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Prognostic factors and long-term outcomes of childhood nasopharyngeal carcinoma
Article first published online: 24 AUG 2010
Copyright © 2010 American Cancer Society
Volume 117, Issue 1, pages 197–206, 1 January 2011
How to Cite
Cheuk, D. K. L., Billups, C. A., Martin, M. G., Roland, C. R., Ribeiro, R. C., Krasin, M. J. and Rodriguez-Galindo, C. (2011), Prognostic factors and long-term outcomes of childhood nasopharyngeal carcinoma. Cancer, 117: 197–206. doi: 10.1002/cncr.25376
- Issue published online: 16 DEC 2010
- Article first published online: 24 AUG 2010
- Manuscript Accepted: 3 MAR 2010
- Manuscript Revised: 9 FEB 2010
- Manuscript Received: 7 SEP 2009
- cumulative incidence;
- long-term effects;
- nasopharyngeal carcinoma
The authors studied the survival and long-term morbidities of children with nasopharyngeal carcinoma (NPC).
This was a retrospective review of children with NPC who were treated at St. Jude Children's Research Hospital between 1961 and 2004. Prognostic factors and long term effects of therapy were analyzed.
Fifty-nine patients (median age, 14.1 years) were identified. Most were male (66.1%) and black (54.2%) and had lymphoepithelioma (93.2%). Thirty-five patients had stage IV disease (59.3%), 20 patients had stage III disease (33.9%), and 4 patients had stage II disease (6.8%). All patients received radiotherapy (RT) to the primary tumor, and most received cervical RT (98.3%) and chemotherapy (88.1%). The 15-year survival and event-free survival (EFS) rates were 67.2% ± 7.5% and 63.5% ± 7.8%, respectively. Five patients (8.5%) developed subsequent malignancies 8.6 to 27 years after NPC diagnosis. EFS was improved in patients who were diagnosed after 1980 (74.8% ± 10% vs 45.5% ± 10.1%; P = .031), in patients who had stage III disease compared with patients who had stage IV disease (79.3% ± 9.6% vs 56.2% ± 11.8%; P = .049), in patients who received cisplatin (81% ± 10.7% vs 45.8% ± 9.7%; P = .013), and in patients who received ≥50 grays of RT (71.4% ± 9.3% vs 43.8% ± 11.6%; P = .048). White patients had higher distant failure rates than black patients (41.7% ± 10.4% vs 15.6 ± 6.5%; P = .045). The 15-year cumulative incidence (CI) of any morbidity was 83.7% ± 5.4%, the CI of sensorineural hearing loss was 52.9% ± 6.7%, the CI of primary hypothyroidism was 42.7% ± 6.6%, and the CI of growth hormone deficiency (GHD) was 14.1% ± 4.7%. Dose-response relations were observed between the RT dose and primary hypothyroidism and GHD.
The outcome of children with NPC improved over the past 4 decades with the use of cisplatin-based chemotherapy and higher RT doses. However, many survivors had long-term treatment-related morbidities. Cancer 2011. © 2010 American Cancer Society.
Nasopharyngeal carcinoma (NPC) is an uncommon malignancy in children with an annual incidence of 0.1 to 1.5 per million in the United States.1 NPC is classified pathologically into 3 subtypes; type III, or undifferentiated carcinoma (also known as lymphoepithelioma), is the most common subtype in children.2 Clinically, the most common presenting symptom of childhood NPC is cervical lymphadenopathy.2, 3
Treatment recommendations for childhood NPC follow guidelines established for adults. The standard of care for patients with locoregional disease includes radiotherapy (RT) to the nasopharynx and cervical lymph nodes.1 Because of the high incidence of local and systemic failure in patients with locally advanced disease, chemotherapy has been incorporated into the treatment of those patients. In recent years, randomized and nonrandomized studies have documented the advantage of the concomitant administration of cisplatin-based chemotherapy and RT. The use of adjuvant and neoadjuvant chemotherapy is a matter of much debate; however, available data would suggest an advantage to the use of neoadjuvant therapy.4
Several studies have analyzed the clinical characteristics and treatment outcomes of NPC in children and young adults.1, 5-29 With combined chemotherapy and RT, survival rates in excess of 60% to70% and up to 91% have been reported.12, 17 However, morbidities like endocrinopathies, hearing loss, bone demineralization, and second neoplasms are not uncommon.5, 6, 12-18, 20, 27-29 Because most published series are small and have short follow-up, the long-term outcome of children with NPC has not been well characterized. Therefore, we performed a retrospective review of all children with NPC who were treated at our institution during the past 43 years to investigate the long-term survival and morbidity in different eras as well as the factors associated with those outcomes.
MATERIALS AND METHODS
With institutional review board approval, we reviewed the medical records of all patients with NPC aged <20 years who were treated at St. Jude Children's Research Hospital between 1961 and 2004. The patients were identified retrospectively in our institutional database. The Survivorship Program at St. Jude Children's Research Hospital performs active, on-site follow-up for 10 years after diagnosis. After that, patients are followed using annual comprehensive questionnaires and telephone calls. We extracted data on presenting features, histopathology, imaging findings, treatment, outcome, and late morbidities. Because staging of NPC has evolved over the past decades, we attempted to restage all patients according to the most recent version of the American Joint Committee on Cancer (AJCC) NPC staging classification30 using the available clinical information and the original radiology reports.
Four major treatment protocols were used for NPC in the past 43 years. Patients who were diagnosed during 1966 to 1980, 1985 to 1990, and 1991 to 2000 were mostly treated using the institutional NPC-77, 85N2, and NPC1 protocols. In some instances, patients were treated outside of those studies but received the same regimens. For the purpose of simplification, those patients were analyzed with the corresponding protocol. Patients who were diagnosed after 2000 were treated on a nonprotocol treatment plan (NPTP) using a chemoradiotherapy (CRT) regimen (NPTP-CRT-PF) that included neoadjuvant and concomitant chemotherapy and RT. Patients who were diagnosed before 1966 or during 1981 to 1984 and patients who were not eligible for these treatment protocols were treated on other NPTPs involving RT and different chemotherapy regimens. The treatment regimens are summarized in Table1. The NPC-77 protocol consisted of RT to the nasopharynx and cervical lymph nodes and cyclophosphamide for 1 year. The 85N2 and NPC1 protocols included RT alone for patients with T1N0 and T2N0 disease and 4 cycles of neoadjuvant chemotherapy followed by RT for patients with T3 and T4 and/or N1 to N3 disease. The NPTP-CRT-PF regimen consisted of neoadjuvant chemotherapy followed by concurrent CRT. Fifty-two patients received 2-dimensional RT, 1 patient received 3-dimensional conformal RT, and 6 patients received intensity-modulated RT. Six patients received amifostine given before cisplatin administration and before daily RT.
|Protocol||Years||No. of Patients||Radiotherapy, Gya||Chemotherapy Regimen|
|NPC-77||1966-1980||18||45-70||CYC 200 mg/m2/wk×6 wks, CYC 300 mg/m2 every other wk×12 mo|
|85N2||1985-1990||5||45-70||Neoadjuvant (4 cycles): MTX 120 mg/m2 on D1, CDDP 100 mg/m2 on D2, 5-FU 1000 mg/m2/d on D1-D5, and LV 25 mg/m2 every 6 h ×6 d on D2-D4|
|NPC-1||1991-2000||12||45-70||Neoadjuvant (4 cycles): MTX 120 mg/m2 on D1, CDDP 100 mg/m2 on D2, 5-FU 1000 mg/m2/d on D1-D5, and LV 25 mg/m2 every 6 h ×6 d on D2-D4|
|NPTP-CRT-PF||2000-2004||6||45-70||Neoadjuvant (3 cycles): CDDP 80 mg/m2 on D1 and 5-FU 1000 mg/m2 d on D1-D4; concurrent chemoradiation (3 cycles); CDDP 100 mg/m2 on D1|
|Other regimens||12||45-70||VCR/BLE/CDDP, VCR/DNR/CDDP, BLE/MTX/CDDP, CYC/MTX, CYC/MTX/5FU, VCR/CYC, and VCR/CYC/MTX|
Overall survival (OS) was defined as the time from the date of diagnosis to the date of death from any cause or the date of last contact. Event-free survival (EFS) was defined as the time from the date of diagnosis to the date of the first event (recurrent or progressive disease, second malignancy, or death from any cause) or the date of last contact for patients without events. OS and EFS were estimated using the Kaplan-Meier method. The standard error (SE) was calculated using the method described by Peto et al.31 Differences in OS and EFS were examined using the exact log-rank test.
