Nasopharyngeal carcinoma in children under 15 years of age: A retrospective review of 65 patients

Annals of Oncology 10: 1499-1502. 1999. © 1999 Khmer Academic Publishers. Printed in the Netherlands.

Original article Nasopharyngeal carcinoma in children under 15 years of age: A retrospective review of 65 patients S. Sahraoui, A. Acharki, A. Benider, N. Bouras & A. Kahlain Centred'Oncologie IBNRochd. Casablanca, Maroc

Summary Background: Nasopharyngeal carcinoma constitutescomprises up to 5% of primary childhood cancers but literature lacks modern uniformly treated large series. Patients and methods: A retrospective review was performed of sixty-five previously untreated patients younger than 16 years of age diagnosed and treated at the Ibn Rochd Centre in Casablanca between 1988 and 1992. Forty-four percent of them were stage T3 t o T 4 and 66% stage N 2 or N3. All patients were irradiated. Prior adjuvant chemotherapy was administered in 33 patients. Thirteen patients were lost to follow-up. Results: Local control was obtained in 85% of the 52 evaluable patients. The five-year overall survival was 42% and

Introduction Nasopharyngeal carcinoma accounts for around l % - 5 % of all primary cancers in children and less than 30% of nasopharyngeal cancers [1-3]. The undifferentiated variant of the disease is the most common, and is closely related to a higher rate of advanced locoregional disease and metastasis [1, 3-9]. However, the five-year diseasefree survival rate is 29%-60%, which is not significantly different from that in adults [6, 10-12], and standard therapy has generally followed the guidelines established for adults. Unfortunately, high-dose radiation in children has been associated with significant morbidity among long-term survivors [5, 8, 13, 14]. This paper describes our 13-year experience in 65 children with nasopharyngeal carcinoma with the aim of contributing to the epidemiological, therapeutical and clinical aspects of this disease.

Patients and methods Between January 1980 and December 1993. 1920 patients were treated for nasopharyngeal carcinomas at the Ibn Rochd Oncology Centre in Casablanca. We reviewed only the 65 of them who were under 16 years of age. The histological diagnosis was made in all cases according to the World Health Organisation (WHO) classification. The extent of disease was determined by complete clinical examination using direct nasopharyngoscopy until 1990, and thereafter direct flexible or rigid nasopharyngoscopy. In addition, standard radiography of the nasopharynx was performed in patients treated before 1989. Since 1989,

disease-free survival 38%. Ten relapses occurred at local and/or regional sites. Six patients have distant metastases. All 24 patients with relapse or persistent disease died despite salvage therapy. Stage, histology and dose of radiation, were statistically significant prognostic variables. Patients treated with chemotherapy followed by irradiation had a better outcome than those treated with radiation alone. Conclusions: Nasopharyngeal carcinoma in children is a rare chemosensitive tumor. However, conclusive treatment guidelines cannot be drawn from this series and prospective co-operative studies are needed for the development of more effective and less toxic therapeutic strategies. Key words: children, nasopharyngeal carcinoma, treatment

Table I. Distribution of 65 children with nasopharyngeal carcinoma according to theTNM (UICC) stage.

No N, N2 N3 Total a

Total

T,

T2

T3

T4

_

2 5 10 2

1 1 4 6

_

5 6 6

8 2 T

3 19 22 21

17

19

12

17

65

One child initially had liver and bone metastasis.

these were complemented by computed tomography (CT) scans. Chest radiography and liver ultasonography were done in all patients. Scinligraphy was performed in three patients treated after 1992 and standard radiography of bone was performed in one patient because of bone pain. TheTNM classification system of the UICC was used to define the extent of disease. The classification was retrospective in the first 20 patients and prospective in the remaining ones (Table 1). All patients received radiotherapy using cobalt (C06O). The primary tumour was treated with two opposed lateral fields. The margins included the nasopharynx, the oropharynx and the upper neck and base of the skull in T 4 tumours. A third anterior field was used in four patients who had nasal extension. A total dose of 60-70 Gy was administered in daily fractions of 2 Gy five days a week and 36 patients received a dose 5 65 Gy. The lower cervical and supraclavicular regions were treated with a single anterior portal and a median shield to protect the larynx and the spinal cord with doses at 45 Gy. Clinically involved neck areas were boosted with two opposed fields to doses of 60-65 Gy. Chemotherapy was introduced early and 31 patients received neo-adjuvant treatment. Between 1980 and 1991 the chemotherapy included cyclophosphamide (400 mg/m 2 day 1-5). Following 1991, patients received chemotherapy

