Forty patients with stage III and IVa/b SCCHN were enrolled in this study. The median follow-up for all patients is 83 months (range = 7–118). The median follow-up for the 15 survivors is 102 months (range = 66–118). Table 1 shows patient demographics. The overall stage was 23 % III, 70 % IVA, and 8 % IVB, and 54 % of patients had T1, T2, or T3 tumors, while 41 % of patients were N0-N2a and 59 % were N2b-N3. All patients were chemotherapy naïve. One patient had a history of previous SCCHN more than 5 years prior to enrollment.
Patients were analyzed on an intent-to-treat basis. Thirty-nine patients were evaluable for response, toxicity, local regional control, distant control, and progression-free and overall survival outcomes; one subject was not evaluable because he was lost to follow-up after cycle 1 of induction. Two other patients received one cycle of induction but are included in the outcome analysis; one refused further induction therapy and another progressed in neck nodes. All remaining patients received the full intended dose of induction therapy and only one patient required 1 week delay in administration of cycle 2 secondary to cytopenias.
Acute toxicity and response date
The details of the acute toxicity and response data have been previously reported , with only neutropenia (50 %), infection (8 %), and dermatologic (8 %), grade 3 and 4 toxicity rates over 5 % and no grade 5 toxicities. The response rates (CR + PR) was 82 % overall, with only one subject showing progressive disease (PD) in lymph nodes. A primary site RR of 90 % was observed, with no PD at the primary site.
Definitive therapy began 3 weeks the last dose of chemotherapy and LDFRT in all subjects and was determined by multidisciplinary conference consensus. Definitive therapy consisted of: concurrent chemoradiation in 20 patients (51 %), radiation alone in 15 patients (39 %), surgery in 2 patients (5 %), and surgery and radiation in 2 patients (5 %). Definitive treatment was influenced by response to induction, location of the primary (oral cavity versus other), tolerance of induction, patient wishes, pattern and bulk of residual disease, and medical co-morbidities. Patients who had poor responses to induction were offered surgical therapy or more intensive radiation or chemoradiation. Compliance with definitive therapy was 95 % (38/40 subjects). Radiation was given without treatment interruptions except in two patients. The first patient refused further radiation after 4,260 cGy and underwent salvage surgery, while the second was non-compliant, stopped therapy at 3,880 cGy, and refused further therapy. Five patients underwent adjuvant neck dissections post-radiation with an 80 % pathologic CR rate, and one patient had planned surgery followed by post-operative radiation.
Patients who completed definitive radiation alone received doses ranging from 6,200–7,660 cGy (median 7,200 cGy). Of the 19 patients who received definitive chemoradiation, 16 received hyperfractionated radiation with intra-arterial cisplatin (HYPERRADPLAT) as previously described by Spring et al. in Cancer , while three others received concurrent intravenous chemotherapy.
Of the 39 evaluable patients, 15 are still alive without evidence of disease. Fifteen patients have died of SCCHN, and 9 patients have died of other causes. Fifteen patients recurred: 7 distant only, 6 locoregional only, and 2 failed both distantly and locally. First sites of distant failure were the lungs in 7 patients and multiple simultaneous sites in the other 2 patients. Absolute rates of locoregional control (LRC) and distant control (DC) are 80 % and 77 %, respectively.
Five-year overall survival (OS), disease-specific survival, and progression-free survival (PFS) are 62 %, 66 %, and 58 %, respectively. OS and PFS curves are displayed in Fig. 2, which also shows OS stratified by primary tumor site and PFS stratified by T category. On univariate analyses, T category was predictive of PFS (p < 0.001), and primary tumor site was predictive of OS (p < 0.001). Table 2 displays adjusted hazard ratios for multivariable models of overall and progression-free survival. On multivariate analysis, T4 disease was associated with worse overall survival compared to T1, T2, or T3 disease (HR 5.0; 95 % CI 2.0–13.0). Oral cavity primary tumors as compared to oropharynx tumors were also associated with worse overall survival (HR 17.1; 95 % CI 3.7–78.6) on multivariate analysis. An increased risk of recurrence was also associated with those patients with T4 tumors (HR = 18.0; 95 % CI 4.9 to 65.7) or oral cavity primaries (HR = 10.3; 95 % CI 2.0 to 52.3).
Late toxicity included 4 pts. with feeding tube dependence greater than 1 year, three cases of laryngeal stenosis, two grade 3 esophageal strictures, one osteoradionecrosis, one upper extremity neuropathy, and one tracheocutaneous fistula post-surgery. Second malignancies occurred in 10 (26 %) patients. These included three skin, two head and neck, two lung, one esophageal, one pancreatic, and one rectal cancer.