Local failure and distant failure were defined as the time from the date of diagnosis to the date of local disease recurrence/progression (involving either the nasopharynx or cervical lymphatics) and distant disease recurrence/progression, respectively. The cumulative incidence (CI) of local and distant failure also was estimated.32 Competing events for local failure included distant failure, second neoplasm, or death before local failure. Competing events for distant failure included local failure, second neoplasm, and death before distant failure. Patients who had simultaneous local and distant failures were considered to have local or distant failure in the respective analysis. Differences in CI were examined using the Gray test.33
Patient and Treatment Characteristics
Fifty-nine patients were diagnosed with NPC from December 1961 to March 2004. The median age at diagnosis was 14.1 years (range, 6.1-19.7 years). Most patients were male (66.1%). Blacks were over-represented significantly in NPC compared with other malignancies in the same period: Blacks constituted 54.2% of NPC diagnoses compared with 20.4% of diagnoses for other malignancies (P < .001) (Table 2).
|Characteristic||No. of Patients (%)a|
|American Indian||1 (1.7)|
|Nonkeratinizing squamous cell carcinoma||4 (6.8)|
|Lymph node classification|
|AJCC combined stage|
Lymphoepithelioma (type III NPC) was the most common histology (93.2%), and the remaining patients had a diagnosis of nonkeratinizing squamous cell carcinoma. The majority of patients had advanced tumor (T) classification, regional lymph node metastases, and high AJCC stage (Table 2). All patients received RT to the primary tumor at doses of 30 to 70 grays (Gy) (median primary tumor dose, 55.1 Gy). All but 1 patient received RT to lymph node sites at doses of 30 to 66.6 Gy (median lymph node dose, 53.9 Gy). Seven patients did not receive chemotherapy.
Survival and Second Neoplasms
Thirty-five patients (59.3%) remained alive at a median follow-up of 16.5 years (range, 4.9-41.9 years). First events included recurrent or progressive disease in 18 patients (3 local, 13 distant, and 2 simultaneous local/distant), second neoplasms in 4 patients, and death in 5 patients. Of the 5 patients who had death as their first event, 2 died in car accidents, and 1 died of aspiration pneumonia. Causes of death were not available for the other 2 patients. The median times to disease progression and death as first events were 7.6 months (range, 3.7-15.3 months) and 16.1 years (range, 7.6-30.3 years), respectively. OS estimates at 5 years and 15 years were 71.2% ± 5.9% and 67.2% ± 7.5%, respectively. The corresponding EFS estimates were 69.5% ± 6% and 63.5% ± 7.8%, respectively (Fig. 1, top left). Both patients with distant metastatic disease died: One patient with metastases to bone and mediastinum died 19 months after diagnosis, and 1 patient with metastases to bone and liver died 16 months after diagnosis of NPC. The 15-year CI for local and distant failure was 8.5% ± 3.7% and 25.4% ± 5.7%, respectively. Only 1 of the 18 patients who had recurrent or progressive disease remained alive. The 15-year postrecurrence survival rate was 5.6% ± 3.8%.
Five patients (8.5%; 3 whites and 2 blacks) developed subsequent neoplasms. One patient developed a basal cell carcinoma 27 years after his diagnosis of NPC. Twenty-two months later, he developed a mucoepidermoid carcinoma in the parotid gland, and he died 8.8 years later. Another patient with a germline TP53 mutation developed colorectal adenocarcinoma with liver metastasis 8.6 years after his diagnosis of NPC. He developed subsequent malignancies (right maxillary squamous cell carcinoma, esophageal adenocarcinoma, adenocarcinoma of minor salivary gland of lip) and died 15.2 years after the diagnosis of colorectal adenocarcinoma. Three patients remained alive 17.7 years, 22.7 years, and 8.8 years after diagnosis of a brainstem tumor, thyroid adenoma, and basal cell carcinoma of the neck, respectively. The latency of these second neoplasms was quite long (24.3 years, 15.7 years, and 23.4 years, respectively).
