Nasopharyngeal carcinoma: Current management, future directions and dental implications

Oral Oncology (2008) 44, 617– 627

available at www.sciencedirect.com

journal homepage: http://intl.elsevierhealth.com/journals/oron/

REVIEW

Nasopharyngeal carcinoma: Current management, future directions and dental implications Mark Agulnik a, Joel B. Epstein

b,c,*

a

Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, 676 North Saint Clair Street, Suite 850, Chicago, IL 60611, USA b Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, University of Illinois, 801 South Paulina Street, Chicago, IL 60612, USA c Interdisciplinary Program in Oral Cancer, Chicago Cancer Center, College of Medicine, University of Illinois, 914 S. Wood Chicago, IL 60612, USA Received 19 February 2007; received in revised form 3 May 2007; accepted 7 August 2007 Available online 3 December 2007

KEYWORDS Nasopharyngeal neoplasm; Chemotherapy; Radiotherapy; Molecular targeted agents; Immunotherapy; Oral complications and oral care

Summary Nasopharyngeal carcinoma (NPC) is a distinct cancer of the head and neck. Approximately 70% of patients with NPC present with locally advanced disease. Phase III clinical trials support combined chemotherapy and radiotherapy for the initial treatment of these patients. Current treatment approaches for metastatic disease are variable. Oral complications of therapy for NPC are very common. In order to support cancer therapy the dental provider must be aware of the diagnosis, prognosis and approach to treatment. Dental care requires that radiation fields be understood as well as the permanent changes that occur with high dose radiation therapy. Radiation causes changes in bone and soft tissue that may result in acute and chronic oral complications. The most common acute complications are mucositis, infection, xerostomia and taste changes. Mucositis is of increased severity and duration when chemotherapy is combined with radiation therapy. Chronic complications are due to late effects of radiation therapy including hyposalivation, infection, taste change, dysphagia and trismus. Treatment innovations with molecularly targeted therapies and immunotherapy are being assessed to improve treatment outcomes in NPC and will impact oral complications and oral care.

ª 2007 Elsevier Ltd. All rights reserved.

* Corresponding author. Address: Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, University of Illinois, 801 South Paulina Street, Chicago, IL 60612, USA. Tel.: +1 312 996 7480; fax: +1 312 355 2688. E-mail addresses: [email protected] (M. Agulnik), [email protected] (J.B. Epstein).

Introduction Nasopharyngeal carcinoma (NPC) is a distinct form of head and neck cancer that differs from other malignancies of the upper aerodigestive tract in etiology, epidemiology, pathology, clinical presentation and response to treatment.

1368-8375/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2007.08.003

618 Outside of endemic areas in Southeast Asia, this tumor is rare, occurring in less than 1/100,000 people.1 In North America, NPC accounts for approximately 0.2% of all malignancies with approximately 1–2 cases per 100,000 males and about one-third of that in females.2–4 In high-risk populations such as the Cantonese Chinese, a 30-fold increased incidence is reported with 30 cases per 100,000 males and 13 cases per 100,000 females.3,5 A review of all patients diagnosed with NPC between November 1988 and July 1992 in Vancouver, Canada identified 57 patients, 13 of these were Caucasian and nearly half of those were of Canadian descent,6 showing that this malignancy is not solely of Asian origin. Therefore, dismissal of the suspicion of NPC in other populations is not prudent. While NPC may occur at any age, it has a bimodal distribution with the first peak of occurrence in the 15–25 years age range and the second peak in the fourth to fifth decade. NPC is associated with the consumption of salted fish,3,7 and in more remote cases, cigarette smoke,8 occupational exposure to dusts,9 herbal medicine use,9 formaldehyde exposure9 and the use of wood fire in cooking.10 EBV infection is clearly associated with NPC.3,7 EBV is present in the cells of almost all primary and metastatic NPC, regardless of tumor histology, stage of disease, or patient geographic location. Plasma EBV DNA quantification has been recommended to follow patients and predict outcome of treatment11 and may serve as an independent biomarker to predict survival.12 Staging patients according to the American Joint Committee on Cancer staging manual13 (Table 1), patients with stage I and II disease have a high rate of cure with radiotherapy (RT) alone. Unfortunately, the majority of cases are identified with advanced disease, and the prognosis for those with distant metastatic spread remains poor. There are few symptoms associated with early stage disease. NPC can mimic temporomandibular disorders (TMD) with facial pain and limited jaw movement due to involvement of the pterygoid muscles.14 Signs and symptoms that overlap TMD include aching pain, limited jaw movement, and coincidental clicking of the temporomandibular joint (TMJ). Symptoms related to ear, nose and throat including decreased hearing, plugged sensation or auditory drainage, epistaxis or nasal obstruction and cranial nerve involvement or presenting with enlarged cervical lymph nodes14 are critical symptoms that are not seen with TMD. The prognosis for patients with NPC depends on the stage of the disease at diagnosis. Unfortunately, most cases are diagnosed with advanced disease, often detected due to metastatic lymph nodes in the neck, cranial nerve involvement or involvement of the base of the skull.5,14–17 Approximately 70% of patients present with locally advanced, non-metastatic stage III or IV disease. Chen et al. report a cumulative 5-year survival rate of 38% in treated patients who were not diagnosed until later-stage symptoms,15,16 commonly with delay in diagnosis from first symptoms of 6–9-months.14,16,17 Due to poor survival rates and complications of treatment, new therapeutic approaches are sought. RT delivered in combination with chemotherapy has become the standard of care, although the optimal regimens of chemotherapy and radiotherapy remain controversial. This review focuses on the evidence to support treatment of locally advanced NPC and provides an update of current therapies and those that are on the horizon.

