Chemotherapy in Advanced Nasopharyngeal Cancer

In contrast to many other cancers of the head and neck, patients with nasopharyngeal carcinoma tend to be younger and have few, if any, comorbidities. In other words, if cured of nasopharyngeal carcinoma, these individuals live long and productive lives. Therefore, the treatment of nasopharyngeal carcinoma, while challenging, can be particularly rewarding for the oncologist.

For years, nasopharyngeal carcinoma was treated almost exclusively by radiotherapy, but, in recent years, che-motherapy has assumed an important role in its management, as detailed by Drs. Ali and Al-Sarraf. However, not all patients with nasopharyngeal carcinoma require chemotherapy. The question is: In which patients do the benefits of chemotherapy outweigh its toxicity?

M1 Disease

Patients with systemic metastases are candidates for chemotherapy. However, Drs. Ali and Al-Sarraf are perhaps too optimistic about the number of these patients cured with present-day therapy, because, by and large, systemic metastases still represent a death sentence. Improved systemic therapy is clearly necessary, and every patient with metastatic disease should be encouraged to enter a clinical trial.

In their article, Drs. Ali and Al-Sarraf consider patients with metastatic disease and those with locally recurrent disease as belonging to the same category—an approach that may not be appropriate in nasopharyngeal carcinoma. Some patients with locally recurrent disease may indeed be cured by further therapy, but there is no such thing as “standard” therapy in this population; treatment requires a great deal of individualization and may include brachytherapy, stereotactic radiotherapy, surgery, and/or chemotherapy.

Bulky Cervical Nodal Metastases

With contemporary radiotherapy, persistence or recurrence of cancer in the neck has become uncommon in nasopharyngeal carcinoma,[1-3] yet patients with advanced neck disease do remain at relatively high risk for developing distant metastases.[4]

The prospective, randomized Intergroup study 0099[2] enrolled 147 assessable patients with nasopharyngeal carcinoma, almost all of whom had stage IV (but M0) disease, and two-thirds of whom had N2 or N3 disease. Results showed a survival benefit from the addition of concomitant and adjuvant chemotherapy. Notably, the site of recurrence was “distant only” in 14 of 69 patients after radiotherapy alone vs 7 of 78 patients after combined therapy. Therefore, cisplatin(Drug information on cisplatin) (Platinol) and fluorouracil(Drug information on fluorouracil), as administered in Intergroup study 0099, are clearly worthwhile for such patients.

Advanced Primary Tumors

Intergroup study 0099[2] began in 1989, with external-beam radiotherapy in doses up to only 70 Gy. The failure rate at the primary site was 33% without chemotherapy—very similar to the 29% reported by M. D. Anderson Cancer Center after similar doses of external-beam radiotherapy alone.[3]

Improvements in technology notwithstanding, most radiation oncologists still do not believe that doses greater than approximately 70 Gy can be safely delivered to the nasopharynx by external beam alone. This opinion stems from the risk of injury to such critical structures as the optic chiasm, brainstem, and temporal lobes of the brain.

However, during the 1990s, several reports from North America,[5-7] Europe,[8] and Asia[9] were published, suggesting that doses considerably higher than 70 Gy could be safely delivered to the nasopharynx by adding brachytherapy. This strategy produced very high rates of local control, exceeding 90%. Brachytherapy was delivered by the permanent interstitial implantation of iodine-125,[6] the temporary low–dose-rate intracavitary implantation of cesium-137,[7] or the temporary high–dose-rate intracavitary implantation of iridium-192.[8,9] Each of these techniques appears to be safe and effective, and, in the absence of controlled studies, the choice is dictated by available expertise and resources.

In addition, Intergroup study 0099 showed a marked improvement in local control when concomitant and adjuvant chemotherapy were added to external-beam radiotherapy. “Local only” failures occurred in 12 of 69 patients after radiotherapy vs 3 of 78 patients after combined therapy. “Local and other” failures occurred in 23 of 69 patients after radiotherapy vs 8 of 78 patients after combined therapy. Thus, cisplatin and fluorouracil, as administered in Intergroup study 0099, improved tumor control at the primary site, albeit when added to what today would be regarded as a suboptimal dose of radiotherapy.

Conclusions

Only further research will determine whether chemotherapy will benefit or harm patients who receive external-beam radiotherapy plus brachytherapy (or whether brachytherapy will benefit or harm those who receive external-beam radiotherapy plus chemotherapy). In the interim, it is reasonable to administer chemotherapy as per Intergroup study 0099 to those with bulky nodal disease and, perhaps, also to those with T4 primary cancer.