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Nasopharyngeal Carcinoma in Children: A Single Institutions Experience

JIUNN-MING SHEEN1, HONG-REN YU1, E NG-YEN HUANG2, KUAN-SHENG WU1, SHIOU-HUEI WEI1, CHIH-CHENG HSIAO1

Nasopharyngeal carcinoma is a very rare disease of children. Between 1992 and 2005, 8 male and 2 female patients [ages ranging from 12 to 17 years,] were treated in our institution. The histopathologies were all undifferentiated type (WHO Type III). Of the ten patients, one was T2, five were T3, and four were T4, respectively (TNM system of the American Joint Committee for Cancer Staging). Eight patients had node metastases, 6/8 had bilateral and 4/8 had nodes larger than 6 cm. The main symptoms at diagnosis were neck mass followed by nasal, aural symptoms, cranial nerve palsy and headache. Four patients received radiotherapy only, while six patients received cisplatin-based concomitant chemoradiotherapy. The mean irradiation doses to the primary sites were 7200 cGy. Two patients developed early systemic relapse and died one year and 4 months, respectively, after relapse. After a median follow-up of 30 months, the event-free survival and overall survival were 70% and 75%, respectively. Although the sample size was small, it seemed that the patients had a good chance of survival in spite of advanced stage. However, late morbidity was a concern. (Acta Paediatr Tw 2005; 46:268-71) Key words: children, nasopharyngeal carcinoma, radiotherapy, chemotherapy

INTRODUCTION Nasopharyngeal carcinoma (NPC) is a very rare malignant tumor in children. The incidence varies greatly by racial and geographical factors. The most common histological type in children is undifferentiated carcinoma (World Health Organization Type III), which associates with advanced locoregional disease at presentation and has greater rate of distant metastasis.1,2 The purpose of this report was to study features at onset, treatment results, and outcome of children with NPC followed in our hospital since 1992.

MATERIALS AND METHODS From April 1992 to March 2005, ten consecutive pediatric patients with NPC were treated in our institution, accounting for 0.8 % of total NPC cases in this period. There were 8 males and 2 females. Ages ranged from

12 to 17 years, with a median age of 15 years. All of the diagnoses were made by open biopsies obtained from the primary sites. The initial workup included complete history, physical examination, hematology and biochemistry profiles, chest X-ray, abdominal echogram, computed tomography or magnetic resonance imaging of brain and skeletal technetium scan to assess for disease extension. The staging was according to the TNM system of the American Joint Committee for Cancer Staging (AJCC). The treatments before 1995 were radiotherapy alone irrespective of stage. Thereafter, concomitant chemoradiotherapy was substituted if the patient was in stage 3 or 4. All patients were treated with megavoltage irradiation except two with Co60. The nasopharynx and upper neck were treated via two shaped parallel-opposed lateral fields. A low anterior portal with spinal cord shield was employed to cover the lower neck and supraclavicular fossa. After the initial doses of 4680 cGy were achieved, the bilateral opposed portals were reduced to spare the

Department of Pediatrics 1 and Radiation Oncology2 , Chang Gung Memorial Hospital, Kaohsiung, Taiwan. Received: August 25, 2005. Revised: September 30, 2005. Accepted: December 1, 2005. Address reprint requests to: Dr. Chih-Cheng HSIAO, Department of Pediatrics, Chang-Gung Memorial Hospital, 123 Ta-Pei Road, Niao-Sung Hsiang, Kaohsiung Hsien, Taiwan. TEL: 886-7-731-7123 ext. 8701 FAX: 886-7-733-8009 E-mail: hsiaojc@adm.cgmh.org.tw

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spinal cord. The total doses to the primary sites were 7000 - 7380 cGy (median 7200 cGy). The neck was boosted with electron beam 1400 - 2400 cGy according to the size of residual mass. Radiation therapy was given 5 days per week using a daily 180-cGy fraction. Two patients also received intracavity brachytherapy using Ir-192 source and high-dose rate remoting after loading technique with 300 cGy 2 cm off axis one time. Six patients received concomitant chemoradiotherapy and adjuvant chemotherapy every month for totally three to six courses. The chemotherapy regimens were cisplatin 6070 mg/m2 on day 1 and 5-fluorouracil 600-750 mg/m2 continuous infusions for 4 days on days 2-5 in four and cisplatin 70 mg/m2 on day 1, 5-fluorouracil 600-700 mg/ m2 continuous infusions for 4 days and leucovorin 120140 mg/m2 for 4 days in two (Table 1). The response was evaluated according to the World Health Organization (WHO) response assessment criteria. 3 Complete response was defined as the disappearance of all evident disease. A decrease of more than 50% was defined as partial response, and a decrease of less than 50% was considered no response/stable disease. A progressive increase in the size of the tumor or the appearance of new lesions was defined as progressive disease. Response was evaluated at the second or third month after completion of radiotherapy. Toxicity was defined according to the Radiation Therapy Oncology Group and the European Organization for Research and

Treatment of Cancer criteria.4 Event-free survival and overall survival estimates were calculated by Kaplan-Meier analysis. Event-free survival period was defined from the date of complete remission to the date of recurrence, death, or last disease-free visit (months). Survival period was defined from the date of registration to the date of death or last visit (months). Data were updated to June 30, 2005.

