Chemotherapy in Advanced Nasopharyngeal Cancer

Many controversies surround the management of advanced nasopharyngeal cancer, with most debates focusing on the role of chemotherapy. The advanced nasopharyngeal tumor is particularly chemosensitive and has a higher incidence of distant spread than other squamous cell carcinomas of the head and neck. It is, therefore, logical to consider adding chemotherapy to radiotherapy when dealing with advanced-stage disease.

Most controversies in treating this disease stem partly from fundamental differences between the East and West. These differences are reflected, for example, in the ethnic composition of the patient populations, the histologic types seen, the staging systems and radiotherapy techniques used, and perhaps even in prevailing treatment philosophies. Paradoxically, despite the higher incidence of advanced nasopharyngeal cancer in the East, as well as the vast amount of experience that Eastern clinicians have reaped in the management of this disease, most published randomized studies have been conducted in the West.

The article by Drs. Ali and Al-Sarraf in this issue of Oncology is a timely and comprehensive review of the role of chemotherapy in the treatment of advanced nasopharyngeal cancer. The authors offer a critical review of published reports on advanced nasopharyngeal cancer from both the East and the West, concluding that chemotherapy is beneficial in the treatment of advanced locoregional disease, at initial presentation, as well as at subsequent recurrence and in metastatic disease.

The authors also emphasize two important points: First, they identify prognostic factors that may influence the response rate to chemotherapy and impact on survival. Second, they cite reports showing that patients receiving adjuvant chemotherapy should have a sufficiently long follow-up, since most differences in survival are observed after 3 years.

Advanced Nasopharyngeal Cancer: East vs West

One fundamental East/West difference is the distribution of histologic types. Between 40% and 80% of most Western series of advanced nasopharyngeal cancer cases have a World Health Organization (WHO) grade I histology, whereas the majority of Eastern series are primarily WHO grade II/III. Key differences between grade I and grade II/III histologies include etiology, association with Epstein-Barr virus, response to therapy, and patterns of failure.

Among the four prospective, randomized trials of adjunctive cisplatin(Drug information on cisplatin) (Platinol)-based chemotherapy in advanced nasopharyngeal cancer, the three trials that failed to demonstrate overall survival benefits included only patients with grade II/III histologies.[1-3] The one study that reported survival benefits included patients with histologic grades I, II, and III.[4]

Exactly how these diverse inclusion criteria affected outcome is unclear. However, one should bear in mind that advanced nasopharyngeal cancer, as referred to in different studies, might comprise different histologic types with different behaviors.

Even the so-called advanced-stage nasopharyngeal cancers with grade II/III histology actually represent a heterogeneous group of tumors with different failure patterns. Between 20% and 25% of these patients have advanced T-stage but early N-stage disease, whereas between 25% and 30% have an early T stage but advanced N stage (manuscript in preparation).[5]

In patients with an early N stage, the main cause of failure is local, and distant metastasis is not an immediate threat. However, in patients with an advanced N stage (as defined by a bulky neck node or low cervical node), failure is mainly attributed to distant metastasis, while local failure is not a major concern.

Disease in which failure is due to distant metastasis is referred to as the “infiltrative type,” whereas disease ending in local failure is known as the “disseminated type.” Clearly, different strategies are needed for these two subtypes.

For the disseminated type, chemotherapy is a logical approach to improving treatment outcome. On the other hand, advances in radiation treatment alone (including modern imaging for better target delineation, dose escalation with conformal radiotherapy, stereotactic radiosurgery, and altered fractionation treatment) might be able to improve treatment outcome in the infiltrative type. Many retrospective studies of adjunctive chemotherapy had neglected the contribution of advances in radiotherapy, which may represent a significant confounding factor.

Adjunctive Chemotherapy

Only three large randomized studies have tested cisplatin-based chemotherapy in advanced nasopharyngeal cancer. Both the International Nasopharynx Cancer Study Group[2] and the Asian-Oceanian Clinical Oncology Association[3] adopted the strategy of induction chemotherapy—and both failed to demonstrate any gains in overall survival. (The benefits of induction chemotherapy shown in retrospective studies should always be interpreted with caution in light of inherent study limitations and biases.)

The only one of these three randomized studies that did show a significant survival benefit was the Intergroup 0099 study,[4] which tested the role of concomitant chemoradiotherapy followed by adjuvant chemotherapy in the management of advanced nasopharyngeal cancer. This important study had a significant impact on the treatment of this disease—in fact, most Western cancer centers have adopted this strategy as standard therapy.

