- Email: [email protected]
Nasopharyngeal carcinoma
symposium article
Annals of Oncology 21 (Supplement 7): vii308–vii312, 2010 doi:10.1093/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
symposium article
epidemiology and aetiology Nasopharyngeal carcinoma (NPC) is rare with an incidence of 0.5–2 per 100 000 in Europe and the USA [1]. In Southern China, NPC is endemic, and the incidence is up to 25 per 100 000. 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.
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 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. E-mail: [email protected]
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].
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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
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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 12–20 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 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
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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/m2 on days 1, 22 and 43 concurrent with RT followed by adjuvant cisplatin 80 mg/m2 on day 1 and 5-fluorouracil (5-FU) 1000 mg/m2 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/m2 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/m2 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
symposium article
symposium article
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. In metastatic disease, platinum-based doublet chemotherapy remains standard treatment while immunological and targeted approaches are being further developed.
disclosure The author has received grant support from Research Grants Council of Hong Kong, Cancer Research UK, Sanofi-Aventis, Merck-Serono, Pfizer and Eli Lilly.
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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.
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39. Rischin D, Corry J, Smith J et al. Excellent disease control and survival in patients with advanced nasopharyngeal cancer treated with chemoradiation. J Clin Oncol 2002; 20: 1845–1852. 40. Oh JL, Vokes EE, Kies MS et al. Induction chemotherapy followed by concomitant chemoradiotherapy in the treatment of locoregionally advanced nasopharyngeal cancer. Ann Oncol 2003; 14: 564–569. 41. Chan AT, Ma BB, Lo YM et al. Phase II study of neoadjuvant carboplatin and paclitaxel followed by radiotherapy and concurrent cisplatin in patients with locoregionally advanced nasopharyngeal carcinoma: therapeutic monitoring with plasma Epstein–Barr virus DNA. J Clin Oncol 2004; 22: 3053–3060. 42. Al-Amro A, Al-Rajhi N, Khafaga Y et al. Neoadjuvant chemotherapy followed by concurrent chemo-radiation therapy in locally advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2005; 62: 508–513. 43. Yau TK, Lee AW, Wong DH et al. Induction chemotherapy with cisplatin and gemcitabine followed by accelerated radiotherapy and concurrent cisplatin in patients with stage IV (A–B) nasopharyngeal carcinoma. Head Neck 2006; 28: 880–887. 44. Hui EP, Ma BB, Leung SF et al. Randomized phase II trial of concurrent cisplatin–radiotherapy with or without neoadjuvant docetaxel and cisplatin in advanced nasopharyngeal carcinoma. J Clin Oncol 2009; 27: 242–249. 45. Yu KH, Leung SF, Tung SY et al. Survival outcome of patients with nasopharyngeal carcinoma with first local failure: a study by the Hong Kong Nasopharyngeal Carcinoma Study Group. Head Neck 2005; 27: 397–405. 46. Chang JT, See LC, Liao CT et al. Locally recurrent nasopharyngeal carcinoma. Radiother Oncol 2000; 54: 135–142. 47. Hui EP, Leung SF, Au JS et al. Lung metastasis alone in nasopharyngeal carcinoma: a relatively favorable prognostic group. A study by the Hong Kong Nasopharyngeal Carcinoma Study Group. Cancer 2004; 101: 300–306. 