Of 355 patients treated with IC and CRT for HNC in two institutions between January 2005 and December 2010, data for 321 consecutive patients were reviewed in this retrospective study. Fourteen patients who presented with disease progression after receiving a second course of IC, 12 patients who underwent salvage neck dissection prior to CRT, and eight patients who refused further therapy were excluded from this study. All patients were diagnosed with previously untreated, biopsy-proven squamous cell carcinoma. DM was undetected from computed tomography (CT) or positron emission tomography (PET)-CT scans at the time of their initial diagnosis. Five patients showed N3 stages, but none of them were included in the analysis due to incomplete treatment. All patients showed a performance status of 0 to 1. Patients with primary tumors of the nasopharynx, paranasal sinus, or salivary gland were excluded from this study.

Clinically significant lymph nodes in the cervical region were distinguished according to the criteria described by van den Brekel et al. [11] (i.e., shortest axis of ≥ 11 mm in the jugulodigastric regions, or ≥ 10 mm in other cervical regions). In addition, conglomerate lymph nodes of borderline size on CT, or any positive results for neck lymph nodes from PET scans, were considered metastatic lesions. The TNM stages of the patients were re-evaluated from their medical records and images at the time of data analysis. Patients were staged according to the 2009 classification of the American Joint Committee on Cancer Staging (AJCC) [12]. The study protocol was approved by the institutional review board (IRB).

IC consisted of three courses of docetaxel (70 mg/m² as 1-hour infusion) and cisplatin (75 mg/m² as 2-hour infusion) every three weeks. Three weeks after completion of the second course of IC, response to IC was evaluated using CT scan. If disease progression was noted, the third course of IC was cancelled and surgical treatment was considered. Neck dissection was performed prior to CRT in some cases where multiple necrotic lymph nodes showing a stable response after IC were presented. Radiotherapy was recommended for patients determined as unresectable or who refused surgery.

After completion of IC, CRT was initiated within four weeks. Conventional fractionated radiation therapy with a daily dose of 2 Gy and a total dose of 66-70 Gy was planned for all patients. Concurrent with radiation therapy, administration of six courses of chemotherapy using weekly cisplatin (40 mg/m² as 1-hour infusion) was planned for patients.

Three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) was performed on a 6 MV linear accelerator (Clinac 21EX, Varian Medical Systems, Palo Alto, CA). The gross tumor volume (GTV) was defined as the pre-IC gross disease volume (primary and node) shown on imaging studies. The clinical target volume (CTV) encompassed the GTV plus a margin of 0.5-1.0 cm for the potential microscopic extension of the disease, and an additional margin of 0.3 cm was considered to compensate for setup uncertainty. Segmentation of nodal CTV into two parts (CTV2 and CTV3) was performed according to estimation of the risk. Standard doses were 66-70 Gy for CTV1 (the area of primary tumor and metastatic nodes), 60 Gy for CTV2 (CTV1 plus the next echelon nodal area or ipsilateral cervical nodal chains), and 50 Gy for CTV3 (contralateral lymph nodal area or uninvolved lower neck nodal region).

Response to treatment was documented using the World Health Organization (WHO) response grading system [13]. The response was evaluated between six and 12 weeks after completion of CRT by physical examination and radiological images (CT, magnetic resonance imaging [MRI], and PET-CT). A biopsy was recommended if there was clinical evidence of residual tumor. A complete response (CR) of the primary site was defined by the disappearance of disease evidence on physical examination, radiological images, or pathological reports. In case of neck nodes, CR included all lymph nodes less than 1.0 cm in greatest axial dimension without contrast enhancement on CT scans and with negative results on PET scans. Patients with less than a CR were recommended to go ahead with additional surgery or close observation. Patients were observed by all members of the multidisciplinary team after completion of therapy. Careful clinical examination including imaging studies (CT, ultrasonography and PET, or MRI) was performed at 1-3 month intervals over the first year, every 3-6 months in the second and third years after treatment, and every 6-12 months thereafter.