M. Agulnik, J.B. Epstein

Chemotherapy and radiotherapy for locally advanced NPC Fifteen phase III clinical trials have been reported in the English literature that seek to establish the best care for patients with locally advanced NPC. While all trials have utilized a RT alone arm as the control, the timing, dosing and cytotoxic chemotherapy regimen has differed greatly. Bleomycin, cisplatin, epirubicin, vincristine, cyclophosphamide, adriamycin, methotrexate, oxaliplatin, leucovorin, uracil-tegafur have all been tried either in combination or as single agents. The timing of the chemotherapy regimen has varied greatly either preceeding (neoadjuvant) RT, given simultaneously with (concurrent) RT, following (adjuvant) RT or a combination of neoadjuvant and adjuvant or concurrent and adjuvant therapy (Table 2). Overall survival (OS) and disease-free survival (DFS) for each of these trials is outlined in Table 3. Four trials have assessed neoadjuvant chemotherapy followed by RT vs. RT alone.18–22 The VUMCA I trial enrolled 339 patients and treated 171 patients with cisplatin, epirubicin and bleomycin as neoadjuvant therapy.18 While this trial failed to show a benefit in OS with the addition of chemotherapy, a statistically significant increase in 3-year DFS rates (52% vs. 32%, interpolated) after a mean 49 month follow-up was seen. This increase DFS was also associated with a treatment-related death rate of 8% in the neoadjuvant arm, and while acute oral complications were not primary endpoints, no significant difference in WHO Grade III mucositis was reported in the patients receiving combined therapy (18%) and in those receiving radiotherapy alone (20%). The Japan-91 study randomized 80 patients to two cycles of cisplatin and 5-fluorouracil (5-FU) administered prior to RT vs. RT alone and a trend to improved 5-year DFS and OS was seen.21 In their initial reporting after a median follow-up duration of 30 months, the Asian-Oceanian clinical oncology association (AOCOA) trial showed a similar trend towards improved OS and DFS with neoadjuvant cisplatin and epirubicin.20 Guangzhou-93 compared 2–3 cycles of neoadjuvant bleomycin, cisplatin and 5-FU followed by RT to RT alone and showed a statistically significant increased DFS in the chemotherapy group (59% vs. 49% at 5 years).22 Updated combined data from these two latter trials involving 784 patients, with a median follow-up of 67 months, showed a statistically significant improvement in 5-year DFS (51% vs. 43%) and 7-year DFS (49% vs. 37%) favoring the neoadjuvant therapy arm, but not in 5-year OS (62% vs. 58%) and reduction in both locoregional and distant failures were observed.23 Although suggested by the trends in these studies, to date, no statistically significant OS advantage has been documented in a phase III randomized trial using neoadjuvant chemotherapy followed by RT for treatment of advanced stage NPC. Three studies have compared concurrent chemoradiotherapy vs. RT alone.24–27 The larger of these three studies, PWHQEH-94, randomized patients to adjuvant weekly low dose cisplatin and standard RT vs. RT alone in 350 patients with advanced stage NPC.24,25 After a median follow-up of 66-months, the 5-year OS was 59% for the RT arm and 70% for the concurrent cisplatin and RT arm (p = 0.065). Subgroup analysis demonstrated that patients with T3 and T4

Nasopharyngeal carcinoma Table 1

619

The American joint committee on cancer (AJCC) nasopharyngeal carcinoma staging, by TNM classification

Primary tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in-situ T1 Tumor confined to the nasopharynx T2 Tumor extends to soft tissues T2a Tumor extends to the oropharynx and/or nasal cavity without parapharyngeal extension T2b Any tumor with parapharyngeal extension T3 Tumor invades bony structures and/or paranasal sinuses T4 Tumor with intracranial extension and/or involvement of cranial nerves, infratemporal fossa, hypopharynx, orbit, or masticator space Regional lymph nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node-metastasis N1 Unilateral metastasis in lymph node(s), not more than 6 cm in greatest dimension, above the supraclavicular fossa N2 Bilateral metastasis in lymph node(s), not more than 6 cm in greatest dimension, above the supraclavicular fossa N3 Metastasis in a lymph node(s) larger than 6 cm and/or to supraclavicular fossa N3a Larger than 6 cm N3b Extension to the supraclavicular fossa Distant metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis AJCC stage groupings Stage 0 Tis, N0, M0 Stage I T1, N0, M0 Stage IIA T2a, N0, M0 Stage IIB T1, N1, M0; T2, N1, M0; T2a, N1, M0; T2b, N0, M0; T2b, N1, M0 Stage III T1, N2, M0; T2a, N2, M0; T2b, N2, M0; T3, N0, M0; T3, N1, M0; T3, N2, M0 Stage IVA T4, N0, M0; T4, N1, M0; T4, N2, M0 Stage IVB Any T, N3, M0 Stage IVC Any T, any N, M1

