Combined-Modality Therapy With Chemotherapy and Radiation Therapy

High-dose radiation therapy alone has a role in managing nasopharyngeal carcinoma. However, studies (in both children and adults) show that combined-modality therapy with chemotherapy and radiation is the most effective way to treat nasopharyngeal carcinoma.[2]

Multiple studies have investigated the role of chemotherapy in the treatment of adult patients with nasopharyngeal carcinoma. The use of concomitant chemoradiation therapy has been consistently associated with a significant survival benefit, including improved locoregional disease control and reduction in distant metastases.[2] The addition of neoadjuvant or adjuvant chemotherapy to concomitant chemoradiation has further improved outcomes. The Meta-Analysis of Chemotherapy in Nasopharyngeal Carcinoma (MAC-NPC) collaborative group presented an analysis of 26 trials that included 7,080 patients. The results showed that the addition of chemotherapy to radiation therapy reduced the risk of death, and that the hazard ratio (HR) for risk of death was lowest for adjuvant or neoadjuvant chemotherapy combined with concurrent chemoradiation therapy, compared with concurrent chemoradiation therapy alone.[3]

In adult patients, recent studies investigated the use of neoadjuvant gemcitabine and cisplatin. A phase III study compared concurrent chemoradiation therapy with or without induction therapy using gemcitabine plus cisplatin for patients with locally advanced nasopharyngeal carcinoma. The study found a significant improvement in overall survival (OS) for patients who received induction chemotherapy with gemcitabine plus cisplatin, compared with those who did not receive induction chemotherapy (5-year OS rates, 87.9% vs. 78.8%; HR, 0.51; 95% confidence interval, 0.34–0.78; P = .001).[4,5]

In children, most studies have used neoadjuvant chemotherapy with cisplatin and fluorouracil (5-FU) followed by concomitant chemoradiation with single-agent cisplatin.[6-8][Level of evidence B4]; [9] Using this approach, 5-year OS rate estimates are consistently above 80%.[7-9] The following two modifications of this approach have been investigated:

For adults with nasopharyngeal carcinoma, gemcitabine plus cisplatin has been shown to be more effective than 5-FU plus cisplatin, both in front-line and recurrent settings.[10,11]

While nasopharyngeal carcinoma is a very chemosensitive neoplasm, high radiation doses to the nasopharynx and neck (approximately 65–70 Gy) are required for optimal locoregional control.[12-14] However, in children, studies using neoadjuvant chemotherapy have shown that it is possible to reduce the radiation dose to 55 Gy or 60 Gy for good-responding patients.[6,7,15] The GPOH reviewed 45 patients enrolled in the NPC-2003 study and an additional 21 patients who were subsequently treated per the NPC-2003 trial.[16] The 66 patients with locoregionally advanced nasopharyngeal carcinoma had an event-free survival (EFS) rate of 93.6% and an OS rate of 96.7% after a median follow-up of 73 months. Seven patients who had complete responses after induction therapy received a reduced radiation dose of 54 Gy. None of these patients experienced a relapse. In young patients with advanced locoregional nasopharyngeal carcinoma, excellent long-term survival rates can be achieved using multimodal treatment, including interferon-beta. Radiation doses may be reduced in patients with complete remission after induction chemotherapy. Reduced radiation doses may limit late effects related to radiation exposure.

The Children's Oncology Group performed a prospective trial to evaluate the impact of induction chemotherapy and concurrent chemoradiation therapy.[9] Patients were scheduled to receive three cycles of induction chemotherapy with cisplatin and 5-FU, followed by chemoradiation therapy with three cycles of cisplatin. Patients with complete or partial responses to induction chemotherapy received 61.2 Gy of radiation to the nasopharynx and neck, and patients with stable disease received 71.2 Gy of radiation. After a feasibility analysis, the study was amended to reduce cisplatin to two cycles during chemoradiation therapy. Results of the study include the following:

The combination of cisplatin-based chemotherapy and high doses of radiation therapy to the nasopharynx and neck are associated with a high probability of hearing loss, hypothyroidism and panhypopituitarism, trismus, xerostomia, dental problems, and chronic sinusitis or otitis.[6,17,18]; [19][Level of evidence C1] The use of proton radiation therapy may reduce the toxicity to the brain and skull base region without compromising disease control.[20] For more information, see Late Effects of Treatment for Childhood Cancer.

In a group of 549 pediatric patients with nasopharyngeal carcinoma diagnosed between 2005 and 2021, recursive partitioning (i.e., successive grouping) was performed based on stage and Epstein-Barr virus (EBV) viral load. This resulted in three groups of patients: low-risk patients, intermediate-risk patients, and high-risk patients.[21]