State Key Laboratory in Oncology in South China, Sir YK Pao Centre for Cancer, Hong Kong Cancer Institute, The Chinese University of Hong Kong

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1 Annals of Oncology 21 (Supplement 7): vii308 vii312, 2010 doi: /annonc/mdq277 Nasopharyngeal carcinoma A. T. C. Chan* State Key Laboratory in Oncology in South China, Sir YK Pao Centre for Cancer, Hong Kong Cancer Institute, The Chinese University of Hong Kong With the improvement in local control achieved by more precise imaging and radiotherapy, the predominant mode of failure for nasopharyngeal carcinoma is distant metastases. Concurrent cisplatin radiotherapy with or without adjuvant chemotherapy is the standard treatment approach for stages IIB and above disease. The addition of neoadjuvant chemotherapy has been most promising, and phase III trial results are awaited. Quantitative Epstein Barr virus (EBV) DNA can be applied clinically for disease monitoring and follow-up, and may in future be used for risk stratification strategies. Targeted therapies against epidermal growth factor receptor and angiogenesis have demonstrated activity, and immunotherapeutic approaches are being investigated. Key words: chemoradiotherapy, Epstein Barr virus, nasopharyngeal carcinoma symposium article epidemiology and aetiology Nasopharyngeal carcinoma (NPC) is rare with an incidence of per in Europe and the USA [1]. In Southern China, NPC is endemic, and the incidence is up to 25 per Intermediate incidence is seen in Southeast Asia, the Mediterranean Basin and the Arctic. In endemic NPC, >95% are classified as the undifferentiated World Health Organization (WHO) type III and is universally associated with Epstein Barr virus (EBV) [2], a strong aetiological factor interacting with genetic predisposition and dietary intake of preserved foods. In North America, 25% are classified as WHO type I keratinizing squamous cell carcinoma (SCC) and 12% as WHO type II differentiated SCC, which are associated with classic head and neck aetiological factors including alcohol and tobacco. staging and diagnosis The strong prognostic significance of nodal staging in NPC is reflected in the UICC/AJCC staging system of 1997, and retained in the 2002 version which is currently widely used [3]. Definitive diagnosis is made by endoscopic biopsy. Magnetic resonance imaging (MRI) of the nasopharynx, skull base and neck is the imaging technique of choice. For patients with advanced N3 nodal stage and/or clinical evidence of distant metastases, positron emission tomography computed tomography (PET-CT) may be performed [4]. EBV testing The titre levels of antibodies to EBV immunoglobulin A viral capsid antigen (IgA VCA) and early antigen (IgA EA) have been *Correspondence to: Dr A. T. C. Chan. State Key Laboratory in Oncology in South China, Sir YK Pao Centre for Cancer, Hong Kong Cancer Institute, The Chinese University of Hong Kong. anthony@clo.cuhk.edu.hk widely used as screening and diagnostic markers for NPC, even though these markers lack specificity [5]. Furthermore, IgA VCA/EA levels usually remain elevated even after disease remission is achieved. In contrast, quantitation of EBV DNA using a real-time PCR technique is highly sensitive and specific for NPC and correlates well with tumour burden [6, 7]. Pre-treatment plasma EBV DNA levels have been shown to complement TNM (tumour node metastasis) staging [8], and elevated EBV DNA levels at 6 weeks after treatment is a powerful prognosticator of recurrence and survival [9, 10]. EBV DNA can be used clinically to monitor disease response and recurrence [11, 12], while ongoing studies are addressing the use of EBV DNA as a screening tool as well as a risk stratification marker guiding therapy [13]. treatment for locoregional disease NPC is highly radiosensitive, and radiotherapy (RT) is the mainstay treatment, achieving a 5-year overall survival of 90% and 84% for early stage I and IIA disease, respectively [14]. Intensity-modulated radiotherapy (IMRT) may improve local control and also diminish the risk of xerostomia through parotid sparing [15, 16]. Stage IIB is considered as intermediate stage disease since there is increased risk of distant failures [17]. Evidence to support the use of chemotherapy radiotherapy (CRT) is limited in this category due to the small numbers included in prospective studies. Chang et al. reported marked improvement in 3-year disease-free survival (DFS) for stage II patients treated with concurrent CRT [18], and Chua et al. reported the benefit of induction chemotherapy for intermediate stage disease by pooling the results for two phase III randomized trials [19]. Until further data emerge, it is recommended that stage IIB patients should be treated with concurrent CRT which is indisputably the standard treatment approach for more advanced NPC [20, 21]. ª The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please journals.permissions@oxfordjournals.org