primary disease derived the most benefit. In a similar study, Taiwan-93, 284 stage III or IV disease patients were randomized to receive either two cycles of cisplatin and 5-FU as a 96-hour continuous infusion during weeks 1 and 5 of RT or RT alone.27 The 5-year OS rates for the chemotherapy arm was 72% vs. 54% in the control arm and the 5-yr DFS rates were 72% vs. 53%, both statistically significant. These studies suggest that patients with advanced locoregional NPC benefit from concurrent chemoradiotherapy over RT alone. Guangzhou-01, the smallest of the three trials, randomized 115 patients to receive RT alone or concurrent chemoradiotherapy with weekly oxaliplatin for 6 weeks.26 After a median follow-up of 24 months, a statistically significant difference in 2-year OS was reported favoring the concurrent arm (100% vs. 77%, p = .01). Both 2-year metastasis free survival and relapse-free survival were also statistically significant in favor of the concurrent therapy as well. These results remain early with 5-year survival rates are still pending. The first of these fifteen published randomized trials compared adjuvant chemotherapy after RT to RT alone. Patients with locally advanced NPC were randomized to be treated with 6 monthly cycles of vincristine, cyclophospha-

mide and adriamycin following RT vs. receiving no chemotherapy.28 No additional benefit was seen at four years in DFS and OS, and distant failure (metastases) was similar in both groups accounting for 50% of relapses. It is important to note that cisplatin, the most active agent in NPC, was not in the regimen used. A second adjuvant trial, TCOG94, that included cisplatin with 5-FU and leucovorin was provided in 9 weekly cycles following radiation in patients with locally advanced NPC.29 As in the previous trial, no differences in OS or DFS between the two groups of patients were seen at 5 years. Based on these trials, adjuvant chemotherapy alone is not recommended for treatment of advanced NPC. Combining neoadjuvant and adjuvant chemotherapy was assessed in one phase III trial, PWH-88, which enrolled 77 patients. Of these patients, 37 received neoadjuvant and adjuvant chemotherapy comprised of 2 and 4 cycles of cisplatin and 5-FU, respectively.30 All patients received identical RT. No significant difference in DFS or OS was seen at a mean of 28.5 months. A landmark study in the management of locally advanced NPC is the phase III randomized multi-center intergroup study 0099 (IG-0099).31 Both arms of the study

620 Table 2 cancer

M. Agulnik, J.B. Epstein Randomized trials of chemotherapy with radiotherapy vs. radiotherapy alone in locally advanced nasopharyngeal

Trial name

No. of pts

Treatment arms

Neoadjuvant chemotherapy + RT vs. RT alone VUMCA I a: 171 a: B 15 mg D1, 12 mg/m2/d D1–5, E 70 mg/m2 D1, and P 100 mg/m2 D1 every 21 days · 3 fi RT b: 168 b: RT Japan-91

a: 40 b: 40

a: P 80 mg/m2 D1 and F 800 mg/m2/d D2–5 every 21 days · 2 fi RT b: RT

AOCOA

a: 167 b: 167

a: P 60 mg/m2 D1 and E 110 mg/m2 D1 every 21 days · 2–3 fi RT b: RT

Guangzhou-93

a: 224 b: 225

a: P 100 mg/m2 D1, B 10 mg/m2 D1 and 5, and F 800 mg/m2/d D1–5 every 21 days · 2–3 fi RT b: RT

Concurrent chemotherapy + RT vs. RT alone Taiwan-93 a: 141 a: P 20 mg/m2/d D1–4 and F 800 mg/m2/d D1–4 on weeks 1, 5 + RT b: 143 b: RT PWHQEH-94

a: 174 b: 176

a: P 40 mg/m2 weekly + RT b: RT

Guangzhou-01

a: 59 b: 56

a: O 70 mg/m2 weekly + RT b: RT

Adjuvant chemotherapy + RT vs. RT alone Italy-79 a: 113 a: RT fi V 1.2 mg/m2 D1, C 200 mg/m2/d D1–4 and A 40 mg/m2 D1 every 28 days · 6 b: 116 b: RT TCOG-94

a: 77 b: 77

a: RT fi P 20 mg/m2 D1, F 2200 mg/m2 D1, and L 120 mg/m2 D1 weekly · 9 b: RT

Neoadjuvant and adjuvant chemotherapy + RT vs. RT alone PWH-88

a: 37 b: 40

a: P 100 mg/m2 D1 and F 1000 mg/m2/d D2–4 every 21 days · 2 fi RT fi P 100 mg/m2 D1 and F 1000 mg/m2/d D2–4 every 21 days · 4 b: RT

Concurrent and adjuvant chemotherapy + RT vs. RT alone IG-0099 a: 93 a: P 100 mg/m2 D1, 22, 43 + RT fi P 80 mg/m2 D1 and F 1000 mg/m2/d D1–4 week 11, 15, 19 b: 92 b: RT

b: 109

a: P 25 mg/m2/d D1–4 week 1,4,7 + RT fi P 20 mg/m2/d D1–4 and F 1000 mg/m2/d D1–4 week 11, 15, 19 b: RT

NPC9901

a: 172 b: 176

a: P 100 mg/m2 D1, 22, 43 + RT fi P 80 mg/m2 D1 and F 1000 mg/m2/d D1–4 week 11, 15, 19 b: RT

NPC9902

a: 51 b: 44 c: 52 d: 42

a: P 100 mg/m2 D1, 22, 43 + RT fi P 80 mg/m2 D1 and F 1000 mg/m2/d D1–4 week 11, 15, 19 b: P 100 mg/m2 D1, 22, 43 + AF RT fi P 80 mg/m2 D1 and F 1000 mg/m2/d D1–4 week 11, 15, 19 c: AF RT d: RT

