A Prospective Study of Molecular Detection of Salvageable Early Recurrent Nasopharyngeal Carcinoma After Radiotherapy

1. Background: Treatment failure can occur at distant sites which have no effective cure yet. Early local residual or recurrent NPC are salvageable with over 50% 5-year survival rate. It is however difficult for clinical detection of early residual or recurrent NPC after radiotherapy by nasoendoscopy in the heavily irradiated nasopharynx with severe nasopharyngitis and inflammatory swelling and crusting changes. Radiologic imaging and nasopharyngeal biopsy have their role, but they are invasive, expensive and cannot be repeated often as routine follow-up screening method. Unfortunately, 50% local recurrences are in advanced rT3-4 stage and 28% local recurrences are not salvageable. Therefore, detection of the early stage residual/recurrent NPC that are missed by our conventional clinical follow-up is important for successful salvage treatment. Non-invasive, inexpensive and repeatable sampling of blood and nasopharyngeal brush/swab for molecular detection of NPC is our research focus for future improvement of treatment result of local failure.

There are two potential molecular markers of detection of minimal residual/recurrent NPC.

1. EBV DNA is a molecular marker for NPC. We have reported that only 61% patients with local recurrence undergoing nasopharyngectomy had positive plasma EBV DNA. The sensitivity was lower in local recurrence compared with same stage in pretreatment NPC, 86% T1 versus 38% rT1. EBV DNA in nasopharyngeal brush has been reported to be 96% sensitive and 96% specific for NPC before treatment. EBV DNA in nasopharyngeal swab was reported to disappear after radiotherapy and re-appear with mucosal local recurrence with 100 % sensitivity and 98% specificity in a small case study of 11 patients with local recurrences, the results demonstrate its potential detection of local recurrences that are missed by our conventional follow-up. It however needs further prospective longitudinal study for verification.

2. Methylation of the CG rich promoter region of many tumor suppressor genes have been found to be a common genetic abnormality in NPC, but not in normal nasopharynx. We have shown that methylated promoter DNA are detectable in peripheral blood and nasopharyngeal swab of NPC patients, but rarely in normal controls. By using combination of 3 methylated genes in plasma, we have found 38% sensitive for detection of local recurrence.

3. Study objective To evaluate the sensitivity and specificity of the combination of EBV and methylation marker genes in body fluids of both plasma and nasopharyngeal brush together for screening of early salvageable local residual and recurrent NPC that are missed by conventional clinical follow-up protocol.

4. Hypothesis tested: