Anne W.M. Lee

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.

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.

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 Hos 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.

Delineation of the neck node levels for head and neck tumors: a 2013 update. DAHANCA, EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, TROG consensus guidelines

In 2003, a panel of experts published a set of consensus guidelines for the delineation of the neck node levels in node negative patients (Radiother Oncol, 69: 227-36, 2003). In 2006, these guidelines were extended to include the characteristics of the node positive and the post-operative neck (Radiother Oncol, 79: 15-20, 2006). These guidelines did not fully address all nodal regions and some of the anatomic descriptions were ambiguous, thereby limiting consistent use of the recommendations. In this framework, a task force comprising opinion leaders in the field of head and neck radiation oncology from European, Asian, Australia/New Zealand and North American clinical research organizations was formed to review and update the previously published guidelines on nodal level delineation. Based on the nomenclature proposed by the American Head and Neck Society and the American Academy of Otolaryngology-Head and Neck Surgery, and in alignment with the TNM atlas for lymph nodes in the neck, 10 node groups (some being divided into several levels) were defined with a concise description of their main anatomic boundaries, the normal structures juxtaposed to these nodes, and the main tumor sites at risk for harboring metastases in those levels. Emphasis was placed on those levels not adequately considered previously (or not addressed at all); these included the lower neck (e.g. supraclavicular nodes), the scalp (e.g. retroauricular and occipital nodes), and the face (e.g. buccal and parotid nodes). Lastly, peculiarities pertaining to the node-positive and the post-operative clinical scenarios were also discussed. In conclusion, implementation of these guidelines in the daily practice of radiation oncology should contribute to the reduction of treatment variations from clinician to clinician and facilitate the conduct of multi-institutional clinical trials.

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.

Clinical Outcomes and Patterns of Failure After Intensity-Modulated Radiotherapy for Nasopharyngeal Carcinoma

PURPOSE To study and report the clinical outcomes and patterns of failure after intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS The treatment outcomes of NPC patients treated with IMRT at Pamela Youde Nethersole Eastern Hospital between 2005 and 2007 were reviewed. The location and extent of locoregional failures were transferred to the pretreatment planning computed tomography for dosimetry analysis. Statistical analyses were performed on dose coverage and locoregional failures. RESULTS A total of 193 NPC patients were analyzed; 93% had Stage III/IV disease. Median follow-up was 30 months. Overall disease failure (at any site) developed in 35 patients. Among these, there were 23 distant metastases, 16 local failures, and 9 regional failures. Four of the locoregional failures were marginal. Dose conformity with IMRT was excellent. Patients with at least 66.5 Gy to their target volumes had significantly less locoregional failure. The 2-year local progression-free, regional progression-free, distant metastasis-free, and overall survival rates were 95%, 96%, 90%, and 92%, respectively. CONCLUSIONS Intensity-modulated radiotherapy provides excellent locoregional control for NPC. Distant metastasis remains the most difficult challenge, and more effective systemic agents should be explored for patients presenting with advanced locoregional diseases.

Clinical diagnosis of late temporal lobe necrosis following radiation therapy for nasopharyngeal carcinoma

This is a preliminary report of 102 patients with clinical diagnosis of late temporal lobe necrosis after radical radiation therapy for nasopharyngeal carcinoma during 1964 to 1983. Histologic verification was available in 12 cases. All but three patients had been treated in our institute using schedules with doses larger than the conventional 200 cGy per fraction. The incidence rate was 1.03%. In our 80 patients with only one course of external irradiation, the doses to the temporal lobes ranged from 1665 to 2127 ret, or 1286 to 1778 brain tolerance unit (btu). The latent interval ranged from 9 months to 16 years. The median observation period is 33 months. The symptomatology, working diagnosis, treatment, and outcome are described. Surgery was hazardous because of the bilaterality of the involvement and exploration for mere verification of diagnosis was unjustified in typical cases. Treatment with corticosteroid achieved durable objective response in 25 (35%) of 72 patients. The importance of early detection and corticosteroid treatment is 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.

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.