QMH-95

a1: 57

SQNP01

a: 111

a2: 53 a3: 54 b: 55

a1: UFT 600 mg/d + RT fi P 100 mg/m2 D1 and F 1000 mg/m2/d D1–3 alternating with V 2 mg, B 30 mg, and M 150 mg/m2 every 21 days · 6 a2: UFT 600 mg/d + RT a3: RT fi P 100 mg/m2 D1 and F 1000 mg/m2/d D1–3 alternating with V 2 mg, B 30 mg, and M 150 mg/m2 every 21 days · 6 b: RT

P = cisplatin, F = fluorouracil, B = bleomycin, E = epirubicin, V = vincristine, O = oxaliplatin, C = cyclophosphamide, A = adriamycin, L = leucovorin, M = methotrexate, UFT = uracil-tegafur, D = day, AF = accelerated fractionation a (a1, a2, a3) = combined therapy arm, b = radiotherapy alone arm.

Nasopharyngeal carcinoma

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Table 3 Overall survival and disease-free survival in randomized trials of chemotherapy with radiotherapy vs. radiotherapy alone in locally advanced nasopharyngeal cancer Trial name

Treatment arm

Neoadjuvant chemotherapy + RT vs. RT alone VUMCA I a b

OS

DFS

Median F/U

3 yr – 60% 54%

3 yr – 52% *p < .01 32%

49 mo

Japan-91

a b

5 yr – 60% 48%

5 yr – 55% 43%

49 mo

AOCOA

a b

3 yr – 78% 71%

3 yr – 48% 42%

30 mo

Guangzhou-93

a b

5 yr – 63% 56%

5 yr – 59% *p = .05 49%

62 mo

AOCOA-Guangzhou-93

a b

5 yr – 64%*p = .029 58%

5 yr – 51%*p = .014 43%

67 mo

5 yr – 72%* p < .01 54%

5 yr – 72%* p < .01 53%

65 mo

a b a b

N/A N/A 5 yr – 70%*p < .05 59%

2 yr – 76% 69% 5 yr – 60% 52%

33 mo

a b

2 yr – 100% * p = .01 77%

2 yr – 96% 88%

24 mo

5 yr – 55% 61%

5 yr – 54% 50%

49.5 mo

4 yr – 59% 67%

4 yr – 58% 56%

43 mo

Neoadjuvant and adjuvant chemotherapy + RT vs. RT alone PWH-88 a 2yr – 80% b 81%

2 yr – 68% 72%

28.5 mo

Concurrent and adjuvant chemotherapy + RT vs. RT alone IG-0099 a 3 yr – 76% * p < .001 b 46% a 5 yr – 67%* p < .001 b 37%

3 yr – 66% * p < .001 26% 5 yr – 58%* p < .001 29%

32.4 mo

Concurrent chemotherapy + RT vs. RT alone Taiwan-93 a b PWHQEH-94

Guangzhou-01

Adjuvant chemotherapy + RT vs. RT alone Italy-79 a b TCOG-94

a b

65 mo

60 mo

SQNP01

a b

2 yr – 85%*p = .02 77%

2 yr – 76% 62%

N/A

NPC9901

a b

3 yr – 77% 76%

3 yr – 67% 61%

25 mo

NPC9902

a b c d

3 yr – 87% 88% 73% 83%

3 yr – 73% 88% 63% 65%

33 mo

QMH-95

a1 a2 a3 b

3 yr – 89% 84% 71% 83%

3 yr – 70% 69% 54% 61%

32.5 mo

a (a1, a2, a3) = combined chemotherapy/radiotherapy arm, b = radiotherapy alone arm OS = overall survival; DFS = disease-free survival. * statistically significant result (p 6 0.05).

