Prediction of concurrent chemoradiotherapy outcome in advanced oropharyngeal cancer

Abstract

The aim of this study was to investigate human papillomavirus (HPV) infection as a predictor of concurrent chemoradiotherapy (CCRT) response and indicator of planned neck dissection (PND) for patients with advanced oropharyngeal squamous cell carcinoma (OPSCC; stage III/IV). Overall, 39 OPSCC patients (32 men, 7 women; median age 61 years, range 39-79 years) were enrolled. The primary lesion and whole neck were irradiated up to 50.4 Gy, and subsequently the primary site and metastatic lymph nodes were boosted with a further 16.2 Gy. Although several chemotherapy regimens were employed, 82.1% of OPSCC patients received the combination of nedaplatin and 5-fluorouracil. HPV-related OPSCC (16 cases) was defined as both HPV DNA-positive status by polymerase chain reaction and p16INK4a overexpression by immunohistochemistry. Patients with N2 and N3 disease received PND 2-3 months after CCRT completion. Compared to non-responders, CCRT responders showed significantly lower nodal stage (N0 to N2b) and HPV-positive status in univariate analysis. Patients with HPV-related OPSCC had longer time to treatment failure (TTF) than those with HPV-unrelated OPSCC (p=0.040). Three-year TTF was 81.3 and 47.8% in the HPV-related and HPV-unrelated groups, respectively. There were also significant differences in disease-free survival (DFS) between the two OPSCC patient groups (p=0.042). Three-year DFS was 93.8 and 66.7% in patients with HPV-related and HPV-unrelated OPSCC, respectively. Multivariate logistic analysis showed a lower risk of TTF event occurrence in HPV-related OPSCC (p=0.041) than in HPV-unrelated OPSCC. Thus, HPV testing in addition to nodal stage was useful for predicting CCRT response, especially in advanced OPSCC. Because patients who received PND showed moderate locoregional control, PND is an effective surgical procedure for controlling neck lesions in patients with advanced HPV-unrelated disease.

Figure 1

Representative treatment scheme. The main chemotherapy regimen was a combination of nedaplatin and 5-fluorouracil (FN regimen), which was, in principle, administered twice with a 4-week interval. A radiographic response of the primary lesion was determined at 39.6 Gy irradiation in all patients to determine whether concurrent chemoradiotherapy would be continued or whether surgery was warranted.

Figure 2

Survival events and treatment. Three patients failed to show a partial response at 39.6 Gy and therefore underwent curative surgery for the primary and neck lesions. All other patients proceeded to the concurrent chemoradiotherapy protocol. CCRT, concurrent chemoradiotherapy; OPSCC, oropharyngeal squamous cell carcinoma; N, nodal recurrence; P, oropharyngeal recurrence; N+P, nodal and oropharyngeal recurrence; PD, progressive disease; PND, planned neck dissection; SD, stable disease; w/o, without.

Figure 3

Examples of p16^INK4a immunoreactivity scores. The scoring criteria for p16^INK4a immunoreactivity were 0 (no staining), 1 (1–10% of tumor cells positive), 2 (11–40% positive), 3 (40–70% positive), and 4 (>70% positive). p16^INK4a overexpression was defined as a score of 3 or 4.

Figure 4

Kaplan-Meier analysis of time to treatment failure in HPV-related and HPV-unrelated oropharyngeal squamous cell carcinoma (OPSCC). Patients with HPV-related OPSCC had longer time to treatment failure (TTF) than those with HPV-unrelated OPSCC (p=0.04). The 3-year probability of TTF was 81.3 and 47.8% in the HPV-related and HPV-unrelated OPSCC groups, respectively.

Figure 5

Kaplan-Meier analysis of disease-free survival in HPV-related and HPV-unrelated oropharyngeal squamous cell carcinoma (OPSCC). There was a significant difference in disease-free survival (DFS) between the two groups (p=0.042). The 3-year probability of DFS was 93.8 and 66.7% in the HPV-related and HPV-unrelated OPSCC groups, respectively.