1500 Table 2. Characteristics and overall survival at five years of the evaluable patients (n = 52). Characteristics

Sex Boys Girls Stage T3-4N0-, T,_2N2_3 T 3 ^N 2 _3 Histology Epidermoid (squamous-cell) Undifferentiated (UCNT) Treatment Radiation only Radiation + chemotherapy XRT dose <65Gy >65Gy

n (%)

Five-year survival (%)

P value

36 (69) 16(31)

38 48

10(19) 24 (46) 18(35)

69 58 28

0.001

10(19) 42(81)

38 62

< 0.001

30 (58) 22 (42)

38 52

0.1

2

Figure 1. Overall (

3

) and disease-free (

4

Years

) survival curves.

patients with relapse and persistent disease were in N3 stage and 14 patients have an epidermoid carcinoma. < 0 001 Persistent disease or relapse occurred in 16 patients who were treated by radiation alone versus 8 patients treated 45 22 (42) by chemotherapy followed by radiotherapy. A total of 24 < 0.001 39 30 (58) patients had died by thefifthyear of follow-up. Six died with distant metastasis, four of whom had no evidence of associated local relapse or regional relapse. Ten paconsisting of epirubicin (45 mg/m 2 on day 1), bleomycin (8 mg/m2 on tients died with distant metastasis after local or regional days 1 and 2) and cisplatinum (35 mg/m 2 on days 1 and 2). The average relapse and eight after failure/persistent disease. number of cycles was 3. Treatment was continued by radiotherapy four The five-year survival rate for males was 38% comweeks after the end of chemotherapy, with the same dose and technique pared with 48% for females (P =0.1). The TNM stage is as described before. The survival curves were calculated by the Kaplan-Meier method. an important predictor of outcome: thefive-yearsurvival The differences between the curves were compared by log-rank test and of patients with T3>4-No,i was 69%, for patients withT,_2, the Chi-square test was used for testing the difference between progN2-3 58% and 28% ' for patients with T3_4, N2_3 nostic factors. (P < 0.001). Thefive-yearsurvival rate was significantly better for patients with undifferentiated carcinoma (Table 2). For patients treated with irradiation, the fiveyear survival rate was 39% for those receiving more than Results 65 Gy and 45% for those receiving less than 65 Gy This series of 65 children under 16 years old comprises (P < 0.001). There was a statistically significant differapproximately 3.5% of all the cases of nasopharyngeal ence between the survival rates of patients who were carcinoma treated at our institution. The median age at treated with irradiation only and those who received diagnosis was 10 years with a range of 7-15 years and chemotherapy followed by radiotherapy (P < 0.001). Acute radiation toxicity, which included mucositis or 65% of patients were ^ 13 years of age. There were 44 boys and 21 girls, with a male to female ratio of 2:1 reaction in 75% of the patients, was tolerable. Over the long term, the dominant complications were a cervical consistent in all age classes. Over time, 13 children were lost to follow-up, so fail- sclerosis in 25 cases and dental damage in 15 cases. ures, survival and disease-free survival at 5 years were Neuroendocrine evaluations were assessed in 10 cases, analysed only for the remaining 52 patients. Table 2 revealing a biological hypothyroidism in 5 cases treated summarises the characteristics of patients and their out- medically. Hearing deficit occurred in nine cases. Three come. Local control was obtained in 85% of cases. The patients recovered from xerostomia of more than two five-year survival was 42% and the disease-free survival years'duration. was 38% (Figure 1). Ten relapses (30%) occurred at local and/or regional sites, only four of which were local. There were six relapses at distant metastatic sites. Sites Discussion of distant metastasis were bone (three patients) and liver (one patient). The remaining two relapses included both The incidence of childhood nasopharyngeal carcinoma distant and locoregional sites. The time to first relapse varies widely according to racial and geographical was 6-46 months with 50% of first relapses occurring factors. In the child it most commonly presents as within the first year. None of the patients who relapsed advanced locoregional disease. Many series report that was salvaged despite additional radiation therapy and/or 15% or fewer of nasopharyngeal carcinomas in pediatric chemotherapy. When relapse and failure/persistent dis- patients are at an early stage (T1.2-N0.1) at the time of ease are considered together, the distribution of 24 diagnosis and that advanced T or N stage has been patients with relapse and persistent disease by T-stage associated with a high rate of distant metastasis [1, 4, 7, yielded 19 patients withT 34 disease. Similarly, 21 of the 13, 15-17]. In our series, stages T 1 2 -N 0 1 were found in

