Sagung Rai Indrasari

Epigenetic markers for early detection of nasopharyngeal carcinoma in a high risk population

BackgroundUndifferentiated nasopharyngeal carcinoma (NPC) is strongly related to Epstein-Barr virus (EBV) infection, allowing aberrant antibodies against EBV and viral DNA load as screening tools in high risk populations. Methylation analysis in the promoter of tumor suppressor genes (TSGs) may serve as a complementary marker for identifying early cases. This study determined methylation status of multiple TSGs and evaluated whether it may improve early detection.MethodsNasopharyngeal brushings were taken from 53 NPC patients, 22 high risk subjects and 25 healthy EBV carriers. Corresponding NPC paraffin tissue was included. DNA was bisulfite-modified preceding analysis by methylation-specific PCR (MSP). Ten TSGs were studied.ResultsNPC paraffin and brushing DNA revealed an 81.8% concordance so that MSP analysis was done using either one of both specimens. NPC samples showed methylation for individual TSGs (DAPK1 79.2%, CDH13 77.4%, DLC1 76.9%, RASSF1A 75.5%, CADM1 69.8%, p16 66.0%, WIF1 61.2%, CHFR 58.5%, RIZ1 56.6% and RASSF2A 29.2%). High risk individuals, having elevated EBV IgA and viral load, showed high frequency of methylation of CDH13, DAPK1, DLC1 and CADM1, but low frequency of methylation of p16 and WIF1 and undetectable methylation of RASSF1A, CHFR, RIZ1 and RASSF2A. Healthy subjects showed similar patterns as high risk individuals. A combination of RASSF1A and p16 gave good discrimination between NPC and non-NPC, but best results were combined analysis of five methylation markers (RASSF1A, p16, WIF1, CHFR and RIZ1) with detection rate of 98%.ConclusionMultiple marker MSP is proposed as a complementary test for NPC risk assessment in combination with EBV-based markers.

A Prospective Study: Current Problems in Radiotherapy for Nasopharyngeal Carcinoma in Yogyakarta, Indonesia

Introduction Nasopharyngeal carcinoma (NPC) has a high incidence in Indonesia. Previous study in Yogyakarta revealed a complete response of 29% and a median overall survival of less than 2 years. These poor treatment outcome are influenced by the long diagnose-to-treatment interval to radiotherapy (DTI) and the extended overall treatment time of radiotherapy (OTT). This study reveals insight why the OTT and DTI are prolonged. Method All patients treated with curative intent radiotherapy for NPC between July 2011 until October 2012 were included. During radiotherapy a daily diary was kept, containing information on DTI, missed radiotherapy days, the reason for missing and length of OTT. Results Sixty-eight patients were included. The median DTI was 106 days (95% CI: 98−170). Fifty-nine patients (87%) finished the treatment. The median OTT for radiotherapy was 57 days (95% CI: 57–65). The main reason for missing days was an inoperative radiotherapy machine (36%). Other reasons were patient’s poor condition (21%), public holidays (14%), adjustment of the radiation field (7%), power blackout (3%), inoperative treatment planning system (2%) and patient related reasons (9%). Patient’s insurance type was correlated to DTI in disadvantage for poor people. Conclusion Yogyakarta has a lack of sufficient radiotherapy units which causes a delay of 3–4 months, besides the OTT is extended by 10–12 days. This influences treatment outcome to a great extend. The best solution would be creating sufficient radiotherapy units and better management in health care for poor patients. The growing economy in Indonesia will expectantly in time enable these solutions, but in the meantime solutions are needed. Solutions can consist of radiation outside office hours, better maintenance of the facilities and more effort from patient, doctor and nurse to finish treatment in time. These results are valuable when improving cancer care in low and middle income countries.

Photodynamic therapy as salvage therapy for patients with nasopharyngeal carcinoma experiencing local failures following definitive radiotherapy

BACKGROUND Treating local failures of nasopharyngeal carcinoma (NPC) is a challenge. This study evaluates photodynamic therapy (PDT) in the treatment of residual and recurrent NPC. METHOD In this phase II study, patients with local recurrent or residual NPC after curative intent (chemo-) radiation could be included. Exclusion criterion was a tumour depth more than 10mm. Foscan® 0.15mg/kg was administered intravenously. After 96h, the illumination was performed under local anaesthesia with a nasopharyngeal light applicator. Tumour response was measured 10 weeks after illumination by endoscopy, biopsy and CT-scan. Kaplan-Meier method was used for survival analysis. RESULTS Twenty-one patients were included. Fourteen patients were treated for residual disease (67%), and two for recurrent (10%). For five patients this distinction could not be made, due to uncertainty about complete response after initial treatment. The median follow-up time was 32 months. Twenty patients (95%) had a complete response 10 weeks post-treatment. Two patients had recurrent local disease at 5 and 7 months post-PDT. They received another course of PDT, one with success. The 2-year local control rate was 75%, progression free survival was 49% and overall survival was 65%. Nine patients (43%) had no evidence of disease and were in a good clinical condition (ECOG Performance Scale 0) at the end of the study period. No serious adverse events were observed. CONCLUSION This study showed that PDT is effective in treating local failures of NPC with a depth of less than 10mm. The treatment was easy to perform under local anaesthesia. Especially in regions were other modalities like radiation and surgery are limited PDT can be a good alternative treatment.