2 Annals of Oncology In locoregionally advanced stages III, IVA and IVB disease, concurrent CRT, with or without adjuvant chemotherapy, has been established as the standard of care based on the publication of multiple prospective randomized trials, as well as meta-analyses of these studies demonstrating a reduction of the risk of death by 18% and an increase in the 5-year overall survival of 4 6% [22, 23]. Concurrent CRT has been demonstrated to provide significant improvements in both local control and distant metastases [24 29]. While it is indisputable that CRT is the standard approach, different regimens have been adopted in clinical trials and also in clinical practice. The US Intergroup regimen, which is accepted as the standard in North America, using cisplatin 100 mg/m 2 on days 1, 22 and 43 concurrent with RT followed by adjuvant cisplatin 80 mg/m 2 on day 1 and 5-fluorouracil (5-FU) 1000 mg/m 2 on days 1 4 for three cycles [24], is associated with significant acute and late toxic effects, and compliance is limited, especially in endemic areas where the nutritional status of patients is not as optimal. Weekly cisplatin 40 mg/m 2 for 6 8 weeks concurrent with RT has demonstrated excellent tolerability and efficacy and has been adopted in many centres as the standard of care [26]. Weekly oxaliplatin 70 mg/m 2 has also been compared with RT alone in a small study, with good tolerability and efficacy [30]. A study of 206 patients demonstrated that the use of carboplatin compared with cisplatin was associated with better tolerability and no difference in overall survival or DFS at a median followup of 26 months [31]; however, the modest sample size cannot definitively prove non-inferiority, and confirmatory trials would be necessary. Meanwhile, for patients with borderline renal function or performance status, substitution of carboplatin for cisplatin can be recommended. Whether the three cycles of adjuvant chemotherapy in the US Intergroup regimen is necessary remains an open question since no trial has randomized patients to concurrent CRT plus adjuvant versus concurrent CRT. Trials of RT plus adjuvant chemotherapy versus RT alone have all been negative [32, 33], and compliance with adjuvant chemotherapy due to toxic effects is difficult after concurrent CRT. The current standard of care for locoregionally advanced NPC is concurrent cisplatin RT, and adjuvant chemotherapy can be considered optional. A risk stratification study randomizing patients with residual post-treatment EBV DNA to chemotherapy versus observation may address this important clinical question. There has been renewed interest in the use of neoadjuvant chemotherapy in non-npc head and neck cancers with the docetaxel cisplatin 5-FU regimen [34, 35]. In NPC, meta-analyses of earlier studies of neoadjuvant chemotherapy followed by RT versus RT alone have demonstrated improvement in DFS without improvement in overall survival [22, 23]. Possible explanations include association with significant treatment-related deaths [36] and underpowered studies [37, 38]. Combining neoadjuvant chemotherapy and concurrent CRT hence presents an attractive multidisciplinary treatment sequence utilizing the most promising benefits of systemic therapy with better tolerability. Multiple single arm phase II studies demonstrated acceptable toxic effects using newer chemotherapy regimens and achieving a highly encouraging clinical outcome [39 43]. A randomized phase II study of neoadjuvant docetaxel cisplatin followed by cisplatin RT versus cisplatin RT demonstrated good tolerability and improvement in overall survival [44]. There are ongoing phase III studies addressing whether neoadjuvant chemotherapy plus concurrent CRT is superior to concurrent CRT with or without adjuvant chemotherapy. treatment for recurrent and metastatic disease A multidisciplinary approach involving surgeons, radiation and medical oncologists in the management of locally recurrent NPC is crucial to salvage a subset of patients amenable to surgery, or reirradiation with or without systemic therapy. Detailed surgical and reirradiation techniques and patient selection are outside the scope of this review [45, 46]. With increasing local control from the primary treatment of NPC, the predominant mode of failure is