Familial Nasopharyngeal Carcinoma 6

Nasopharyngeal Cancer in Pediatric and Adolescent Patients 299patients with neoadjuvant chemotherapy with adjuvantrecombinant IFN-b (Mertens et al. 1997). Atotal dose of 59.4 Gy was given to all patients, independentof their T-status, with a response rate of 91%.Definitive results of this study were reported recentlyfor 59 patients treated between 1992 and 2003, with amedian follow-up time of 48 months (Mertens et al.2005). In their study, 58 of 59 patients responded tothree courses of chemotherapy and only one patientprogressed during chemotherapy. Based on thepotentially strong role of EBV infection in the pathogenesisof the disease, all the patients received adjuvantrecombinant IFN-b. Using this approach, anexcellent outcome was reported with only distantrelapse in three and local recurrence in one patient. Anew treatment protocol was initiated by the samegroup by changing several treatment parameterswith the primary aim to further improve the outcomein this patient group. The major changes were as follows:methotrexate was omitted from combinedschedule due to the severe mucositis with this agent,chemoradiation therapy introduced based on adultstudies that showed enhanced survival, and a totalradiotherapy dose reduction to 54 Gy, instead of 59 Gy,was made in patients with complete response (CR)after three courses of chemotherapy, with the intentof reducing late-term fibrosis and bone necrosis.The second prospective study was reportedrecently by the Pediatric Oncology Group (POG9486) (Rodriguez-Galindo et al. 2005). This studyincluded 18 patients less than 22 years of age treatedfrom 1990 to 1994. All the patients were enrolledfrom south eastern or midwestern United States.About 65% of the patients were African-Americans.Stage I–II patients were treated with radiotherapyalone and stage III–IV patients were treated withfour courses of preradiation chemotherapy. The primarytumor and involved lymphatics were treatedto a total tumor dose of 61.2 Gy with a shrinkingfieldtechnique volume. The target volume was theprechemotherapy volume as defined by any combinationof CT/MRI scans or nasopharyngeal examination.The overall response rate to inductionchemotherapy was 93.7% with 4-year EFS and OSrates of 77% and 75%, respectively. The investigatorsinitiated the new ARAR 0331 study, in which theyexplored the use of induction chemotherapy withcisplatin and 5-FU, followed by concurrent chemotherapysimilar to the German protocol.Both the studies revealed that the total primaryradiotherapy dose reduction to 60 Gy is feasible.However, the OS and disease-free survival rates weresuperior in the German study when compared withthe U. S. study, despite the fact that the POG-studypatients received one chemotherapy cycle more anda slightly higher total dose of radiation. The results ofRCN study, by some means, conflict with the abovementionedprospective studies opposing dose reduction;however, both the patients and neoadjuvantchemotherapy schedules in these centers were nothomogeneous. Therefore, this divergence might indicatethat higher doses still play an important role inthe absence of effective chemotherapy regimens andresponse-directed radiotherapy schedules.At this time, the standard treatment of pediatricNPC consists of high-dose radiotherapy and chemotherapy.The primary disease, the structures surroundingnasopharynx and the entire neck should beincluded in the high-dose radiation portal. Althoughpediatric NPC patients usually have an excellentacute tolerability to the treatment, long-term radiation-inducedtoxicities such as dental caries, trismus,xerostomia, hearing impairment, growth retardationof the facial bones, and soft-tissue fibrosis are majorconcerns.Pediatric NPC is one of the pediatric malignancieswhere significant reduction in radiation dosehave not yet been proven, although the results ofthe two prospective studies and retrospective IGRanalysis suggest such measure may be possible.Therefore, every effort should be made to preventthese patients from severe late sequelae withoutjeopardizing the good disease control. These effortsmay include the use of high-tech treatments likeintensity-modulated radiotherapy (IMRT), use ofradioprotectors (e.g., amifostine) during radiotherapy,response-based total radiotherapy dose reduction,radiotherapy field reductions (e.g., omittingsupraclavicular fields, except in patients with N3bdisease), use of brachytherapy, use of new chemotherapeuticagents or modifiying their administrationsequence when managing pediatric NPCs(Chua et al. 2005; Selek et al. 2005).Intracavitary brachytherapy was used to reduceEBRT after 50–55 Gy by several centers in the literature(Ozyar et al. 2002; Nakamura et al. 2005).Although early T-disease can be treated adequatelyby brachytherapy boost, patients with locallyadvanceddiseases are not good candidates forbrachytherapy because of the nonhomogenous dosedistribution. A large cohort of pediatric NPC patientstreated with brachytherapy boost dose was recentlyreported from a center at Brazil (Nakamura et al.2005). A total of 16 patients received neoadjuvant