1501 18.5% and 96% of the patients had palpable lymph nodes. However, the overall survival rates are not significantly different between children and adults with nasopharyngeal carcinoma. The five-year disease-free survival rate is 38% in our series which is within the 29%-60% range reported in paediatric series [5-7, 12, 18]. Staging has been a prognostic aid in patients with nasopharyngeal carcinoma, with advanced Tor N stages reported to be associated with adverse outcome [6, 12, 16, 19]. Because the majority of patients in this series had T34 and/or N 3 disease, comparison for outcome between T and N stages would not be feasible. Analysis of the five-year survival for our patients indicates that stages T or N and histological type were significant. Standard therapy for nasopharyngeal carcinoma in children has generally followed the guidelines established for adults, which consist of high-dose radiation to nasopharynx and involved cervical node areas as well as moderate doses to uninvolved cervical node sites. The total dose to the tumour appears to be an important prognostic factor for adults, but the significance of dose for survival is less clear in paediatric patients. Although high-dose radiotherapy in children can be curative it has been associated with significant morbidity among longterm survivors [2, 6, 7, 10, 13, 20]. However, a higher dose may improve the local control [6, 21], Ingersoll [6] reports a better control of patients treated by radiotherapy with doses greater than 65 Gy. Ayan [4] reports no major differences between treatment groups in radiation technique and doses at the median dose was 62 Gy, but it was observed that ultimate local control improved with total doses exceeding 60 Gy. Some authors [5, 7, 15, 18] report more local relapses outside and within borders of radiation fields. Labo-Sanahuja [22] and Lombardi [12] report having found no correlation among radiation dose, local relapse and survival time. Berry [18] and Jenkin [15] note that local control could be obtained with the radiation dose of 35-65 Gy. At present, a dose between 62-66 Gy in the initial tumour volume is recommended for children older than 10 years and 5%10% less for the children of less than 10 years [6]. The major obstacle to the cure of childhood nasopharyngeal carcinoma is distant metastasis. There is a clear need for early, effective systemic treatment, but it is uncertain whether current chemotherapeutic agents can fulfil the promise of eradicating occult metastases [23-27]; the number of patients in each series was small and only a few were randomised. In the adult literature, clinical trials for advanced tumors evaluating the use of chemoradiotherapy should be considered [28, 29]. Two randomized prospective trials compared combination chemotherapy plus radiotherapy to radiotherapy alone [30, 31]. Although disease-free survival was improved in the chemotherapy groups of both series, improvement in overall survival was reported only in the one from the intergroup study 0099 [30]. In our series, there is a suggestion that the pediatric patients who had chemotherapy before radiation did better than those who were treated by radiation alone. Ingersoll [6] reported encour-

aging results in 14 young adults treated with chemotherapy before radiation. The durations of relapse-free time ranged from 6 months to 23 years. For Gasparini [32], the three-year relapse-free survival rate was 75% for children treated by neo-adjuvant chemotherapy as opposed to 8% in the group treated with radiation therapy alone. In this series all of the children had stages T34. Kim [33] also reported good results in 7 children treated with combination chemotherapy 12-24 months following radiation therapy. The relapse-free survival rate was 86% with a follow-up ranging from 22 months to 12 years. Ghim [20] obtained local control in 9 of 12 patients aged between 6 and 20 years treated for locally advanced or metastastatic stages by radiation therapy after chemotherapy. Local control was obtained in 9 cases with a median of 11 years of follow-up. In the Ingersoll series [6], only one of 14 patients who received combined radiotherapy and chemotherapy relapsed locally. Distant metastasis remains the major pattern of failure in nasopharyngeal carcinoma [5, 6, 11, 12] and our results in the combined treatment group are in keeping with this observation. Reports of long-term results including late effects of treatment in children with nasopharyngeal carcinoma are rare. Late endocrine effects manifested by stunted growth, thyroid dysfunction, and soft tissue fibrosis, bone and dental problems have been reported as a consequence of high-dose radiotherapy [6, 7, 13, 15, 3235]. Dental complications have been noted in 15 children in our study. Second malignancies have been reported as a consequence of high-dose radiotherapy with or without chemotherapy [5, 6, 12, 15, 36]. Ayan [4] reports 3 of 48 treated patients who developed second malignant tumours, occurring either within or outside the radiation field after a median of 77 months. Ingersoll [6] reports 3 cases of secondary cancer among 57 children treated, two of whom received chemotherapy after 6 and 11 years. In conclusion, the results of our retrospective analysis of children with nasopharyngeal carcinoma appear comparable to those reported in the literature. There is evidence that this tumour is chemosensitive and that neoadjuvant chemotherapy may be effective. Indeed, the disease-free survival ranges from 75%-100% in several series after chemotherapy. However, because of the rarity of nasopharyngeal carcinoma, conclusive data on the impact of chemotherapy cannot be collected without co-operative studies. New strategies for prevention, and more effective and less toxic treatment should be developed.