48. Boussen H, Cvitkovic E, Wendling JL et al. Chemotherapy of metastatic and/or recurrent undifferentiated nasopharyngeal carcinoma with cisplatin, bleomycin, and fluorouracil. J Clin Oncol 1991; 9: 1675–1681. 49. Au E, Ang PT. A phase II trial of 5-fluorouracil and cisplatinum in recurrent or metastatic nasopharyngeal carcinoma. Ann Oncol 1994; 5: 87–89. 50. Yeo W, Leung TW, Chan AT et al. A phase II study of combination paclitaxel and carboplatin in advanced nasopharyngeal carcinoma. Eur J Cancer 1998; 34: 2027–2031. 51. Taamma A, Fandi A, Azli N et al. Phase II trial of chemotherapy with 5fluorouracil, bleomycin, epirubicin, and cisplatin for patients with locally advanced, metastatic, or recurrent undifferentiated carcinoma of the nasopharyngeal type. Cancer 1999; 86: 1101–1108. 52. Ngan RK, Yiu HH, Lau WH et al. Combination gemcitabine and cisplatin chemotherapy for metastatic or recurrent nasopharyngeal carcinoma: report of a phase II study. Ann Oncol 2002; 13: 1252–1258. 53. Chua DT, Sham JS, Au GK. A phase II study of docetaxel and cisplatin as firstline chemotherapy in patients with metastatic nasopharyngeal caricnoma. Oral Oncol 2005; 41: 589–595. 54. Li YH, Wang FH, Jiang WQ et al. Phase II study of capecitabine and cisplatin combination as first-line chemotherapy in Chinese patients with metastatic nasopharyngeal carcinoma. Cancer Chemother Pharmacol 2008; 62: 539–544. 55. Ma BB, Hui EP, Wong SC et al. Multicenter phase II study of gemcitabine and oxaliplatin in advanced nasopharyngeal carcinoma—correlation with excision repair cross-complementing-1 polymorphisms. Ann Oncol 2009; 20: 1854–1859. 56. Chua D, Wei WI, Sham JS, Au GK. Capecitabine monotherapy for recurrent and metastatic nasopharyngeal cancer. Jpn J Clin Oncol 2008; 38: 244–249. 57. Foo KF, Tan EH, Leong SS et al. Gemcitabine in metastatic nasopharyngeal carcinoma of the undifferentiated type. Ann Oncol 2002; 13: 150–156. 59. Chua DT, Nicholls JM, Sham JS, Au GK. Prognostic value of epidermal growth factor receptor expression in patient with advanced stage nasopharyngeal carcinoma treated with induction chemotherapy and radiotherapy. Int J Radiat Oncol Biol Phys 2004; 59: 11–20. 60. Chan AT, Hsu MM, Goh BC et al. Multicenter, phase II study of cetuximab in combination with carboplatin in patients with recurrent or metastatic nasopharyngeal carcinoma. J Clin Oncol 2005; 23: 3568–3576.
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22. Langendijk JA, Leemans CR, Buter J et al. The additional value of chemotherapy to radiotherapy in locally advanced nasopharyngeal carcinoma: a meta-analysis of the published literature. J Clin Oncol 2004; 22: 4604–4612. 23. Baujat B, Audry H, Bourhis J et al. Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients. Int J Radiat Oncol Biol Phys 2006; 64: 47–56. 24. Al-Sarraf M, LeBlanc M, Giri PG et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized intergroup study 0099. J Clin Oncol 1998; 16: 1310–1317. 25. Lin JC, Jan JS, Hsu CY et al. Phase III study of concurrent chemoradiotherapy versus radiotherapy alone for advanced nasopharyngeal carcinoma: positive effect on overall and progression-fee survival. J Clin Oncol 2003; 21: 631–637. 26. Chan AT, Teo PM, Ngan RK et al. Concurrent chemotherapy–radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: progression-free survival analysis of a phase III randomized trial. J Clin Oncol 2002; 20: 2038–2044. 27. Wee J, Tan EH, Tai BC et al. Randomized trial of radiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union against cancer stage III and IV nasopharyngeal cancer of the endemic variety. J Clin Oncol 2005; 23: 6730–6738. 