622 received identical RT while the chemotherapy arm received both concomitant and adjuvant chemotherapy. Cisplatin was administered on days 1, 22 and 43 of RT, and 3 adjuvant cycles of cisplatin with 5-FU were given monthly following chemoradiotherapy. At three years, the DFS was 69% in the chemotherapy group and 24% in the RT alone arm, and survival at 3 years was 78% vs. 47%, favoring chemotherapy. Analysis at 5 years32 confirmed 5 year-DFS of 58% vs. 29%, and 5-year OS rates of 67% vs. 37%, favoring combined therapy. The National Cancer database has been reviewed to determine patterns of practice since the IG0099 study and showed that 38% of patients enrolled in the database matching the eligibility criteria of the IG0099 study received chemotherapy along with RT prior to 1997 and since the publication, 65% of these patients received RT and concurrent and adjuvant chemotherapy,33 therefore establishing the current standard of care for advanced stage NPC. One quarter of the patients treated on the IG-0099 protocol had keratinizing squamous cell carcinoma (World Health Organization (WHO) stage I histology). A phase III randomized trial using a similar chemotherapy and RT plan has been completed, with enrollment restricted to patients with non-keratinizing squamous cell carcinoma (WHO type IIa) and undifferentiated carcinoma (WHO IIb).34 The chemotherapy regimen differed slightly from the IG-0099 trial with the same total dose of cisplatin, but administered in divided doses rather than a single dose. The 2-year DFS and OS rates were statistically significant favoring the use of chemotherapy. The Hong Kong NPC study group, NPC9901, randomized patients with non-keratinizing (WHO IIa) or undifferentiated (WHO IIb) NPC to the IG-0099 regimen.35 Preliminary analysis after a median follow-up of 2.3 years, showed trends that favored the addition of chemotherapy with respect to DFS, but no benefit in OS was noted. Locoregional control was improved with the addition of chemotherapy. A third trial, NPC-9902, utilized the identical chemotherapy as IG-0099, but assessed both the therapeutic gain with concurrent and adjuvant chemotherapy and/or accelerated RT.36 Four arms were evaluated, conventional RT vs. accelerated fraction RT vs. conventional RT with concurrent and adjuvant chemotherapy vs. accelerated fraction RT with concurrent and adjuvant chemotherapy. After 189 patients were randomized, the study was closed due to poor accrual. Preliminary data after a median follow-up of 2.9 years, showed no statistically significant change in either OS or DFS at 3-years. Tumor control may be improved when chemotherapy is added to accelerated fractionation over conventional RT alone. In addition to the trials described above which compared concurrent chemoradiotherapy plus adjuvant chemotherapy vs. RT alone, a factorial study of four different regimens, QMH-95, has been published.37 This study assessed RT alone vs. RT with adjuvant chemotherapy, concurrent chemoradiotherapy and concurrent chemoradiotherapy followed by adjuvant chemotherapy. UFT (uracil and tegafur in 4:1 molar ratio) was used as the concurrent chemotherapy agent while the adjuvant chemotherapy protocol consisted of alternating cycles of cisplatin/5-FU with vincristine/bleomycin/methotrexate. Although a trend towards improved DFS and OS was noted with the addition of concurrent che-

M. Agulnik, J.B. Epstein motherapy, statistical significance was not achieved at 3 years, however a significant reduction in distant metastases was seen for those provided concurrent chemotherapy. In this study adjuvant chemotherapy did not improve outcome. The meta-analysis of chemotherapy in NPC (MAC-NPC) collaborative group has recently published an individual patient data meta-analysis of eight randomized trials and 1753 patients treated in phase III clinical trials of chemotherapy with RT vs. RT alone.38 This meta-analysis is based on individual patient data for all studies with completed accrual prior to January 1, 2002. Information was obtained from the following eight trials: PWH-88, AOCOA, VUMCA 1, Japan-91, IG-0099, PWHQEH-94, QMH-95, and TCOG-94. Their conclusions support the use of concurrent chemotherapy with RT, which produces a statistically significant survival advantage. Unfortunately, their meta-analysis only incorporates 8 of 15 randomized trials, as 4 trials had not completed accrual by the specified date,26,34–36 the data from one trial was lost at the institution,28 and two trials were excluded because they did not meet the eligibility criterion of unpredictable treatment assignment.22,27

RT for locally advanced NPC Control of NPC is correlated with the RT dose delivered to the tumor. Radiation doses delivered in the trials described above are summarized in Table 4. The dosing is similar in these trials, with most using two lateral opposed facial fields and an anterior field if necessary. A few studies use hyperfractionated RT (twice per day), but the majority report conventional fractionation to a tumor dose of greater than 67 gray (Gy). In 1998, use of intensity-modulated RT (IMRT) for NPC was implemented at Memorial Sloan-Kettering Cancer Center, and increased RT dose to 77.3 Gy was administered, while the dose to adjacent structures such as the spinal cord, mandible, temporal lobes and parotid glands were decreased.39 A 2-year follow-up of 39 patients treated with IMRT confirmed a local relapse-free survival (LRFS) of 97% vs. 78% in historical controls treated with conventional technique with a three-dimensional (3D) boost.40 This same group reported an update with a median followup of 35 months in 74 patients treated with IMRT.41 The 3year actuarial rate of local control was 91%, and regional control was 93%; freedom from distant metastases, progression-free survival, and overall survival at 3 years were 78%, 67%, and 83%, respectively. IMRT has been used in other trials for treatment of NPC.42–44 IMRT improved tumor target coverage and spared sensitive normal tissue. Thirty-five patients were treated with IMRT for NPC, of whom, 72% had stage III or IV disease and at 22 months of follow-up, no local or regional failures were documented. Local control was attributable to improved tumor target coverage, increased total dose (75.8 Gy) and increased dose per fraction to the tumor. Of these patients, 75% received concurrent and adjuvant chemotherapy as per the intergroup protocol 0099 regimen. At 31 months, 67 patients confirmed the above with only one case of local recurrence. The vast majority of failures in this series were attributed to distant metastases. The Prince of Wales Hospital (PWH) Hong Kong confirmed the

Nasopharyngeal carcinoma

623

Table 4 Radiation dose and schedule in randomized trials of chemotherapy with radiation therapy vs. radiation therapy alone in locally advanced NPC Trial name

Weekly fractions

Primary tumor dose

Involved nodes dose

Remaining nodal area

65–70 Gy 66–68 Gy 66–70 Gy (36%) >70–74 Gy (64%) 68–72 Gy

65 Gy 66–68 Gy 60–66 Gy (82.5%) >66–76 Gy (17.5%) 60–62 Gy

50 Gy 50 Gy 60 Gy

70–74 Gy

70–74 Gy

50–60 Gy

66 Gy 70–74 Gy

N/A 60–64 Gy

N/A 50 Gy

60–70 Gy

60–70 Gy

50 Gy

70–72 Gy

70–72 Gy

50 Gy

Neoadjuvant and adjuvant chemotherapy + RT vs. RT alone PWH-88 N/A 66 Gy ± boost

58 Gy + 7.5 Gy boost

58 Gy

Concurrent and adjuvant chemotherapy + RT vs. RT alone IG-0099 5 · 1.8–2.0 Gy/d SQNP01 2.0 Gy/d NPC9901 5 · 2.0 Gy/d NPC9902 5 · 2.0 Gy/d or 6 · 2.0 Gy/d QMH-95 4 · 2.5 Gy/d to 40 Gy then 5 · 2.5 Gy/d or 5 · 2.0 Gy/d

