Between January 2005 and January 2019, 37 Asian patients were newly diagnosed with NPC at our institution. Of these, 27 patients received ACRT as part of their standard care. The remaining patients with early-stage NPC, distant metastasis, or impaired renal condition received radiotherapy only, CCRT, or palliative treatments. Patients were staged according to the TNM classification by the Union for International Cancer Control (UICC) staging system. The exclusion criteria were patients with histological proof of T1, N0, M0 carcinoma of the nasopharynx. The following pretreatment clinical data were evaluated in all patients: medical history; physical examination findings; laryngoscopy and esophagoscopy results; and diagnostic imaging results (Computed Tomography [CT], Magnetic Resonance Imaging [MRI], and/or F-fluorodeoxy Glucose Positron Emission Tomography [FDG-PET]). Since FDG-PET became available after November 2005 at our institution, four patients who began treatment prior to November 2005 did not undergo FDG-PET scans for initial staging.

All 37 patients were evaluated by head and neck surgeons and radiation oncologists before treatment initiation. The study protocol was approved by the Institutional Review Board of our institution (approval number 20054), and all patients provided written informed consent before initiation of treatment. This study was conducted in accordance with the tenets of the Declaration of Helsinki.

ACRT was administered based on a modification of the original method by Fuwa et al.,7 which was published in 2007 (Fig. 1). Briefly, a course of chemotherapy was performed in three cycles (one week per cycle). Between each chemotherapy cycle, patients were administered two courses of radiotherapy. The interval between chemotherapy and radiotherapy was two or three days.

Figure 1.

Study design of alternating chemoradiotherapy. During the course of chemotherapy (one-week period; three cycles), patients were irradiated at 2- or 3-day intervals of chemotherapy. 5-fluorouracil (5-FU) (800mg/m2/day) was intravenously administered continuously for 24h from days 1 to 5. Cisplatin (50mg/m2/day) was intravenously administered continuously for 24h from days 6 to 7. The same chemotherapy regimen was used in all three cycles of chemotherapy. Radiotherapy was delivered to the nasopharynx and whole neck, at 1.8–2Gy/fraction, 5 fractions/week, until a dose of 50Gy. Subsequent radiotherapy was delivered to the primary region and the remaining lymph nodes. The total dose during the study period was 68.4–73.4Gy in 35–40 fractions.

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Regarding the chemotherapy protocol, patients were continuosuly intravenously administered 5-FU at a dose of 800mg/m2/day for 5 days (day 1–5) and then Cisplatin (CDDP) at a dose of 50mg/m2/day for 2 days (day 6–7). The total doses of 5-FU and CDDP during three cycle of chemotherapy were 12,000mg/m2 and 300mg/m2, respectively.

Regarding radiotherapy, the first 19 patients were treated with fixed multiport irradiation at an irradiation dosage of 68.4–73.4Gy in 36–40 fractions until June 2014. Between June 2014 and January 2015, three patients were treated with a combination of fixed multiport irradiation and Intensity-Modulated Radiation Therapy (IMRT) at an irradiation dosage of 70.4–72.4Gy in 38–39 fractions. After March 2015, five patients were treated with IMRT at an irradiation dosage of 70Gy in 35 fractions. The initial irradiation field overlapping first and second radiotherapy courses was the whole neck from the skull base to the supraclavicular fossa at an irradiation dosage of 50Gy, with a rest period of 2 weeks, during which patients underwent the second chemotherapy cycle. Subsequently, a shrinking irradiation field was used, which was administered to the primary lesion and the lymph nodes. The total dose for the entire radiotherapy was 68.4–73.4Gy in 35–40 fractions.

Pharyngeal endoscopic examination during and after treatment was used to evaluate the anti-tumor effects of ACRT. We primarily focused on the results of FDG-PET scans performed three months after the completion of ACRT. The assessments of response were also performed using MRI, CT, or palpation. Tumor response rate was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST).8 All adverse events encountered during therapy were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE; version 5.0).

We analyzed Epstein-Barr Virus (EBV)-DNA in plasma specimens of the 27 patients before and three months after ACRT. Histological samples were examined to determine whether cancer cells were positive for EB-encoded small RNA 1 (EBER).

All procedures performed in this studies involving human participants follows the 1964 Helsinki declaration and its later amendments or comparable ethical standards. We obtained written informed consent from all individual participants included in the study.

All statistical analyses were performed using GraphPad Prism version 9 (GraphPad Software, San Diego, CA, USA). Overall Survival (OS) and Progression-Free Survival (PFS) were calculated using the Kaplan-Meier method and compared using the log-rank test.

The characteristics of the 27 patients who received ACRT and 10 patients who did not receive ACRT are shown in Table 1 and Supplemental Table 1, respectively. Of the 27 patients who underwent ACRT, 21 were men and six were women. The patients’ ages ranged from 22 to 74 years (median, 57 years). Histological examination revealed that 23 and 4 cases of NPC were non-keratinizing and keratinizing subtypes, respectively. In addition, EBER in situ hybridization was positive in 17/25 cases (68%). Two patients were not assessed for EBER status because EBER status evaluation did not become available at our institution until after 2007. Of the 27 patients who received ACRT, 5, 13, 8, and 1 patient(s) were staged as II, III, IVA, and IVB, respectively (Tables 1 and 2).

Of the 27 patients, 25 (93%) completed the ACRT regimen as planned without interruption. One patient could not complete the third chemotherapy cycle, and the other patient received a 50% reduced dose of the third chemotherapy cycle, both due to renal failure.

The occurrence and incidence of hematological and non-hematological toxic events associated with ACRT are shown in Table 3. No treatment-related deaths occurred. Grade 3–4 hematologic adverse events were observed in 62% of patients. Grade 3–4 mucositis was observed in 70% of patients. No grade 3–4 renal toxicities were observed.

Three months after ACRT completion, all patients achieved complete responses at the primary site. The plasma EBV-DNA viral load in detectable 13 patients decreased to undetectable levels (Fig. 2).

Figure 2.

Plasma EBV-DNA level before and after ACRT. (a) Plasma EBV-DNA before ACRT, (b) Plasma EBV-DNA three months after ACRT. Measurable EBV-DNA were detected in 13 of 27 cases. All 13 cases showed a decrease in EBV-DNA three months after ACRT.

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Although neck dissection surgeries were performed after ACRT in two patients, pathological examination revealed no viable tumor cells in either case.

As of February 2021, 21 of the 27 patients were alive, and all 21 living patients were tumor-free. One patient developed recurrence at the primary site, and two patients developed distant metastases (lung or liver). Three patients died of other causes, comprising pneumonia, arrhythmia, and amyotrophic lateral sclerosis.

A summary of the clinical factors affecting survival rates is presented in Table 4. Only clinical stage IV was associated with a poor 5-year OS, and the 5-year PFS rate was comparable in all groups. The OS and PFS times in each stage treated with ACRT are shown in Fig. 3. The 5-year OS and PFS rates were 83.7% and 88.9%, respectively.

Figure 3.

Kaplan Meier plot of overall survival and progression-free survival for patients in each stage. The 5-year OS (a) and PFS (b) of nasopharyngeal patients treated with ACRT are shown. The 5-year OS and PFS rates were 83.7% and 88.9%, respectively.

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