28. Lee AW, Lau WH, Tung SY et al. Preliminary results of a randomized study on therapeutic gain by concurrent chemotherapy for regionally-advanced nasopharyngeal carcinoma: NPC-9901 trial by the Hong Kong Nasopharyngeal Cancer Study Group. J Clin Oncol 2005; 23: 6966–6975. 29. Chen Y, Liu MZ, Liang SB et al. Preliminary results of a prospective randomized trial comparing concurrent chemoradiotherapy plus adjuvant chemotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma in endemic regions of China. Int J Radiat Oncol Biol Phys 2008; 71: 1356–1364. 30. Zhang L, Zhao C, Peng PJ et al. Phase III study comparing standard radiotherapy with or without weekly oxaliplatin in treatment of locoregionally advanced nasopharyngeal carcinoma: preliminary results. J Clin Oncol 2005; 23: 8461–8468. 31. Chitapanarux I, Lorvidhaya V, Kamnerdsupaphon P et al. Chemoradiation comparing cisplatin versus carboplatin in locally advanced nasopharyngeal cancer: randomized, non-inferiority, open trial. Eur J Cancer 2007; 43: 1399–1406. 32. Chi KH, Chang YC, Guo WY et al. A phase III study of adjuvant chemotherapy in advanced nasopharyngeal carcinoma patients. Int J Radiat Oncol Biol Phys 2002; 52: 1238–1244. 33. Rossi A, Molinari R, Boracchi P et al. Adjuvant chemotherapy with vincristine, cyclophosphamide, and doxorubicin after radiotherapy in local–regional nasopharyngeal cancer: results of a 4-year multicenter randomized study. J Clin Oncol 1988; 6: 1401–1410. 34. Vermorken JB, Remenar E, van Herpen C et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007; 357: 1695–1704. 35. Posner MR, Hershock DM, Blajman CR et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007; 357: 1705–1715. 36. Preliminary results of a randomized trial comparing neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy vs radiotherapy alone in stage IV (> or = N2, M0) undifferentiated nasopharyngeal carcinoma: a positive effect on progression-free survival. International Nasopharynx Cancer Study Group. VUMCA I trial. Int J Radiat Oncol Biol Phys 1996; 35: 463–469. 37. Chua DT, Sham JS, Choy D et al. Preliminary report of the Asian–Oceanian Clinical Oncology Association randomized trial comparing cisplatin and epirubicin followed by radiotherapy versus radiotherapy alone in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma. Asian–Oceanian Clinical Oncology Association Nasopharynx Cancer Study Group. Cancer 1998; 83: 2270–2283. 38. Ma J, Mai HQ, Hong MH et al. Results of a prospective randomized trial comparing neoadjuvant chemotherapy plus radiotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma. J Clin Oncol 2001; 19: 1350–1357.
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66. Hui EP, Sung FL, Yu BK et al. Plasma osteopontin, hypoxia, and response to radiotherapy in nasopharyngeal cancer. Clin Cancer Res 2008; 14: 7080–7087. 67. Chan AT, Tao Q, Robertson KD et al. Azacitidine induces demethylation of the Epstein–Barr virus genome in tumors. J Clin Oncol 2004; 22: 1373–1381. 68. Lee SP, Tierney RJ, Thomas WA, Brooks JM, Rickinson AB. Conserved CTL epitopes within EBV latent membrane protein 2: a potential target for CTL-based tumor therapy. J Immunol 1997; 158: 3325–3334. 69. Chua D, Huang J, Zheng B et al. Adoptive transfer of autologous Epstein–Barr virus-specific cytotoxic T cells for nasopharyngeal carcinoma. Int J Cancer 2001; 94: 73–80. 70. Lin CL, Lo WF, Lee TH et al. Immunization with Epstein–Barr virus (EBV) peptidepulsed dendritic cells induces functional CD8+ T-cell immunity and may lead to tumor regression in patients with EBV-positive nasopharyngeal carcinoma. Cancer Res 2002; 62: 6952–6958. 71. Straathof KC, Bollard CM, Popat U et al. Treatment of nasopharyngeal carcinoma with Epstein–Barr virus-specific T lymphocytes. Blood 2005; 105: 1898–1904.