Predictors of Outcome
Men and white patients appeared to have worse outcomes, but the differences were not statistically significant (Table 3). Patients who were diagnosed after 1980 had improved EFS (15-year estimates: 74.8% ± 10% vs 45.5% ± 10.1%; P = .031) (Fig. 1, top right). There also was a significant difference in EFS between patients with AJCC stage III disease and patients with AJCC stage IV disease (79.3% ± 9.6% vs 56.2% ± 11.8%, respectively; P = .049) (Fig. 1, bottom left). Outcome distributions among the 5 major treatment groups were not significantly different (Table 3). However, patients who received cisplatin had improved EFS (81% ± 10.7% vs 45.8% ± 9.7%; P = .013). Nevertheless, the use of cisplatin was highly correlated with treatment era (P < .001); all patients who received cisplatin were diagnosed after 1980, whereas 22 of 24 patients who did not receive cisplatin were diagnosed before 1980. Patients who received RT ≥50 Gy to the primary tumor had improved OS (73.8% ± 8.9% vs 50% ± 11.8%; P = .044) and improved EFS (71.4% ± 9.3% vs 43.8% ± 11.6%; P = .048). Similarly, patients who received RT ≥50 Gy to lymph node sites had better OS (78.2% ± 8.6% vs 47.6% ± 11.5%; P = .018) and better EFS (78.2% ± 8.6% vs 38.1% ± 11.3%; P = .054). We further investigated the use of cisplatin in conjunction with the primary tumor RT dose. Patients who received cisplatin and RT ≥50 Gy had the highest 15-year OS and EFS (81% ± 10.7%). Patients who did not receive cisplatin but received RT ≥50 Gy had intermediate OS (60% ± 13.4%) and intermediate EFS (53.3% ± 13.8%). Patients who did not receive cisplatin and received RT <50 Gy had the lowest OS (50% ± 11.8%) and EFS (43.8% ± 11.6%) (Fig. 1, bottom left).
|Factor||No. of Patients||OS±1 SE, %||Pa||EFS±1 SE, %||Pa|
|Age at diagnosis, y|
|Lymph node classification|
|Use of CDDP|
|RT to primary tumor, Gy|
|RT to lymph nodes, Gy|
|CDDP and primary RT dose|
|CDDP and primary RT ≥50 Gy||28||81±10.7||.088||81±10.7||.042|
|Primary RT ≥50 Gyg||15||60±13.4||53.3±13.8|
|Primary RT <50 Gy||16||50±11.8||43.8±11.6|
We did not examine predictors of local failure because of the small number of patients who had this event. We did examine potential predictors of distant failure. White patients had a significantly higher CI of distant failure compared with black patients (15-year estimates: 41.7% ± 10.4% vs 15.6% ± 6.5%; P = .045). Tumor and lymph node staging did not correlate with distant failure. However, treatment-related parameters were correlated strongly with distant recurrence. The CI of distant failure was lower in patients who received cisplatin (14.3% ± 6.7% vs 37.5% ± 10.2%; P = .047) and in patients who received RT ≥50 Gy to the primary tumor (18.6% ± 6% vs 43.8% ± 13%; P = .041) or to lymph node sites (13.2% ± 5.6% vs 47.6% ± 11.3%; P = .003). The 15-year CI of distant failure was lowest for patients who received cisplatin and RT ≥50 Gy (14.3% ± 6.77%), intermediate for patients who received no cisplatin but did receive RT ≥50 Gy (26.7% ± 11.9%), and highest for patients who received no cisplatin but did receive RT <50 Gy (43.8% ± 13%).
The evaluation of long-term morbidities must be considered in the context of the limitations imposed by the retrospective nature of the study. The CIs for various screened morbidities are shown in Table 4. The CI of primary hypothyroidism was much higher in the modern treatment era (after 1980; 15-year estimates: 65.6% ± 8.3% vs 4.6% ± 4.6%; P < .001), and a similar phenomenon was observed for growth hormone deficiency (GHD) (19.5% ± 6.8% vs 4.6% ± 4.6%; P = .041) and for osteopenia (17.1% ± 6.6% vs 0% ± 0%; P = .044). The CI for any degree of sensorineural hearing loss (SNHL) appeared to be higher in patients who received cisplatin (68.4% ± 9.3% vs 37.5% ± 10.2%; P = .052). There also was a dose-response relation between RT dose and developing SNHL or severe SNHL (grade ≥3) (Table 5). Patients who received RT ≥50 Gy had a significantly higher CI of SNHL (65.9% ± 7.6% vs 18.8% ± 10.1%; P = .002); and patients who received RT >65 Gy had a significantly higher CI for severe SNHL (25% ± 10% vs 2.7% ± 2.7%; P = .012). The 15-year CI for SNHL was higher in patients who received cisplatin and RT ≥50 Gy (68.4% ± 9.3%) and in patients who did not receive cisplatin but received RT ≥50 Gy (61.1% ± 13.7%) than in patients who received neither cisplatin nor RT ≥50 Gy (18.8% ± 10.1%) (Fig. 2, top).
