Encouraging Outcomes With Manageable Toxicity Using Neoadjuvant Chemotherapy and Intensity-modulated Radiotherapy in Advanced Pediatric Nasopharyngeal Carcinoma: Single-Center Experience From a Developing Country

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To the Editor:
Nasopharyngeal carcinoma (NPC) is rare among pediatric malignancies (<1%).1 Children account for ∼2% of all NPC, and have a distinct disease profile.2 Management is frequently based on experience in adults. Survival data from low-middle income countries are limited.1,3–5 We retrospectively evaluated the clinical features, results, and toxicities in managing children (below 18 y) with NPC enrolled at a referral cancer hospital in India, between January 2012 and May 2016. Staging was performed according to UICC/AJCC (7th edition).6 Neoadjuvant chemotherapy consisted of 3 cycles of cisplatin (100 mg/m2) with 5-fluorouracil (1000 mg/m2/d for 5 d). Radiation was delivered with volumetric arc–based intensity-modulated radiotherapy or with helical tomotherapy with simultaneous integrated boost. The prescription dose was 60 to 66 Gy in 30 fractions over 6 weeks to the primary tumor and involved nodal levels with margins. The elective nodal levels were treated to 54 Gy in 30 fractions. Concurrent chemotherapy (weekly cisplatin at 30 mg/m2/wk for 6 to 7 wk) during radiation was administered at the physician’s discretion. Kaplan-Meier method was used for survival analysis. Statistical analysis was performed using SPSSv20 (IBM).
Fourteen patients were enrolled. Median age was 13.5 years (range, 9 to 17 y). Nine patients (64%) were males. Median symptom interval was 4.2 months (range, 1.5 to 18 mo). Presenting complaints included swelling (12; 85.7%), epistaxis (4; 28.5%), nasal obstruction (5; 35.7%), and pain (9; 64.3%). Five (35.7%) had bilateral nodal involvement. Median tumor size was 4.5×4 cm. All had type III, undifferentiated histology. Advanced disease was frequent (78.5%) (locally advanced [stage III, IVA, IVB]: 8; metastatic [IVC]: 3). Metastatic sites included bone (n=3/3) and XII cranial nerve (n=1/3).
Eleven patients (78%) underwent treatment. Five of 11 patients (45.5%) received concurrent chemoirradiation. Median follow-up was 23 months. Three (30%) children relapsed; 1 at 3 months and 2 children at 6 months following end of therapy. Sites of relapse were the skull, the liver and spine, and the liver alone. Relapse was not related to age, sex, symptom duration, stage, or nonreceipt of concurrent chemoradiotherapy (P>0.1). Four-year progression-free and event-free survival was 75%±1.5% and 62%±1.7%, respectively. Chemotherapy-related toxicities included: mucositis (5; 45%), fever-neutropenia (3; 27%), and tubular injury (3; 27%). Radiation-related toxicities included: mucositis (8; 73%), xerostomia (6; 54%), skin fibrosis (3; 27%), and hypothyroidism (100%). There was no treatment-related mortality.
As compared with adults, children have advanced disease (77%), type III histology (87%), superior survival (83% vs. 62%, P<0.001), and an increased risk of second cancers.1 Outcomes reported from developing countries are limited. Guruprasad et al3 reported 5-year event-free survival of 64.3% (n=18); 72% had stage IV disease. Laskar et al reported 2-year disease-free survival of 60.6% in stage II/III disease (n=36).1 Sahai et al4 have reported 3-year event-free survival of 55.8%. Zaghloul et al5 reported 3-year event-free survival of 77%, with limited late toxicity with use of neoadjuvant chemotherapy followed by intensity-modulated radiation therapy. Only recently in adults has neoadjuvant chemotherapy (cisplatin, fluorouracil, docetaxel) followed by concurrent chemoradiotherapy been reported to improve survival.7 Addition of docetaxel had failed to improve survival in children.8 In contrast, maintenance therapy with interferon, which plausibly boosts immune regulation against cells harboring the Epstein-Barr virus (EBV) genome, has resulted in overall survival of 97% in children with nonmetastatic disease.9 Type III histology, frequent in children, is associated with EBV infection. Cell-based immunotherapy and therapeutic vaccination have generated interest.10 Gemcitabine has demonstrated potential for metastatic/recurrent disease.11
In conclusion, we report 4-year progression-free survival of 75% in children with NPC presenting with advanced disease, using neoadjuvant therapy followed by combined chemoirradiation, with no life-threatening toxicity. EBV-directed strategies are needed to help improve outcomes.

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