Remarkable response to photodynamic therapy in residual T4N0M0 nasopharyngeal carcinoma: A case report

Local treatment of residual or recurrent nasopharyngeal carcinoma (NPC) is a challenge. Photodynamic therapy (PDT) is an established treatment modality for incurable head and neck carcinoma. Several studies reported induction of an immune response after PDT. We present a patient with residual T4N0M0 NPC who was treated with PDT for residual disease after initial treatment with neo-adjuvant chemotherapy and radiotherapy. Five years after PDT, the tumor did not progress and the patient is still in good condition. We discuss this remarkable long-term response to PDT and speculate on possible mechanisms.

The Impact of the Overall Radiotherapy Time on Clinical Outcome of Patients with Nasopharyngeal Carcinoma; A Retrospective Study

Purpose In Yogyakarta, nasopharyngeal carcinoma (NPC) shows a poor response to radiotherapy treatment. Previous study showed a prolonged overall treatment time (OTT), due to interruptions during treatment. This study explores the association between clinical outcome and OTT. Secondary, the relation between clinical outcome and disease stage, waiting time to radiation (WT) and chemotherapy schedule was explored. Methods In this retrospective cohort, 142 patients who started curative intent radiotherapy for NPC between March 2009 and May 2014, with or without chemotherapy, were included. The median follow up time was 1.9 years. Data was collected on WT, OTT, disease stage, and chemotherapy schedule. Time factors were log-transformed. Clinical outcome was defined as therapy response, loco-regional control (LRC), disease free survival (DFS) and overall survival (OS). Results The median WT was 117 days (range 12–581) and OTT was 58 days (43–142). OTT and disease stage were not associated to any of the clinical outcome parameters. The log- WT was associated to poor therapy outcome (HR 1.68; 95% ci: 1.09–2.61), LRC (HR 1.66; 95% ci: 1.15–2.39), and DFS (HR 1.4; 95% ci: 1.09–1.81). In the multivariable analysis, significant hazard risk for poor therapy response, LRC, DFS and OS were seen for patients who didn’t received concurrent chemotherapy. Conclusion Not receiving concurrent chemotherapy showed the strongest risk for poor outcome. Since the choice of chemotherapy is related to a variety of factors, like the WT and patient’s physical condition when radiation can start, careful interpretation is needed. Reason for not finding a relation between OTT and clinical outcome might be the low number of patients who finished radiotherapy within 7 weeks, or by a stronger detrimental effect of other factors.

Effectiveness of a multicentre nasopharyngeal carcinoma awareness programme in Indonesia

Objective To evaluate the effectiveness of a nasopharyngeal carcinoma (NPC) awareness programme on the short-term and long-term improvement of knowledge and referral of patients with NPC by primary healthcare centres (PHCCs) staff in Indonesia. Design The NPC awareness programme consisted of 12 symposia including a Train-The-Trainer component, containing lectures about early symptoms and risk factors of NPC, practical examination and the referral system for NPC suspects. Before and after training participants completed a questionnaire. The Indonesian Doctors Association accredited all activities. Participants 1 representative general practitioner (GP) from each PHCC attended an NPC awareness symposium. On the basis of the Train-The-Trainer principle, GPs received training material and were obligated to train their colleagues in the PHCC. Results 703 GPs attended the symposia and trained 1349 staff members: 314 other GPs, 685 nurses and 350 midwives. After the training, respondents’ average score regarding the knowledge of NPC symptoms increased from 47 points (of the 100) to 74 points (p<0.001); this increase was similar between symposium and Train-The-Trainer component (p=0.88). At 1½ years after the training, this knowledge remained significantly increased at 59 points (p<0.001). Conclusions The initial results of this NPC awareness programme indicate that the programme effectively increases NPC knowledge in the short and long term and therefore should be continued. Effects of the improved knowledge on the stage at diagnoses of the patients with NPC will still need to be scrutinised. This awareness programme can serve as a blueprint for other cancer types in Indonesia and for other developing countries.

Seroprevalence of IgA anti Epstein-Barr virus is high among family members of nasopharyngeal cancer patients and individuals presenting with chronic complaints in head and neck area

Epstein-Barr (EBV) infection and presence of a nasopharyngeal cancer (NPC) case in the family increases the risk of developing NPC. Aberrant anti-EBV immunoglobulin A (IgA) antibodies (EBV-IgA) may be present in the sera of non-cancer individuals and predict NPC. Limited studies report the presence of EBV-IgA antibodies within non-cancer individuals in Indonesia where the disease is prevalent. This study aimed at exploring whether EBV-IgA was found more frequently among first degree relatives of NPC patients and individuals presenting with chronic symptoms in the head and neck area compared to healthy controls. A total of 967 non-cancer subjects were recruited, including 509 family members of NPC cases, 196 individuals having chronic complaints in the head and neck region, and 262 healthy donors of the local blood bank. Sera were analyzed using a standardized peptide-based EBV-IgA ELISA. Overall, 61.6% of all individuals had anti-EBV IgA reactivity equal to or below cut off value (CoV). Seroreactivity above CoV was significantly higher in females (38.7%) compared to males (28.7%) (p = 0.001). Older individuals had more seroreactivity above CoV (42.5%) than the younger ones (26.4%) (p< 0.001). Seroprevalence was significantly higher in family members of NPC patients (41.7%), compared to 32.7% of individuals with chronic head and neck problems (p = 0.028) and 16.4% healthy blood donors (p< 0.001). As conclusion, this study showed a significant higher seroprevalence in healthy family members of NPC cases and subjects presenting with chronic symptoms in the head and neck area compared to healthy individuals from the general community. This finding indicates that both groups have elevated risk of developing NPC and may serve as targets for a regional NPC screening program.