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61. Ma BB, Leung SF, Kam MK et al. A phase II study of concurrent cetuximab– cisplatin and intensity-modulated radiotherapy (IMRT) in locoregionally advanced nasopharyngeal carcinoma (NPC) with correlation using dynamic contrastenhanced magnetic resonance imaging (DCE-MRI). J Clin Oncol 2008; 26(15 Suppl): abstract 6055. 62. Chua DT, Wei WI, Wong MP, Sham JS, Nicholls J, Au GK. Phase II study of gefitinib for the treatment of recurrent and metastatic nasopharyngeal carcinoma. Head Neck 2008; 30: 863–867. 63. Ma B, Hui EP, King A et al. A phase II study of patients with metastatic or locoregionally recurrent nasopharyngeal carcinoma and evaluation of plasma Epstein–Barr virus DNA as a biomarker of efficacy. Cancer Chemother Pharmacol 2008; 62: 59–64. 64. Ma BB, Lui VW, Poon FF et al. Preclinical activity of gefitinib in non-keratinizing nasopharyngeal carcinoma cell lines and biomarkers of response. Invest New Drugs 2010; 28: 326–333. 65. Hui EP, Chan AT, Pezzella F et al. Coexpression of hypoxia-inducible factors 1alpha and 2alpha, carbonic anhydrase IX, and vascular endothelial growth factor in nasopharyngeal carcinoma and relationship to survival. Clin Cancer Res 2002; 8: 2595–2604.
Annals of Oncology
Annals of Oncology 21 (Supplement 7): vii308–vii312, 2010 doi:10.1093/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
symposium article
epidemiology and aetiology Nasopharyngeal carcinoma (NPC) is rare with an incidence of 0.5–2 per 100 000 in Europe and the USA [1]. In Southern China, NPC is endemic, and the incidence is up to 25 per 100 000. 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.
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 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. E-mail: [email protected]
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 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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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
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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 12–20 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 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
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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/m2 on days 1, 22 and 43 concurrent with RT followed by adjuvant cisplatin 80 mg/m2 on day 1 and 5-fluorouracil (5-FU) 1000 mg/m2 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/m2 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/m2 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
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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. In metastatic disease, platinum-based doublet chemotherapy remains standard treatment while immunological and targeted approaches are being further developed.
disclosure The author has received grant support from Research Grants Council of Hong Kong, Cancer Research UK, Sanofi-Aventis, Merck-Serono, Pfizer and Eli Lilly.
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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.
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61. Ma BB, Leung SF, Kam MK et al. A phase II study of concurrent cetuximab– cisplatin and intensity-modulated radiotherapy (IMRT) in locoregionally advanced nasopharyngeal carcinoma (NPC) with correlation using dynamic contrastenhanced magnetic resonance imaging (DCE-MRI). J Clin Oncol 2008; 26(15 Suppl): abstract 6055. 62. Chua DT, Wei WI, Wong MP, Sham JS, Nicholls J, Au GK. Phase II study of gefitinib for the treatment of recurrent and metastatic nasopharyngeal carcinoma. Head Neck 2008; 30: 863–867. 63. Ma B, Hui EP, King A et al. A phase II study of patients with metastatic or locoregionally recurrent nasopharyngeal carcinoma and evaluation of plasma Epstein–Barr virus DNA as a biomarker of efficacy. Cancer Chemother Pharmacol 2008; 62: 59–64. 64. Ma BB, Lui VW, Poon FF et al. Preclinical activity of gefitinib in non-keratinizing nasopharyngeal carcinoma cell lines and biomarkers of response. Invest New Drugs 2010; 28: 326–333. 65. Hui EP, Chan AT, Pezzella F et al. Coexpression of hypoxia-inducible factors 1alpha and 2alpha, carbonic anhydrase IX, and vascular endothelial growth factor in nasopharyngeal carcinoma and relationship to survival. Clin Cancer Res 2002; 8: 2595–2604.
Annals of Oncology