66–70 Gy N/A 66 Gy 66 Gy 62.5 Gy 66 Gy

50 Gy N/A N/A 50 Gy N/A N/A

Neoadjuvant chemotherapy + RT vs. RT alone VUMCA I 5 · 2 Gy/d Japan-91 5 · 2.0 Gy/d or 4 · 2.2 Gy/d AOCOA 5 · 2 Gy/d (n = 110) or Hypofractionated (n = 176) Guangzhou-93 5 · 2.0 Gy/d Concurrent chemotherapy + RT vs. RT alone Taiwan-93 5 · 2.0 Gy/d (n = 240) or hyperfractionated (n = 44) PWHQEH-94 5 · 2.0 Gy/d Guangzhou-01 5 · 2.0 Gy/d Adjuvant chemotherapy + RT vs. RT alone Italy-79 1.8 Gy/d (n = 103) or hyperfractionated (n = 13) TCOG-94 5 · 1.8–2.0 Gy/d

70 Gy 70 Gy 66 Gy 66 Gy 62.5 Gy 68 Gy

50 Gy

Gy = grays, d = day a (a1, a2, a3) = combined therapy arm, b = radiotherapy alone arm.

benefits of IMRT, where in 63 patients with NPC (Stage I–IV disease), a 3 year LRFS of 92%, and OS of 90% were seen.45 While not primary end-points in studies using IMRT, favorable toxicity profiles were described with IMRT that may be due to the reduced volumes of normal tissue irradiated. Oral mucositis and xerostomia were the commonest side effects experienced by patients treated with conventional two-dimensional (2D) RT for NPC and up to 97% of treated patients reported xerostomia as a complication of therapy.46 Xerostomia was reduced with use of IMRT, when RT dose to the major salivary glands are reduced. Following IMRT, University of California, San Francisco reported no patient complaint of xerostomia at 2 years,42 while PWH reported 23% with grade 2–3 xerostomia at 2 years and 17% at 2 years in a subset of patients treated with less than 31 Gy to the parotid glands.45 The initial data assessing IMRT are encouraging for both locoregional disease control and reduced report of xerostomia. Furthermore, if residual functional salivary gland tissue remains, use of sialogogues are anticipated to be more effective in stimulating salivary production, impacting symptoms, and reducing risk of oral infections and dental complications.47 Other techniques are being explored in early and advanced stage NPC to improve upon locoregional response rates while limiting toxicities. High-dose-rate intracavitary brachytherapy and sterotactic radiosurgical boost have been shown to increase locoregional control rates when

used as an adjuvant to external beam RT.48–50 These approaches limit radiation exposure to oral and salivary tissues. Given the findings in these phase II studies, the future direction of RT in the treatment of NPC will certainly be of use of IMRT. A more defined role for stereotactic radiosurgery and intracavitary brachytherapy in the management of locally advanced NPC remains to be established. IMRT re-irradiation of locally recurrent NPC is offered at selected institutions based upon several reports.51–53 Twenty-one patients with local recurrence received re-irradiation to an additional mean dose of 55 (range 45–70) Gy with local control at 21 months follow-up in 71.8%, OS 32.3% and a 5-year DFS of 21.2%.53 Approximately 25% experienced high grade late effects including necrosis of brain structures and mucosal necrosis, and re-irradiation was considered an option for local recurrence. Thirty-six patients with locally recurrent NPC received re-irradiation with 54 Gy and boost of 16, 20 or 24 Gy,52 resulting in a 3-year survival of 72% in high dose, 37% and 28% respectively in lower RT dose groups (p = 0.047). Toxicities included mucositis (grade 3) in 25%. Another study of 31 patients received IMRT re-irradiation for local recurrent disease to a median dose of 54 Gy with cisplatin-based induction in 68% and radio-surgery boost of 8.5–12.5 Gy in 32% of cases.51 One year follow-up revealed OS of 53% with IMRT alone, and 90% when combined with chemotherapy induction and for 25% with radiosurgery boost.51 Therefore, these trials show

624 that re-irradiation can be considered for local recurrent NPC, and that IMRT may allow a boosted dose of up to 78 Gy, and that increased vigilance is needed due to local/regional complications.