Survival times were calculated from the initial date of IC. The Kaplan-Meier method was used for progression-free survival (PFS), distant metastasis-free survival (DMFS), and OS. Except for the OS calculations, a patient was considered censored at death if the event had not occurred. A logistic regression model was used for multivariate analysis of risk factors related to DM. As stated in the Introduction, previous studies reported an association of five variables; tumor stage, nodal stage, primary site, tumor differentiation, and lower neck node involvement with development of DM in patients treated with radiotherapy alone or CRT [7,8]. Therefore, these tumor-related factors were assessed as potential prognostic factors having an effect on DM, PFS, DMFS, and OS. Treatment related factors, including number of concurrent chemotherapy cycles and overall duration of radiotherapy were also evaluated as variables. Response to IC was included in the potential prognostic factors in order to evaluate its predictive role for disease control and survival outcome. We performed multivariate analysis with a logistic regression model and used a binomial distribution statistical model to determine the 95% confidence interval of the probability of development of DM. Multivariate analyses of survival outcome were performed using a Cox’s regression model. PASW software (PASW ver. 18.0, SPSS Inc., Chicago, IL) was used for the statistical analyses. p < 0.05 was used to indicate statistical significance.

The median age of patients was 60 years (range, 27 to 79 years), and 275 patients (85.7%) were men. Three hundred five patients (95.0%) were treated with IMRT, and 16 patients (5.0%) received 3D-CRT. The median dose (for CTV1) of radiation therapy was 70 Gy (range, 56 to 70 Gy), delivered in a median of 35 fractions (range, 28 to 35 fractions) over 45-73 days (median, 51 days). The tumor characteristics are described in Table 1.

Three hundred eleven patients (96.9%) received the prescribed total radiotherapy dose (range, 66 to 70 Gy). In the majority of patients (304 patients, 94.7%), the overall treatment time for radiotherapy was ≤ 8 weeks. Seventeen patients (5.3%) required more than eight weeks to complete treatment because of a variety of treatment-induced toxicities. All patients received three cycles of IC. The dose of docetaxel in the third cycle was reduced by 25% in 21 patients who presented with grade III neutropenia. Two hundred thirty-six patients (73.5%) completed all six cycles of concurrent chemotherapy; however, 23 patients (7.2%) received less than five cycles of weekly cisplatin.

According to results for response to IC, 59 patients showed a CR (18.4%), 208 showed a partial response (PR; 64.8%), and 54 showed an stable disease (SD; 16.8%). Responses after CRT were as follows: CR at the primary site was seen in 227 patients (70.7%); 201 patients (62.6%) had CR of the metastatic lymph nodes in the neck; 96 patients (29.9%) had PR at the primary site or lymph node; treatment failure occurred in 59 of 211 patients (28.0%) who presented with complete remission at the three-month post-treatment assessment; local recurrence was noted in 41 patients, isolated regional recurrence in 13 patients, and locoregional recurrence in nine patients; DM was detected in 24 patients who had achieved CR after CRT—in 18 of these patients, development of DM was preceded by occurrence of locoregional failure; and DM manifested in 36 patients with persistent locoregional disease following treatment. Detailed data regarding the patterns of failure are shown in Fig. 1. The 5-year locoregional recurrence and distant metastasis rates were 23.6% and 18.2%, respectively. At the time of the last follow-up, DM was reported in 60 of 321 patients (18.7%). The sites of metastases were distributed as follows: lung, 28 cases (8.7%); liver, 15 cases (4.7%); bone, 12 cases (3.7%); and multiple sites (lung and bone), five cases (1.6%). Results of multivariate analysis of risk factors related to DM are shown in Table 2. Significantly high risk of DM was observed in patients with N2c stage, lower neck node involvement, prolonged overall duration of radiotherapy, and poor response to IC.

The median follow-up period for all patients and survivors was 52 months (range, 4 to 83 months) and 68 months (range, 33 to 90 months), respectively. At the time of analysis, 132 patients (41.1%) had died. The causes of death were as follows: cancer progression in 103 patients, other causes in 24 patients, treatment-related toxicity in three patients, and undetermined in two patients. The PFS, DMFS, and OS at five years were 41.2%, 50.7%, and 55.1%, respectively. Various factors related to survival outcomes were evaluated by multivariate analysis, and the results are shown in Tables 3 and 4, respectively.

In multivariate analysis, the significant factors affecting DMFS and PFS were lower neck node involvement (p=0.008 and p= 0.021, respectively) and response to IC (p < 0.001 and p < 0.001, respectively). The DMFS rate at five years according to lower neck lymph node (positive vs. negative) was 34.3% versus 55.2% (Fig. 2) and response to IC (CR, PR, and SD) was 68.9%, 47.3%, and 0% (Fig. 3), respectively. However, OS was not affected by any of these prognostic factors.