W.M. Sze

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.

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.

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.

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.

Screening for family members of patients with nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is well known for its peculiarly skewed distribution with highest incidence in Southern Chinese population. Familial aggregation is evident, hence screening for early detection is offered by oncology centers in Hong Kong to first‐degree relatives of patients with NPC. During the period 1994–2001, 929 family members were screened in our center. The screenees were advised to attend an annual examination that includes serological test against Epstein Barr Virus (EBV), physical examination to exclude cervical lymphadenopathy and cranial nerve palsy, and endoscopic examination of the nasopharyngeal region. Two different methods were used for the serology test: indirect immuno‐fluorescent (IF) test for IgA against viral capsid antigen; and starting in 1997 enzyme‐linked immunosorbent assay (ELIZA) against nuclear antigen and viral capsid antigen. Twelve cases of nasopharyngeal carcinoma were diagnosed, giving a detection rate of 5/1,155 (433/100,000) person‐year for male and 7/1,404 (499/100,000) person‐year for female participants observed. The corresponding average annual incidence in Hong Kong during this period was 24.1 and 9.6 per 100,000, respectively. Forty‐one percent of these detected cases had Stage I disease, whereas only 2% of patients referred to the department for primary treatment presented with such early disease. Six cases were detected at first visit, and all were EBV‐positive. Another 78 screenees with positive serology at first visit were followed up for 204 person years, and thus far NPC was detected in 3 after an interval of 6–32 months. Of the 845 initially EBV‐negative screenees followed up for 2,337 person‐years, NPC was detected in 3 after an interval of 12–45 months. One showed sero‐conversion at the time of diagnosis. We conclude that family members of known patients do show a substantially higher risk of developing NPC, and regular screening by current method improves the chance of early detection.

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).

Preliminary experience on treating advanced nasopharyngeal carcinoma (NPC) affecting/abutting neurological structures with induction chemotherapy followed by concurrent chemo-radiation with accelerated fractionation

5525 Background: To study the possibility of improving treatment tolerance and outcome for NPC with extensive infiltration affecting/ abutting neurological structures by induction chemotherapy followed by concurrent chemo-radiation with accelerated fractionation. METHODS During April 2001 to Feb 2003, 33 NPC patients with such ominous infiltration were treated with this strategy. Ninty-four percent of patients had UICC (5th edition) Stage IVA-B and 6% had Stage III disease. Thirty-two patients (97%) had undifferentiated carcinoma and only 1 patient had well differentiated squamous cell carcinoma. The chemotherapy plan included 3 cycles of Cisplatin (80 mg/m2 ) and Gemcitabine (1250 mg/m2 D1,8) for induction phase, and 2 cycles of Cisplatin (100 mg/m2 D1) for the concurrent phase. All patients were irradiated to a total dose of 70 Gy using 3-D conformal techniques and accelerated fractionation at 2 Gy per fraction, 6 daily fractions per week, throughout the whole course. RESULTS All patients completed the intended radiotherapy dose and the median overall treatment time was 41 days (range: 39-53). Grade ≥3 mucositis and skin reaction were observed in 82% and 21% patients, respectively. The mean weight loss during the whole course of treatment was 11% of the initial body weight. The chemotherapy toxicities and compliance are shown in table 1. With a median follow-up of 1.5 years (range: 0.6-2.3), the 2-year local failure-free, distant failure-free, progression-free and overall survival rates were 97%,76%, 73% and 76% respectively. CONCLUSIONS The early treatment results achieved for this very poor prognostic group was very encouraging, but late toxicity has yet to be fully assessed and confirmation of therapeutic gain by prospective randomized trial is warranted. [Figure: see text] No significant financial relationships to disclose.