References 1. Attia AB, Maalaj M, Ellouz R, Ayed FB. Results of radiotherapy and adjuvant chemotherapy in the treatment of nasopharyngeal cancer in young patients. A review of 28 cases. J Eur Radiother 1986:4: 161-7. 2. Healy GB. Malignant tumors of the head and neck in children:

1502

3. 4.

5. 6.

7.

8. 9. 10. 11.

12. 13. 14.

15.

16.

17

18. 19. 20.

21. 22.

Diagnosis and treatment Otolaryngol Clin North Am 1980; 13: 483-8. Pick T, Maurer HM, McWilhams NB. Lymphoepithelioma in children. J Pediatr 1974; 84: 96-100. Ayan 1, Altun M. Nasopharyngeal carcinoma in children of Istanbul, Turkey. Int J Radiat Oncol Biol Phys 1996; 35 (3): 48592. Deutsch M, Mercado R, Parsons JA. Cancer of the nasopharynx in children. Cancer 1978; 41: 1128-33. Ingersol L, Woo SY, Donaldson S et al. Nasopharyngeal carcinoma in the young: A combined M.D. Anderson and Stanford experience. Int J Radiat Oncol Biol Phys 1990; 19: 881-7. Pao WJ, Hustu O, Douglass EC et al. Pediatric nasopharyngeal carcinoma: Long-term follow-up of 29 patients. Int J Radiat Oncol Biol Phys 1989; 17- 299-305. Sham JST. Poon YF, Wei WI, Choy D. Nasopharyngeal carcinoma in young patients. Cancer 1990; 65: 2606-10. Singh W. Nasopharyngeal carcinoma in Caucasian children. A 25years study. Laryngol Otol 1987; 101: 1248-53. Baker SR, McClatchey K.D Carcinoma of the nasopharynx in childhood. Head Neck Surg 1981; 89: 555-9. Kalifa C, Schwaab G, Lemerle J. Les carcinomes indifferencies du nasopharynx; problemes pediatriques. In Masson (ed). no. 1. Paris- Actualites Carcinologiques Institut Gustave-Roussy. 1983; 100-5. Lombardi F, Gasparini M, Gianni C et al. Nasopharyngeal carcinoma in childhood. Med Pediatr Oncol 1982; 10: 243-50. Fernandez CH, Cangir A, Samaan NA, Rivera R. Nasopharyngeal carcinoma in children. Cancer 1976; 37: 2787-91. Sarrazin D, Schwaab G, Fontaine F et al. La radiotherapie des carcinomes du nasopharynx chez l'enfant apres chimiotherapie prealable. Resultats preliminaires sur 21 cas traites a I'Institut Gustave-Roussy 1978 et 1981. Ann Oto Laryng 1985; 102: 175-8. Jenkins DT, Anderson JR, Jereb B et al. Nasopharyngeal carcinoma - a retrospective review of patients less than thirty years of age: A report from Children's cancer Study Group Cancer 1981; 47: 360-6. Jereb B, Huvos EG, Steinherz P, Unal A. Nasopharyngeal carcinoma in children Review of 16 cases. Int J Radiat Oncol Biol Phys 1980; 6: 487-91. Mertens R, Granzen B. Lassay L et al. Nasopharyngeal carcinoma in childhood and adolescence: Concept and preliminary results of the cooperative GPOH study NPC-91. Gesellschaft fur Padiatrische Onkologie und Hamatologie. Cancer 1997: 80 (5). 951-9 Berry MP, Smith CR, Brown TC et al. Nasopharyngeal carcinoma in the young. Int J Radiat Oncol Biol Phys 1980; 6: 415-21. Roper HP. Essex-Cater A. Marsden HB et al. Nasopharyngeal carcinoma in children. Pediatr Hematol Oncol 1986; 3: 143-52 Ghim TT, Briones M, Mason P et al. Effective adjuvant chemotherapy for advanced nasopharyngeal carcinoma in children: A final update for a long-term prospective study in a single institution. J Pediatr Hematol Oncol 1998: 20 (2): 131-5. Martin WMO, Shah KJ. Carcinoma of the nasopharynx in young patients. Int J Radiat Oncol Biol Phys 1994: 28: 991-9. Labo-Sanahuja F, Garcia I, Xarranza A. Camacho A. Treatment outcome of undifferential carcinoma of the nasopharynx in childhood: A 13 years experience. Med Pediatr Oncol 1986; 14. 6-11.

