Introduction

Nasopharyngeal carcinoma is a highly aggressive tumor with a tendency to invade the adjacent nasal cavity and paranasal sinus, skull base, and foramina, and spread early to the cervical lymphatics. The undifferentiated type of nasopharyngeal carcinoma, which is the predominant histological type in endemic regions, also has a high risk of distant metastases compared with other head and neck cancers. As a result, surgery has a limited role in the treatment of newly diagnosed nasopharyngeal carcinoma, and radiotherapy with or without chemotherapy is the usual treatment for this disease. In patients with locoregional recurrence, salvage surgery may be feasible, especially in those with disease confined to the nasopharynx and/or neck. Reirradiation using different techniques should be considered in patients that are not candidates for surgery. In advanced recurrence and distant metastases, palliative chemotherapy can often achieve durable control of symptoms and disease control. Occasional long-term survivors have been reported after aggressive systemic chemotherapy.

Radiotherapy

Radiotherapy is the mainstay of treatment for locoregionally confined nasopharyngeal carcinoma. The outcome of patients who received radiotherapy for nasopharyngeal carcinoma has improved significantly in the past four decades, from a gloomy 5-year survival rate of 25% in the 1950s,1 to 50% in the 1970s to 1980s,2 and to 75% in the 1990s.3 The improvement of outcome can be attributed to earlier disease at presentation, introduction of new and advanced imaging techniques, improved radiotherapy techniques, and the use of combined chemoradiotherapy.

Intensity-Modulated Radiotherapy

One major advance in radiotherapy of nasopharyngeal carcinoma during the 2000s was the advent of intensity-modulated radiotherapy (IMRT). IMRT is a complicated technique that allows the delivery of a dose distribution closely conformed to the target and critical structures through optimization of the intensity of multiple beams. The treatment design is based on the computer algorithm to calculate the best result that matches the user-defined parameters in a process called inverse planning. An advantage of IMRT is the ability to deliver highly conformal radiotherapy to an irregular target, such as the generation of a concave or U-shaped dose distribution, which is very useful if the target volume wraps around critical structures such as the brainstem and spinal cord, as in the case of nasopharyngeal carcinoma (Fig. 25.2); other advantages include the ability to treat primary and regional lymphatic in one volume, and the ability to deliver simultaneous integrated boost in the same setting. IMRT is ideal for treatment of nasopharyngeal carcinoma with the potential of improving dose distribution and therapeutic ratio. IMRT has already achieved excellent local control rates for newly diagnosed nasopharyngeal carcinoma, with a reported local control rate of 92 to 97% at 3 to 4 years.7,8 Apart from improvement of tumor control, IMRT also reduces the risk of late complications such as xerostomia in early-stage disease.9

Combined Chemoradiotherapy

Combining chemotherapy and radiotherapy has many theoretical advantages in the treatment of nasopharyngeal carcinoma; this malignancy has a high incidence of distant metastases, which constitute the major cause of treatment failure and death, and chemotherapy is needed to address this issue. Local failure still constitutes another important cause of failure in advanced T stage despite improvement in outcome with modern radiotherapy, and the use of chemotherapy may allow rapid shrinkage of the tumor to facilitate radiotherapy. Some recurrent and metastatic disease has shown good response to chemotherapy, with occasional observation of long-term survivors, suggestive that the disease is highly chemosensitive. Unlike patients with other head and neck cancers, most patients with nasopharyngeal carcinoma are younger with good performance status and absence of comorbidities, and hence they should tolerate chemoradiotherapy better.

Randomized Trials

Many randomized trials have been conducted to explore the benefits of combined chemoradiotherapy in nasopharyngeal carcinoma. Most studies employed cisplatin-based regimens and the main difference has been the timing of chemotherapy in relation to radiotherapy: before (induction), during (concurrent), or after (adjuvant) radiotherapy.

Four randomized phase III studies have been reported comparing induction chemotherapy followed by radiotherapy versus radiotherapy alone in nasopharyngeal carcinoma.10–13 None of these studies has demonstrated survival benefits after adding chemotherapy to radiotherapy. Two of these studies were recently updated and the data pooled for analysis; although significant improvement in disease-free survival in the chemotherapy arm was observed, overall survival was not improved.14 Only two adjuvant chemotherapy phase III studies have been reported, and both showed no survival benefits.15,16 The adjuvant chemotherapy trials had limitations since nonplatinum chemotherapy was used in one study and chemotherapy compliance was rather poor in the other study. These studies showed that induction chemotherapy alone has a limited role in nasopharyngeal carcinoma, whereas the role of adjuvant chemotherapy remains undefined.

In recent years, concurrent chemoradiotherapy has emerged as the treatment of choice for locoregionally advanced nasopharyngeal carcinoma, largely due to the positive findings of the Intergroup 0099 trial, which was the first randomized trial to demonstrate survival benefit with the use of chemotherapy in nasopharyngeal carcinoma.17 The Intergroup trial employed both concurrent and adjuvant chemotherapy in the study arm and reported an absolute improvement of survival of 31% (i.e. from 47% to 78%) at 3 years. The Intergroup study, however, has a high proportion of patients with WHO type I histology and a relatively poor outcome in the radiotherapyalone arm. Thus there were initially some concerns in extrapolating the findings of the Intergroup study to patient groups in the Asian context where the disease is endemic and the majority of patients have undifferentiated carcinoma, WHO type III histology.

Subsequent randomized trials conducted in endemic regions have largely confirmed the benefits of concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma, although different regimens and schedules were being employed in these studies.18–21 Interestingly, only one study employed the same chemotherapy regimens used in the Intergroup study, but the final report from that study showed no survival benefits, although there was improvement in failure-free survival and progression-free survival.22 Nevertheless, current evidence indicates that concurrent chemoradiotherapy may have a role in advanced-stage nasopharyngeal carcinoma, but the optimal regimen and schedule remain to be defined. The design of most chemotherapy trials that employed both concurrent and adjuvant chemotherapy does not allow the role of adjuvant treatment to be separately defined, but one common observation in these trials was the low compliance rate of adjuvant chemotherapy, especially when given after concurrent chemoradiotherapy. On the other hand, it may be easier to combine induction with concurrent chemotherapy with the added benefit of rapid tumor shrinkage prior to radiotherapy, and preliminary reports showed that excellent control can be achieved using this approach in advanced T stage tumors.23 Based on current evidence, chemoradiotherapy should be given to all patients with nodal disease and/or T3–4 disease, whereas radiotherapy alone should be reserved for those with T1–2 N0 disease. Following this treatment concept, the overall survival of patients with early and advanced-stage disease has been reported to be 96% and 62%, respectively (Table 25.1).24