Various concerns regarding the application of these results to Eastern populations stem from ethnic and histologic differences between the two cultures. Another consideration is the fact that, compared with most Eastern studies, outcome in the control arm of the Intergroup study was much worse. Ongoing, prospective studies in the East are testing the role of concomitant chemotherapy with or without adjuvant chemotherapy, and should help resolve the controversy.[6,7]

Chemotherapy for Recurrent vs Metastatic Disease

Although Drs. Ali and Al-Sarraf quote a 15% to 20% long-term survival rate after treatment with chemotherapy for recurrent/metastatic disease, the prognosis and treatment options for patients with locoregional recurrence and distant metastases are very different, and should perhaps be addressed separately.

For locoregional recurrences, treatment options other than chemotherapy include surgery, brachytherapy, reirradiation, and more recently, stereotactic radiosurgery and photodynamic therapy. In selected patients amenable to surgery, a long-term survival rate of approximately 43% has been reported.[8]

Although patients who undergo reirradiation for locally recurrent disease generally represent those with more advanced disease (and are therefore not suitable for other options, such as surgery and brachytherapy), long-term survival rates of 17% to 36% are nevertheless reported.[9-11] Because locoregional recurrence is a potential source of distant spread,[12] it would be logical to test whether combining chemotherapy with surgery and/or brachytherapy would enhance locoregional control and improve survival.

For distant metastases, the well-shared occasional observations of long-term remission after chemotherapy are limited to only a small number of patients, and the chance of cure for most of these patients is still remote. Even with an aggressive regimen, such as CAPABLE (cyclophosphamide, Adriamycin [doxorubicin], Platinol [cisplatin], amethopterin [methotrexate], and bleomycin(Drug information on bleomycin)), the complete response rate is only 6.8%, with a median survival of 14 months.[13]

Teo et al reviewed the outcomes of 247 patients who developed distant metastases after primary radiotherapy and found that only 6.9% of patients survived more than 2 years.[14] In this report, factors that predicted long-term survival included young age at first presentation, absence of locoregional recurrence, metastases confined to intrathoracic sites, use of aggressive multimodal salvage therapies (including chemotherapy, radiotherapy, and/or surgery), and complete response to salvage treatments. These investigators also found that complete response to multimodal treatments was a prerequisite to long-term survival, with partial response carrying no chance of cure. In a similar population, Cheng et al reported a 2-year survival rate of 80% for surgical resection of pulmonary metastases in selected patients, with or without additional chemotherapy and/or radiotherapy.[15]

Clearly, chemotherapy should play an important role in the management of metastatic disease. However, the majority of patients with distant metastases would probably not benefit, in terms of survival gains, from the use of chemotherapy alone. Future studies should try to identify the subset of patients who may benefit in terms of survival from multimodal treatment, and then evaluate the impact of treatment on quality of life—a particularly important aspect of treatments that are mostly palliative in nature.

Conclusions

Is there a widely accepted treatment for advanced nasopharyngeal cancer that is based on experience from both sides of the world? The answer is no, because the disease is rare in the West, and ethnic and histologic differences between the populations pose distinct treatment challenges.

Based on the findings of the Intergroup study, it is reasonable to treat locoregionally advanced nasopharyngeal cancer in Western populations using cisplatin-based chemotherapy concomitant with conventional radiotherapy followed by adjuvant chemotherapy. It must be emphasized that concomitant chemoradiotherapy and induction chemotherapy are different strategies and that the benefits achieved with one therapy cannot be extrapolated to the other.

In the East, where this disease presents primarily as WHO grade II/III, it is reasonable to continue using radiotherapy alone for the management of the infiltrative type of advanced nasopharyngeal cancer, if one employs an aggressive radiotherapy protocol and if vigorous salvage treatments are available.

For the management of patients with a high risk of distant failure, it is still unclear whether overall survival can be improved by the addition of chemotherapy. It is, however, imperative that randomized trials continue to address the role of systemic treatment.

When managing locoregional recurrence, regardless of histologic type, it is important to select patients who can be adequately treated by other curative salvage treatments (with or without chemotherapy as part of a multimodal treatment) before resorting to chemotherapy alone. For locoregional recurrences that are clearly beyond salvage, and for distant metastases, it is reasonable to offer cisplatin-based chemotherapy after associated morbidities have been discussed with the patient.

Patients who choose chemotherapy should be monitored closely. Prolonged cycles of treatment should be administered only to patients who initially achieve a partial response, and subsequently, a complete response.