23. Decker DA. Drelichman A, Al-Sarraf M et al. Chemotherapy for nasopharyngeal carcinoma. A 10-year experience. Cancer 1983; 52: 602-5. 24. Dimery W, Legha SS, Peters LJ et al. Adjuvant chemotherapy for advanced nasopharyngeal carcinoma. Cancer 1987; 60: 943-9. 25. Ervin TJ, Clark JC, Weichselbaum RR et al. An analysis of induction and adjuvant chemotherapy in the multidisciplinary treatment of squamous-cell carcinoma of the head and neck. J Clin Oncol 1987: 5: 10 20. 26. Huang SC, Lui LT. Lynn TC. Nasopharyngeal cancer. Study III. A review of 1206 patients treated with combined modalities. Int J Radiat Oncol Biol Phys 1985; 11: 1789-93. 27. Khoury GG, Paterson CM. Nasopharyngeal carcinoma: A review of cases treated by radiotherapy and chemotherapy. Clin Radiol 1987; 38: 17-20 28. Gasparini M, Lombardi F, Rottoli L et al. Combined radiotherapy and chemotherapy in stage T 3 and J4 nasopharyngeal carcinoma in children. J Clin Oncol 1988; 6: 491-4. 29. Kim TH, McLaren J, Alvarado CS et al. Adjuvant chemotherapy nasopharyngeal carcinoma in childhood. Cancer 1989; 63: 1922-6. 30. Al Saraf M, Le Blanc M, Giri PG. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099. J Clin Oncol 1998; 16.1310-7 31. International Nasopharynx Cancer Study Group. VUMCA I Trial: Preliminary results of randomized trial comparing neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy vs. Radiotherapy alone in stage IV ( > N 2 , M u ) undifferentiated nasopharyngeal carcinoma. A positive effect on progression-free survival. Int J Radiat Oncol Biol Phys 1996; 35 (3): 463-9. 32. Azli N, Armand JP, Rahal M et al. Alternative chemo-radiotherapy with cisplatin and 5-fluorouracil plus bleomycin by contimous infusion for locally advanced undifferentiated carcinoma nasopharyngeal type. Eur J Cancer 1992, 28A (11): 1792-7. 33. Chan A,Teo P, LeungTet al. A propspective randomized study of chemotherpy adjuvantive to definitive radiotherapy in advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 1995; 33 (3)- 569-77. 34. Strojan P, Benedik MD, Kragelj B. Jereb B. Combined radiation and chemotherapy for advanced undifferentiated nasopharyngeal carcinoma in children. Med Pediatr Oncol 1997; 28 (5): 366-9. 35. Vita HC, Mendiondo OA, Shaw DL et al. Nasopharyngeal carcinoma in the second decade of life. Radiology 1983; 148: 253-6. 36. Morales P. Bosch A, Salaverry S. Cancer of nasopharynx in young patients. J Surg Oncol 1984: 27: 181-5. Received 27 November 1998; accepted 9 September 1999.

Correspondence to DrS. Sahraoui, MD Centre d'Oncologie IBN Rochd Casablanca Maroc E-mail. ssahraoui(a pfizer.co.ma