Molecular targeted therapy and immunotherapy Recurrent or metastatic NPC remains largely incurable, although there have been reports of long-term survivors among those who achieved complete responses to conventional chemotherapy54 and to re-irradiation for local recurrent disease (see above). Combinations of cytotoxic chemotherapeutic agents such as the platinums, 5-FU, methotrexate, anthracyclines, gemcitabine, and taxanes typically yield high response rates of limited duration, and are associated with normal tissue toxicity frequently involving oral tissue. Gemcitabine-based therapy has been assessed as first-line therapy for recurrent or metastatic NPC with response rates of 34% as a single agent among platinum-refractory patients, or 64% when used in combination with cisplatin among platinum-sensitive patients. The median duration of response was 17 and 24 weeks, and 1-year survival rates were 48% and 69%, respectively.55 In order to maximize long-term survivors among patients with recurrent or metastatic NPC, increasing RT tumor dose, additional systemic agents and combination therapy are needed. Studies are being conducted using molecular targeted agents that while potentially more effective, may have reduced toxicity profiles. Several molecular targets have been identified in NPC. Expression or over-expression of epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), c-KIT, and c-erbB-2 (HER2) has been seen in NPC. A retrospective study examined the correlation between EGFR expression and treatment outcome in patients with advanced stage NPC19. Of the specimens tested, 89% of the cases demonstrated EGFR expression. While the extent and intensity of the immunocytochemistry staining did not correlate with stage of disease, patients in whom greater than 25% of their tissue cells stained positive for EGFR had a reduced survival and increased risk of locoregional failure. A second trial examined 75 patients with undifferentiated NPC56 and found EGFR expression in 83%. The patients with EGFR expression had more locally aggressive disease, but DFS and OS rates did not differ between the two groups. Given the finding of the high prevalence of EGFR expression, a phase II study of cetuximab (Erbitux, C-225), an intravenous immunoglobulin G1 monoclonal antibody that specifically targets the EGFR with high affinity and competitively inhibits endogenous ligand binding, combined with carboplatin for patients with metastatic or recurrent NPC was undertaken.57 Fifty-six of sixty patients had EGFR expression and were enrolled in the trial and demonstrated an overall response rate of 12%, and partial response or stable disease in 60%. This preliminary data supports EGFR is a viable target for further clinical trials. A phase II study of gefitinib, an orally active EGFR tyrosine kinase inhibitor, in metastatic or locoregionally recurrent NPC has recently been presented in abstract form.58 Preliminary data from their study confirms the tolerability of gefitinib, and while no responses were

M. Agulnik, J.B. Epstein documented, disease stabilization for greater than 6 months was seen in 2/11 (18%) of patients. Clearly the results are preliminary and final study results will be of interest. VEGF is an angiogenic growth factor that contributes to angiogenesis and is important in tumor growth, invasion and metastasis. Expression of VEGF has been assessed in tissue samples obtained from normal nasopharynx, benign tumors of the nasopharynx and NPC and the rates of VEGF expression were 10%, 40%, and 80% respectively.59 VEGF expression was statistically significantly increased in advanced disease compared with those having early stage NPC.59 A phase II study of sorafenib, a potent inhibitor of multiple receptor tyrosine kinases and serine-threonine kinases including Raf isoforms, VEGFR-2 and PDGFR-ß, in patients with recurrent or metastatic squamous cell carcinoma of the head and neck and NPC has shown a partial response in 1/23 and stable disease in 9/23 patients.60 Although, not specifically treating NPC alone, this study suggests that anti-VEGF therapy could serve as a potential target in future studies. A retrospective study of 49 patients with NPC assessed cellular expression of HER2 and c-KIT.61 C-KIT over-expression was found in 33% of the cases and was associated with positive EBV status (by in-situ hybridization) in patients with non-keratinizing or undifferentiated NPC. These cases show a trend towards higher survival. The potential therapeutic role for inhibitors of c-KIT such as imatinib mesylate remains unknown. In this same cohort of patients, HER2 over-expression was uniformly negative.61 This finding differs from a Hong Kong study of 78 Chinese patients with undifferentiated NPC62 where HER2 over-expression was seen in 31% of the patients and was associated with increased stage of disease. Also, a study of 45 cases of NPC from Southern China using immunohistochemical (IHC) and fluorescent in-situ hybridization (FISH) analyzes of HER2 found 33% of patients had HER2 expression on IHC staining, but these findings did not correlate with clinical outcome, and no significant alterations in gene copy number of HER2 were detected by FISH.63 At the present, no studies of HER2 inhibitors have been reported in NPC. A recent study assessed plasma EBV DNA concentrations in patients with advanced NPC.11 Ninety-nine patients were treated with neoadjuvant cisplatin and 5-FU on alternate weeks for 10 weeks followed by RT to a total of 70–74 Gy. EBV DNA concentrations in blood were assessed one day prior to beginning treatment, at days 35 and 64 during neoadjuvant chemotherapy, and one week after completing RT. At baseline, 94 of 99 patients with stage III and IV disease, and all patients with metastatic disease had detectable plasma EBV DNA. No healthy controls had detectable EBV DNA. In addition, EBV DNA concentrations were significantly higher in the group that subsequently relapsed compared with the group that remained in a clinical remission. Higher pretreatment EBV DNA corresponded to a decreased OS and DFS. This study suggests and EBV DNA quantification has potential to act as a marker to monitor and predict treatment outcomes in patients with advanced NPC. The association of EBV and NPC has lead to consideration of a role for immunotherapy. NPC cells express two distinct EBV latent membrane proteins, LMP-1 and LMP-2. These proteins may become targets for adoptive immunotherapy. A phase I study using EBV-specific cytotoxic T lymphocytes

Nasopharyngeal carcinoma (CTL) were generated and then infused in 10 patients. Four patients treated in remission remained disease-free 19–27 months after infusion. Of the patients with refractory disease, 2 had complete responses, 1 had a partial response, 1 had stable disease and 2 had no response.64 Except for the development of increased swelling at the site of preexisting disease in one patient, CTL appeared to be well tolerated. Further studies utilizing CTL appear indicated.

