The Ethics Review Board of our institution approved this study (IRB-022-0028). Written informed consent for treatment was obtained from all enrolled patients. We reviewed the medical records of patients who started radical CRT for LA-HNSCC between July 2006 and October 2022. The inclusion criteria were as follows; aged ≥ 70 years, CRT using weekly CDDP + RT, and cancer in the oropharynx, hypopharynx, or larynx with a clinical stage of 3 or 4 without distant metastases based on the Union for International Cancer Control (UICC) staging system (8th edition). Finally, 49 patients were included (Table 1). Patients were deemed refractory to standard 3-weekly CDDP + RT at a multidisciplinary conference attended by all medical professionals involved in the practice. Although there were no absolute criteria for the indication of chemotherapy, we considered the following factors: the patient’s general condition, organ function, and complications in each case. The enrolled older patients predominantly had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≥ 1 at the initial visit. Patients who underwent lymph node dissection prior to CRT and those who switched to weekly CBDCA therapy during treatment were also included in the analysis.

If the patient had no allergies or other contraindications to the procedure, contrast-enhanced computed tomography (CT) was used for the planning CT. Enhanced or unenhanced magnetic resonance imaging (MRI) was used to assess the extent of the primary tumor or lymph node metastasis. The general contour procedure was as follows: the gross tumor volume (GTV) was contoured as the primary tumor, and lymph node involvement was determined using available imaging modalities, including CT, MRI, and positron emission tomography (PET). Clinical target volume 1 (CTV1) was created with a 5 mm margin added to the GTV. CTV1 was modified for areas of overlap with the air, bone, or outside the body. CTV2 was generated as a high-risk region with a potential tumor but without CTV1. CTV3 was also generated as a moderate- or low-risk region that included the entire neck, except for CTV1 and CTV2. For X-ray radiotherapy, planning target volume 1 (PTV1) was generated by adding a margin of 3–5 mm to CTV1. PTV2 was generated by adding a margin of 3–5 mm to CTV2, excluding PTV1 for more strict dose delivery to PTV2. Similarly, PTV3 was generated as CTV3 with a 3–5 mm margin, excluding both PTV1 and PTV2.

The planned dose prescription was 70 Gy in 35 fractions for all study patients. In 3-dimensional conformal radiotherapy, 44–46 Gy was prescribed to the whole neck region, including the GTV, followed by a boost of 24–26 Gy using an X-ray or electron beam to the tumor and lymph node metastases. In intensity-modulated radiotherapy (IMRT), doses were prescribed for at least 95% of the PTV (PTV D95). In IMRT using the simultaneous integrated boost method, 70 Gy was prescribed to PTV1; 56–63 Gy and 50.4–56 Gy were prescribed to PTV2 and PTV3, respectively. In IMRT using the sequential boost method, 44–46 Gy was prescribed to all regions of PTV1, PTV2, and PTV3, then 24–26 Gy was prescribed to the reduced region, including the original GTV. In proton beam therapy using the intensity-modulated proton beam therapy (IMPT) technique, doses similar to those used in IMRT were prescribed for 99% volume of each CTV, assuming a relative biological effectiveness of 1.1. Robust optimization was used to prescribe the assumption of setup uncertainties of 3 mm and range uncertainties of 3.5%.

In photon radiotherapy, XiO (Elekta AB, Stockholm, Sweden), Pinnacle3 (Philips, Amsterdam, The Netherlands), or RayStation (RaySearch Laboratories AB, Stockholm, Sweden) were used as treatment planning systems. For the linear accelerator (LINAC), radiotherapy with a 6- or 10-mega voltage X-ray was delivered using Varian CL2300 (Varian Medical Systems, Palo Alto, CA), MHCL-15SPLINAC (Mitsubishi Electronics Co., Ltd., Tokyo), Varian CLINIC iX (Varian Medical Systems), or TrueBeam (Varian Medical Systems). In proton beam therapy with PROBEAT-RT (Hitachi, Ltd., Tokyo, Japan), VQA (Hitachi) was used for treatment planning.

All patients received at least one cycle of concurrent chemotherapy during CRT. CDDP was administered weekly at 40 mg/m2 in 45 patients (91.8%). Other regimens administered 34, 30, and 20 mg/m2 of weekly CDDP. The cisplatin dose was adjusted based on the age and general condition of the patients. In three patients, the weekly cisplatin regimen was changed to a weekly carboplatin regimen. In two of them, the replacement was due to deterioration in renal function during CRT, while in the third patient, it was due to difficulty with hydration prior to CDDP administration. In the multivariate analysis, the cut-off dose of CDDP was defined as 200 mg/m2, according to previous reports [8,9,10].

After CRT completion, patients were evaluated every 1–3 months during the first year, 3–4 months during the second and third years, and every 6–12 months after that, depending on the patient’s status. A laryngoscopy was performed at each follow-up visit. Computed tomography or magnetic resonance imaging studies were performed every 3 months during the first year and at most follow-up visits thereafter. Adverse events were assessed for grade 3 or higher hematologic and non-hematologic toxicities according to the Common Terminology Criteria for adverse events version 5.0 (CTCAE v5.0).

The primary endpoint of the study was the 3-year overall survival (OS). The secondary endpoints were the 3-year progression-free survival (PFS) and 3-year cause-specific survival (CSS). The OS, PFS, and CSS with a 95% confidence interval (95% CI) were calculated from the first day of CRT. OS was calculated until the last follow-up day or the date of death. PFS was calculated until the day of recurrence, death, or the last follow-up day. For CSS, deaths due to causes other than LA-HNSCC were excluded. The Kaplan–Meier method was used to calculate survival rates, and the log-rank test was used to evaluate statistical significance. A Cox proportional hazards model was used for the multivariate analysis of prognostic factors. These analyses were performed using JMP Pro version 16 (SAS, Cary, NC, USA), and statistical significance was set at p < 0.05.