|Morbidity||No. of Patients With Morbidity||15-Year CI±1 SE, %|
|Sensorineural hearing loss||32||52.9±6.7|
|Chronic/recurrent otitis media||10||17.6±5.2|
|Growth hormone deficiency||10||14.1±4.7|
|Cranial nerve palsy||5||8.5±3.7|
|RT Dose, Gy||No. of Patients||No. of Patients (%)|
|SNHL Grade 1-3||Severe SNHL: Grade ≥3|
|65||20||14 (70)||5 (25)|
|50-65||23||15 (65.2)||1 (4.3)|
|<50||16||3 (18.8)||0 (0)|
There was also a dose-response relation between cervical RT dose and the CI of primary hypothyroidism (P < .001). The highest 15-year CI of hypothyroidism occurred in patients who received RT ≥60 Gy (77.2% ± 11.7%), followed by patients who received RT 50 to 60 Gy (47.4% ± 12%), and patients who received RT <50 Gy (9.5% ± 6.6%) (Fig. 2, bottom). Patients who received RT ≥50 Gy to the primary tumor also had a higher CI of GHD (19.6% ± 6.4% vs 0%; P = .015).
We observed that blacks were over-represented in our cohort of patients with NPC compared with other malignancies. The higher incidence of NPC in blacks has been described previously, but the underlying reason for this racial disparity is uncertain.34 This is in contrast with other Epstein-Barr virus (EBV)-related malignancies, in which the incidence among blacks is the same or lower than that among whites.35 The racial disparity in NPC appears to be more pronounced in children compared with adults.34 Taken together, these data suggest that different pathways of EBV tumorigenesis according to ethnicity and age may be involved.
Survival and Event-Free Survival
The 5-year OS (71.2% ± 5.9%) and EFS (69.5% ± 6%) for our cohort were comparable to previous reports. The more relevant prognostic factors for outcome were related to locoregional stage and treatment administered. Patients with AJCC stage IV disease had significantly lower EFS. Likewise, the presence of progressive or recurrent disease resulted in dismal outcomes despite salvage treatments. Most recurrences, as observed previously, were distant rather than locoregional.5, 15, 18, 21, 27, 36 An important finding of our study was the association of race with outcome; black patients tended to have better EFS with significantly lower incidence of distant failure compared with white patients. The reason for this difference was not apparent and requires further investigation.
The long-term outcome of patients with childhood NPC seldom has been described, and the reported 10-year survival has ranged between 36% and 58%.1, 14, 20, 21 Uzel et al reported a 15-year survival rate of 62.4% in 32 patients with a median follow-up of 8.9 years.16 Our estimated OS and EFS rates were 67.2 ± 7.5% and 63.5 ± 7.8%, respectively, at 15 years and 64.3 ± 8.8% and 57.6 ± 9.4%, respectively, at 20 years. A longer follow-up will be required to document whether the disease-related outcome estimates continue to decrease. EFS estimates increased from 46% to 75% after 1980. Improvements in RT planning and delivery, chemotherapy, and supportive care likely contributed to this trend. Higher RT doses were used in the recent era, and RT ≥50 Gy to the primary tumor or to lymph node sites was associated with lower distant failure and better EFS. A similar association between RT dose and survival was reported previously.5, 13, 14, 21, 23 The switch from cyclophosphamide-based chemotherapy to cisplatin-based chemotherapy in the most recent era also may have contributed to improved outcomes; patients who received cisplatin had a lower incidence of distant failure and better EFS, consistent with the recent report by Kupeli et al.20 We also demonstrated that cisplatin and higher RT doses may have additive or synergistic beneficial effects; patients who received cisplatin plus RT ≥50 Gy had superior EFS compared with patients who did not receive cisplatin, and those who did not receive cisplatin but did receive RT <50 Gy had the worst outcome. Data from adult NPC studies suggest that concurrent cisplatin and RT is superior to RT alone.4, 37 Likewise, there appears to be an added benefit to the incorporation of neoadjuvant chemotherapy.4 Whether the same benefit of concurrent CRT applies to children remains uncertain; this issue is being studied currently in the ongoing Children's Oncology Group (COG) ARAR331 trial.
The incidence of long-term morbidities in survivors of childhood NPC has not been well reported. With a median follow-up of 16.5 years and up to almost 42 years, we attempted to estimate the CI of long-term morbidities. Most morbidities started early—within 5 years from diagnosis. Some complications tended to cluster within the first 2 years, including trismus, chronic or recurrent sinusitis or otitis media, and pulmonary fibrosis. In contrast, the frequency of some endocrinopathies, such as GHD, gonadotropin deficiency, and primary hypothyroidism, increased with time, and some cases were diagnosed after 30 years.