Oral and dental care The evolution of care for NPC will not change the need for oral/dental preventive care and ongoing considerations for care due to the need to continue utilizing radiation therapy for early stage and locally recurrent disease and in combination with chemotherapy for advanced disease and potential future advances as outlined above. The evolution of IMRT with increasing ability to reduce exposure to major salivary glands may reduce hyposalivation, the principle chronic complication of therapy. The use of altered fractionation RT and higher total doses of RT and re-irradiation suggest mucositis will continue to be a significant acute complication of therapy, with or without chemotherapy, and alveolar bone in the high dose fraction will be at increased risk of osteonecrosis. Trismus is unlikely to be reduced. The potential advantage of targeted therapies is improved cure rates, improved palliation, and less severe acute and chronic complications than those seen with combined radiation therapy and non-targeted chemotherapy, the current standard of care. Therefore, oral health care provides will continue to have important roles from detection of NPC, oral assessment and dental care prior to cancer therapy, and oral/dental care during and following cancer therapy. NPC may present first to the dental profession due to development of facial pain, a neck mass and restricted jaw movement resembling TMD. Recognition of the signs and symptoms of NPC are essential in order to lead to the correct diagnosis, and to avoid delay in diagnosis and treatment of the cancer. Differentiation between NPC and TMD may be facilitated by attention to other key symptoms of NPC, such as neck masses, nasal obstruction, unilateral hearing deficit and epistaxis. Enlarged lymph nodes are seen at diagnosis in 60% of patients with NPC and otitis media and hearing loss are present in nearly 50%.17,65 Less common signs and symptoms may mimic those of TMD, with limited jaw opening and pain. Diagnosis requires nasopharyngoscopy, imaging of suspicious lesions using computerized tomography (CT) and/or magnetic resonant imaging (MRI) and tissue diagnosis by biopsy. Once diagnosed, oral health care providers should thoroughly assess the patient, institute prevention programs to maintain oral health and manage the oral condition following therapy. Complications include candidiasis; taste alterations and nutritional compromise with weight loss, and dysphagia and trismus due to muscle fibrosis. The most devastating consequences are: hyposalivation with demineralization and tooth damage and post-radiation osteonecrosis (PRON). Treatment planning prior to radiation should be based upon a full dental, periodontal and radiographic assessment and treatment to establish a dentition that the patient may

625 maintain for their lifetime. This may include dental extractions of teeth with poor prognoses and preventive programs. Mucositis and candidiasis are common during RT and risk of candidiasis continues with hyposalivation. Infection risk is increased due to candida, cariogenic flora and periodontal disease. The use of dentures is more challenging, mucosal irritation and decreased healing of soft tissues may be altered in post-radiation mucosa. Topical fluoride gel and chlorhexidine rinses may be used to control cariogenic flora during and after radiation therapy. Fluoride carriers should be fabricated and are recommended for daily use as long as xerostomia persists. Use of remineralizing products may be beneficial, particularly in patients with hyposalivation. If compliance is poor with carriers, high fluoride (1.1% neutral Na F providing 0.5% fluoride ion) dentrifice may be brushed on the teeth, although equivalent effect on caries prevention is not proven. Prior to IMRT, all of the salivary glands, with the occasional exception of the most anterior portion of the floor of the mouth were irradiated and no significant return of salivary function in these patients. IMRT offers the potential for reduced exposure of the salivary glands, so that residual function can be stimulated following cancer therapy. The risk of PRON may be reduced in IMRT, as high RT dose to bone may be reduced, however, increased total dose and re-irradiation may result in sites of increased risk, and close communication with radiation therapy and oral health care providers are needed. Prevention of PRON requires expert dental review and treatment prior to cancer therapy, and patient compliance during and following treatment.

Conclusions Current evidence strongly supports a role for concomitant chemoradiotherapy followed by adjuvant chemotherapy in treating NPC. Concomitant chemoradiotherapy has shown statistically significant improvement in OS and DFS for all histological types of locally advanced NPC, and achieving 5-year OS rates of about 70% in patients with non-metastatic stage III and IV disease. IMRT and increasing total RT dose to the tumor has shown improved outcomes. IMRT has been associated with reduced xerostomia. Acute mucosal toxicity is increased with concomitant therapy. The addition of further neoadjuvant or adjuvant chemotherapy may cause reduction in locoregional and distant failures when delivered using validated regimens. Incorporation of newer, less toxic and more effective anticancer agents such as taxanes, cetuxmimab and gemcitabine or other molecular targeted agents in combined modality regimens are being assessed in locally advanced NPC. Exploration of the role of targeted agents such as inhibitors of EGFR, VEGF, c-KIT, and HER2 are necessary. Adoptive immunotherapy with EBV-specific cytotoxic T lymphocytes awaits further exploration. Certainly, the treatment strategies for NPC will continue to change and evolve as a better understanding is gained of the molecular and immune mechanisms that drive this disease. Collection of toxicity data, especially those related to mucositis, salivary function, swallowing functions, nutritional status, ototoxicity, neuropathy and other late side effects, are required in future studies.

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Conflicts of Interest Statement Drs. Silverman and Epstein are members of the Zila Medical Advisory Board. Dr. Bride is VP, Medical Affairs for Zila Pharmaceuticals.

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