unquestionably distant metastases. The median survival of metastatic NPC depends on the site and volume of metastases. Hui et al. reported that patients with lung metastases only had superior survival to those with liver or bone metastases if they were treated in an aggressive manner [47]. NPC is highly chemosensitive, and first-line doublet chemotherapy achieves 50 80% response rates, with a median time to progression of 5 11 months. However, the median survival is only months [48 55]. Combining cisplatin with either infusional 5-FU or one of the active modern agents including gemcitabine, paclitaxel, docetaxel, irinotecan and vinorelbine has not been compared in a randomized manner and they are considered valid therapy options. Increasing the number of drugs ( 3) is associated with higher response rates and toxic effects which have not been demonstrated to lead to superior survival compared with platinum-based doublets. Carboplatin is used to substitute for cisplatin in patients with borderline renal function or performance status. Oxaliplatin has also been demonstrated to be very active in combination with gemcitabine [55]. In the second-line setting, gemcitabine, capecitabine, irinotecan and vinorelbine have been shown to have significant activity, although the median survival is limited at 7 11 months [56, 57]. There is clearly an urgent need for novel therapeutics in this disease setting. targeted therapy symposium article Epidermal growth factor receptor (EGFR) is highly expressed in NPC, and strong expression is associated with poor survival outcome [58, 59]. Combination of the monoclonal antibody against EGFR, cetuximab, with carboplatin in patients with metastatic NPC who have failed prior platinum-based therapies achieved a response rate of 12% and a clinical benefit rate of 60% [60]. Cetuximab has been combined with cisplatin and IMRT in locoregionally advanced NPC, demonstrating good tolerability despite a significant incidence of radiation dermatitis, mucositis and dysphagia [61]. The approach of adding EGFR-targeted therapy to conventional treatment Volume 21 Supplement 7 October 2010 doi: /annonc/mdq277 vii309

3 approaches is being actively studied in locoregionally advanced NPC. Gefitinib, a tyrosine kinase inbitor against EGFR, has minimal activity in chemotherapy-refractory metastatic NPC [62, 63]. In NPC cell lines, gefitinib resistance may be explained by a persistent p-akt activation despite successful suppression of other kinases [64]. EGFR mutations have not been detected in NPC. Overexpression of the markers associated with hypoxia, including hypoxia-inducible factor 1a (HIF-1a), carbonic anhydrase 9 (CA-9) and vascular endothelial growth factor (VEGF), is associated with poorer survival outcome in NPC [65]. A high expression of osteopontin is associated with poorer response to RT [66]. Prospective studies are needed to validate the use of these biomarkers as predictors of treatment outcome and evaluate the therapeutic activities of antiangiogenic targeted agents in NPC. immunotherapy and epigenetic therapy The presence of EBV antigens in NPC cells provides a possible immotherapeutic target for therapy. Immunotherapy against NPC cells aims to boost the levels of cytotoxic T lymphocytes (CTLs) that recognize the subdominant viral antigens such as EBNA-1, LMP-1 and LMP-2 [67]. Adoptive transfer of CTLs specific for LMP-2 and EBNA-1 has been tested with limited success [68]. The antitumour response could be further enhanced by pulsing the dendritic cells with peptides derived from LMP-2 [69]. Autologous CTL therapy has been used to treat 10 NPC patients, with promising results [70]. CpG methylation is associated with silencing of EBV immunodominant antigens and tumour suppressor genes. Epigenetic therapies may reactivate the host s immune response through demethylation of the genes or antigens. The demethylating agent 5-azacytidine was shown consistently to achieve demethylation of the promoter regions in EBV genes but had limited efficacy in up-regulating the immunodominant antigens [71]. The combination of 5-azacytidine and a histone deacetylase inhibitor SAHA is being investigated to test the hypothesis that restoring both methylation and histone deacetylation may achieve a greater degree of gene transcription. conclusions Concurrent cisplatin RT with or without adjuvant chemotherapy is the current standard of care for locoregionally immediate and advanced NPC. The use of neoadjuvant chemotherapy, targeted therapy and EBV DNA risk stratification strategies is being actively investigated. 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