Treatment
The median follow-up time was 24 (range, 1–124) months in all patients. Treatment characteristics of the study group are summarized in Table 2
Patients were not initially treated with surgery because (a) some were considered unresectable because of primary tumor invasion; (b) patients with early-stage disease preferred/selected organ-preserving treatment over surgery; and (c) surgery was unsuitable for some patients because of comorbidities, poor PS and/or old age.
Reasons for patients to not receive IACRT included (a) difficulty in using contrast medium because of renal or liver dysfunction or allergy (n = 4); (b) difficulty in placing/inserting catheters because of dementia or anticoagulant use (n = 7); and (c) advantage or preferability of using systemic chemotherapy because of co-morbidity (e.g., history of another carcinoma or tuberculosis, n = 6). One patient switched to systemic chemotherapy because she had a stroke after catheter placement.
Completion rates for treatment were IACRT: 90.9% and SCRT: 88.9%. Six IACRT patients (9.1%) and two SCRT patients (11.1%) discontinued RT because of complications/coexisting disease (such as infection, bleeding from gastrostomy, or delirium) or patients’ request.
Tumor control
Initial complete response (CR) rates were IACRT: n = 45 (68.2%), and SCRT: n = 7 (38.9%). In the IACRT group, 10 of 14 patients who had residual tumors had salvage therapy; of these 10 patients, three were considered to have CR after salvage therapy. In the SCRT group, four of 7 patients had salvage therapy, but none of them controlled the disease.
Among IACRT patients whose primary tumors were considered to have CR, four patients underwent neck lymph node dissections; three of these four patients had no evidence of malignancy in their neck lymph nodes. Three-year LC significantly differed between the IACRT group (77.17%, 95% confidence interval [CI]: 64.23–86.41) and the SCRT group (41.96%, 95% CI: 17.65–70.90, P = 0.015, Fig. 1–1). However, seven IACRT patients (10.6%) developed primary tumor recurrences, compared with zero SCRT patients; five IACRT patients (7.6%) developed cervical lymph node recurrences compared with only one SCRT patient (5.6%); and eight IACRT patients (12.1%) experienced distant metastases (lung metastases with or without other sites: n = 6, pleural dissemination or subcutaneous metastasis: n = 2) compared with four SCRT patients (22.2%; lung metastases: n = 3, liver metastases: n = 1). Lung metastasis rates were IACRT group: 9.1%, and SCRT group: 16.7%. Four IACRT patients who had salvage therapy after their recurrences were alive at the last follow-up.
Survival
At 3 years, the two groups significantly differed in OS (IACRT: 78.75%, 95% CI: 66.00–87.62; SCRT: 50.37%, 95% CI: 27.58–73.00; P = 0.039) and PFS (IACRT: 75.64%, 95% CI: 62.69–85.17; SCRT: 41.96%, 95% CI: 17.65–70.90; P = 0.028; Figs. 1–2, 1–3).
Among the 66 IACRT patients, 47 patients were alive, and 43 patients were considered to have had CR (median survival: 46 months, range: 7–124 months) as May 31, 2019. Of the 19 IACRT patients who died within 1–56 months after treatment, 16 died of cancer and three died of non-cancer-related causes.
In comparison, nine patients were alive in SCRT group, and only four of the 9 patients were considered to have CR (median follow-up time: was 84.5 months; range: 50–94 months). Nine patients died (6 of cancer and 3 of non-cancer-related causes) and 5 patients changed hospitals to receive palliative care. Neither group had any therapy-related mortality.
Analysis of prognostic factors
Univariate and multivariate analyses of factors associated with OS, PFS and LC are summarized in Tables 3 − 1 and 3 − 2. In univariate analysis, age ≥ 65 years, poorer performance status (PS), and SCRT treatment were significantly associated with worse OS (P = 0.003, P = 0.024, P = 0.047). Among patients aged ≥ 65 years, clinical stage IV, > T4, > N2b, and SCRT treatment were significantly associated with worse PFS and worse LC (P = 0.033, P = 0.029, P = 0.041, P = 0.004, P = 0.048). Prescribe dose > 60 Gy was significantly associate with favorable PFS (P = 0.038).
In multivariate analysis, age ≥ 65 years, clinical stage IV, and SCRT group were significantly correlated with poor OS (P = 0.022, P = 0.009, P = 0.041). Patients with poorer PS had significantly worse PFS (P = 0.032).
Toxicities
Table 4 shows therapy-related acute (≥ Grade 3) toxicities. The two groups significantly differed in ≥ Grade 3 leukopenia (P = 0.012), radiation dermatitis (P = 0.034), and dysphagia (P = 0.008). Interestingly, 22 IACRT patients had Grade 4 lymphopenia, but immediately recovered after treatment.
In both groups, osteoradionecrosis (mandibular: n = 13, maxillary: n = 2) was the most common late toxicity; it affected nine IACRT patients (n = 9, 13.6%, median: 32 months, range: 17–107 months) and five SCRT patients (n = 6, 33.3%, median 43 months, range: 3–16 months) (P = 0.081). One IACRT patient developed a pharyngeal fistula and required surgery (Grade 4). No SCRT patient developed any other late severe (≥ Grade 3) toxicity associated with treatment.