Xerostomia and dental problems, well known, unavoidable adverse effects of RT to the salivary glands, occurred in most patients, consistent with previous reports.6, 15-17, 19 Intensity-modulated RT (IMRT) potentially can ameliorate mucosal damage and xerostomia in patients with NPC.38, 39 The administration of amifostine also may be beneficial in patients who are receiving RT to the head and neck area. In a report by Brizel et al,40 adult patients with head and neck cancer who were receiving RT were randomized to receive amifostine, which was given daily before RT. Moderate-to-severe, chronic xerostomia was significantly less prevalent with the use of amifostine. It is noteworthy that the long-term outcome was similar for both groups of patients, demonstrating that the use of amifostine does not influence the antitumor efficacy of the treatment.40 Nevertheless, there is significant controversy regarding the role of this radioprotectant in patients who are receiving treatment for NPC.41 The currently open COG ARAR0331 trial is exploring this issue.
SNHL is a debilitating complication of cisplatin and RT to the head and neck region. However, to our knowledge, there are no data documenting the CI of SNHL in childhood NPC. SNHL affected >50% of patients by 15 years. Most patients had grade 2 SNHL, but nearly 20% of patients had grade ≥3 SNHL and required hearing aids. We noted a higher incidence of SNHL in patients who received cisplatin plus RT ≥50 Gy and observed a dose-response relation with RT doses. Whether concurrent CRT increases the risk of SNHL remains to be determined.
We observed a relatively high incidence of primary hypothyroidism. Hypopituitarism also was common, especially GHD and gonadotropin deficiencies. The endocrinopathies probably were secondary to RT, which was supported by dose-response relations between the RT dose and primary hypothyroidism or GHD. However, this observation may represent detection bias, because we performed screening of endocrinopathies more stringently in the more recent era. It has been suggested that a reduction of RT dose based on the response to neoadjuvant chemotherapy may not compromise survival.42 Therefore, response-adapted RT is worth further evaluation to minimize endocrine morbidities. It is noteworthy that 4 of the 6 patients who received IMRT developed neuroendocrine deficits.
Pulmonary fibrosis occurred in 5 patients in our cohort, probably secondary to bleomycin. Two patients died subsequently, and pulmonary fibrosis was a contributory cause of death. One patient had symptomatic, restrictive lung disease, and 2 patients were asymptomatic. Visual impairment occurred infrequently, usually was mild, and mostly was secondary to RT-induced cataracts, retinopathy, or optic atrophy. Although not major health issues, these problems may compromise the quality of life of the affected patients. Osteopenia has been observed recently in some patients as we started screening for bone density with dual-energy x-ray absorptiometry (DEXA) scans and quantitative computed tomography. Therefore, the incidence of osteopenia probably is underestimated.
The current study is 1 of the largest studies in childhood NPC to date and adds important information regarding treatment and outcomes. A limitation of our study is its retrospective nature. Monitoring for long-term morbidities was heterogeneous, and the incidence of various morbidities probably was underestimated. In addition, because patients were treated on different regimens over a 40-year period, it is difficult to determine whether differences in outcome were related to treatment or to changes over time.
In conclusion, the survival of children with NPC has improved over the past 4 decades with improved RT and chemotherapy. However, life expectancy is reduced by second neoplasms, and quality of life may be impaired by long-term morbidities. Better treatments are needed to improve the cure of advanced or recurrent disease and to reduce long-term morbidities. New chemotherapeutic agents, such as taxanes, along with improved RT techniques as well as the use of EBV-directed cytotoxic T lymphocytes, likely will provide further advances in the management of these patients43, 44; whereas more efforts will have to made to minimize acute and late effects with the incorporation of chemotherapy and RT protectants and imaging-guided and risk-adapted RT.
CONFLICT OF INTEREST DISCLOSURES
Supported by Grants P30-CA23099 and CA21765 and by the American Lebanese Associated Charities.
- 23[Long-term efficacy of radiotherapy on children with nasopharyngeal carcinoma.] Ai Zheng. 2004; 23: 1322-1324., , , , ,
- 25Nasopharyngeal carcinoma in children: a single institution's experience. Acta Paediatr Taiwan. 2005; 46: 268-271., , , , ,
- 30AJCC Cancer Staging Manual. 6th ed. Philadelphia, Pa: Lippincott -Raven; 2002., , , et al, eds.
- 32The Statistical Analysis of Failure Time Data. New York: John Wiley & Sons; 1980., .