 72% and 67.8% (p = 0.2), respectively. The corresponding 5-year actuarial LFFS rates for T1, T2, and T3 disease were 94.7%, 88.2%, 67.4%, and 84.1%, 79.8%, 62.6%. In assessing the local control, only the T staging was significant on multivariate analysis (p = 0.0004). Other parameters such as age, sex, and persistence of disease (giving brachytherapy) were all nonsignificant. Complications were comparable between the two groups. In the persistent group, the local failure rates of the patients treated with and without neoadjuvant chemotherapy were 17% (2/12) and 13% (10/75) respectively. When analyzed according to different brachytherapy sources, the 5-year LFFS rates of the T1, T2, and T3 patients treated with iridium and cobalt sources were 100% vs. 85.7 (p = 0.19), 93.6% vs. 70% (p = 0.04), and 67.7% vs. 60% (p = 0.72). The difference was statistically significant for the T2 groups. When early T-stage (T1 and T2) patients were grouped together for analysis, the iridium group again showed a statistically significant improvement in 5-year LFFS rate when it was compared with the cobalt group (95.3% vs. 76.5%, p = 0.03) and the ERT alone group (95.3% vs. 81.5%, p = 0.03). The improvement of local control is attributed to a higher nasopharyngeal mucosal dose that is achieved by using small-size flexible applicators with an iridium source. It is interesting to note that the 5-year LFFS rates for the ERT alone group (T1: 84.1%, T2: 79.8%, T3: 62.6%) are comparable to the corresponding rates of the cobalt group. This information supports our speculation that an adequate booster treatment could compensate for inadequate primary treatment. The prognosis of patients with locally recurrent NPC is grave. Maximizing the local control is therefore crucial for the survival of the patients. (ABSTRACT TRUNCATED)

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).

Metastatic tumour of the tunica vaginalis testis from carcinoma of the stomach.

A 50-year-old man with advanced inoperable gastric adenocarcinoma and diffuse peritoneal metastasis received six cycles of palliative chemotherapy and responded clinically with weight gain. Two months after the completion of chemotherapy, however, he developed a left hydrocele. Aspiration yielded 70 ml of yellowish hydrocele fluid, which contained metastatic adenocarcinoma cells, consistent with a gastric primary tumour. A diagnosis of malignant hydrocele was made. Two weeks later, he developed a painful recurrent left hydrocele with increasing pain and swelling. Left orchidectomy was performed. Tiny white mural nodules measuring 1 mm in size were noted on the tunica vaginalis. No focal lesion was noted in the testis. On microscopic examination, the tunica vaginalis showed reactive mesothelial hyperplasia and extensive lymphatic permeation by poorly differentiated adenocarcinoma, consistent with a gastric primary tumour.

Caution on the use of altered fractionation for nasopharyngeal carcinoma.

Randomized trials and overviews on the value of altered fractionation for head and neck cancers are reviewed. Attention is drawn to the unexpectedly high incidence of temporal lobe necrosis incurred in patients with nasopharyngeal carcinoma. Preliminary analyses suggest that incomplete repair is likely to be the major factor, even a 6-h interfraction interval may be inadequate if substantial volumes of nervous tissues are included within the target volume.