Final Report of a Prospective Randomized Trial to Evaluate the Dose-Response Relationship for Postoperative Radiation Therapy and Pathologic Risk Groups in Patients With Head and Neck Cancer

Abstract

Purpose: To present the long-term and final report of a phase 3 trial designed to assess dose-response relationship for postoperative radiation therapy (PORT) and pathologic risk groups in head and neck cancer.

Methods and materials: Patients who underwent primary surgery for American Joint Committee on Cancer stage III or IV squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx and who required PORT were eligible. Patients' primary sites and involved necks were independently assigned to higher- or lower-risk categories based on a cumulative point score representing increasing risk of recurrence. The sites in the lower-risk group were randomized to receive 57.6 or 63 Gy and those in the higher-risk group were randomized to receive 63 or 68.4 Gy, all at 1.8 Gy per fraction.

Results: A total of 264 patients were included. The actuarial 5-year locoregional control rate was 67%. A second primary cancer was documented in 27% of patients. The 5- and 10-year freedom-from-distant metastasis rates were 64% and 60%, respectively, whereas the 5- and 10-year overall survival rates were 32% and 20%, respectively. There was no statistically significant difference in tumor control between different dose levels in both the lower- and higher-risk groups. On multivariate analysis, nonwhite race (P=.0003), positive surgical margins (P=.009), extracapsular extension (ECE, P=.01), and treatment package time (TPT) ≥85 days (P=.002) were independent correlates of worse locoregional control, whereas age ≥57 years (P<.0001), positive surgical margins (P=.01), ECE (P=.026), and TPT ≥85 days (P=.003) were independently associated with worse overall survival.

Conclusions: This long-term report of PORT delivered at 1.8 Gy/d to total doses of 57.6 to 68.4 Gy without chemotherapy for head and neck squamous cell carcinoma demonstrated that increasing dose did not significantly improve tumor control. On multivariate analysis, the only significant treatment variable was TPT. The results confirm that positive surgical margins and/or nodal ECE remains the most significant predictive pathologic factors.

Figure 1

Risk scores and study design. Risk scoring criteria for primary site and neck. Patients’ primary sites and involved necks were independently assigned to higher or lower risk categories based on the cumulative point score representing lower versus higher risk of recurrence then randomized to different dose levels.

Figure 2

Survival and oncologic outcomes. Kaplan-Meier curves calculated for all patients (n=264) showing locoregional control (LRC), freedom from distant metastasis (FDM), cancer specific survival (CSS), and Overall survival (OS). Short vertical lines represent censored data and shaded colors represent 95% confidence intervals

Figure 3

Competing risk analysis for all patients A) competing risk of death cancer mortality predominates throughout the entire follow up duration, followed by non-cancer-related death and death from second primary cancer, B) competing risk of failure where loco-regional failure slightly exceeds the risk of distant metastasis. Black dots represent aggregated data points, black line represents fitted line of the aggregated data points, and dashed blue lines represent 95% confidence intervals.

Figure 4

Kaplan-Meier curves for A) local control (LC) in both risk groups by radiation dose, and B) regional control (RC). It shows there were no statistically significant differences in LC or RC rates between different dose levels in both the lower and higher risk groups except for LC of patients who were treated prior to 1985 with lower dose level A <54 Gy (n=17).