RESULTS Of the 10 consecutive patients treated in our hospital, an overt male predominance was noted (male/female ratio, 4/1). The pathologies of their tumors were all undifferentiated type (WHO Type III). The stages were IV in 7 and III in 3. Antibody titers against Epstein-Barr virus (EBV) were available in 5 patients. The data showed IgM were all negative, IgA were all positive (1/20 to1/ 1280), and IgG were all highly elevated (>1/1280). The main symptoms at diagnosis were neck mass (80%), followed by nasal symptoms (70%), aural symptoms (60%), cranial nerve palsy (30%) and headache (20%). The interval from symptoms to diagnosis was 4-24 weeks (median 8 weeks) (Table 2). As regards neck mass, 6 of 8 were bilateral, and the diameter was longer than 6 cm in 4 patients at least on one side. Two patients developed new symptoms two months

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after radiotherapy before the workup for response. One complained of pain over the right hip, and the bone scan revealed multiple metastases over the skull base, right sacroiliac joint and right iliac crest. She was then treated with chemotherapy. The regimens included cisplatin and 5-fluorouracil; oncovin, epirubicin and cyclophosphomide; mitoxantrone, but all in vain. The other patient complained of bilateral leg soreness and pain such that he could not walk. Bone scan revealed multiple metastases over lateral aspects of the right 10th rib, middle portion of the right femur and trochanteric region of the left femur. He refused chemotherapy and received radiotherapy only for palliative care. Neither patient had evidence of locoregional relapse. They died 1 year and 4 months, respectively, after systemic relapse. Complete remission was achieved in 6/10 (60%) patients, partial response in 2/10 (20%) patients. We gave two courses of chemotherapy to the two partial response patients. The one who received radiotherapy only before achieved complete remission after chemotherapy. The other one refused further image examination after chemotherapy. With a median follow-up of 30 months (range, 7150 months), event-free survival, and overall survival estimates were 70% and 75%, respectively, at 60 months (Fig. 1). Acute toxicity was limited to mild and moderate mucositis and skin reactions. No patient required hospitalization or tube feeding due to mucositis. In late toxicity, xerostomia occurred in all patients at varying degrees. Four patients suffered from chronic sinusitis. Hearing impairments were noted in four patients and otitis media in three patients. Three patients had neck fibrosis, and one of them even needed an emergent tracheostomy when full mouth restoration for multiple caries was performed. We did not have sufficient records about

Fig. 1. Overall survival and event-free survival in 10 children with nasopharyngeal carcinoma.

endocrine effect. No osteoradionecrosis or second malignancy has been found till now.

DISCUSSION NPC is very rare in children. It represents less than 1% of all childhood malignant tumors, although it constitutes of 20 to 50% of pediatric malignancies of the nasopharynx.1,2 There were only 10 pediatric NPC patients treated in our institution during the 13-year study period. In our patients, the tumor histologies were all WHO Type III, and the stages were all advanced (stage 3 or 4) that were similar to previous reports.1 Most of the initial presentations of NPC patients, e. g. nasobstruction and epistaxis are common to pediatric practice and could be overlooked. However, in our patients, 80% had neck mass, and the size was larger than 6 cm in 50% of them when the diagnosis was made. Furthermore, the long interval from symptoms to diagnosis (median: 8 weeks) revealed that we should pay more attention to make differential diagnosis with NPC, especially if the patient is a teenager and has neck mass and one or more of the above symptoms. As in other rare childhood tumors, the treatment strategy for NPC has been adopted from guidelines for adults. The mainstay of therapy was external beam irradiation historically. However, with this approach, almost half of the patients developed distant metastasis. 5,6 In our study, the two patients who developed early distal metastases in the absence of regional relapse might implicate the presence of occult systemic disease at presentation and favor early administration of an effective chemotherapeutic agent being needed for treatment of

Table 2. Initial Presentations in Ten Children with Nasopharyngeal Carcinoma Neck mass Nose Nasobstruction Epistaxis Blood-tinged saliva Auditory Otalgia Otitis media Hearing loss Cranial nerve palsy Ophthalmoplegia Trismus Dysphagia Headache 80% 70%

60%

30%

20%

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childhood NPC. In adults, most studies agreed that highdose radiotherapy decreased locoregional relapse rate, chemotherapy decreased systemic relapse rate, chemotherapy was preferable for first-line treatment in advanced-stage disease, and the combination of radiotherapy with systemic chemotherapy yielded better disease-free survival results.7-9 However, in children, due to the small sample sizes and the use of non-randomized studies, neither the effect of chemotherapy on survival could be determined nor were standard chemotherapy combinations or treatment schedules available. 2,10,11 Recently, several studies reported the response rate and disease-free survival with chemotherapy were increased compared with historical controls in children.12-14 However, different chemotherapy regimens and administration schedules (before, concurrently with, or after radiotherapy) still need further studies. Although high-dose radiotherapy decreases local regional relapse, it may be associated with significant morbidity among long-term survivors in children.15,16 In most childhood cancers, including EBV-related lymphoid malignant diseases, the use of radiotherapy could be substituted by systemic chemotherapy.1 Moreover, in cases where complete responses have been achieved with chemotherapy alone, or by use of chemotherapy before and after radiotherapy, reduction of radiation doses may be considered. 11 In our patients, the survival seemed much improved after introduction of concomitant chemoradiotherapy. However, the patient number was too small, and the treatments were without uniform regimens and accrued over long periods. In addition, prognostic factors could not be found by the same reasons. Previous reports revealed metastatic disease at presentation, high T or N stage, and insufficient total irradiation dose (less than 6000 cGy) were associated with lesser chances of survival.
6,14

In summary, we have presented the treatment results of ten pediatric NPC patients. The result seemed encouraging, however, further study is mandatory.

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