Postoperative concurrent radiochemotherapy (RCT) versus radiotherapy (RT) in high-risk SCCA of the head and neck: Results of the German phase III trial ARO 96-3

Reviewer: Charles Wood, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 5, 2006

Presenter: Fietkau R
Presenter's Affiliation: University of Rostock, Rostock, Germany
Type of Session: Scientific


  • Characteristics of high-risk SCCA of the head and neck on surgical pathology include, but are not limited to, involvement of 3 or more lymph nodes (LN), extracapsular extension of disease (ECE), and microscopically positive surgical margins
  • In 1997, post-operative RT without chemotherapy was the standard of care following surgical resection for high-risk SCCA of the head and neck, though recurrence in the original tumor bed was frequent
  • This trial sought to compare post-operative RCT versus post-operative RT in patients with high-risk SCCA of the head neck

Materials and Methods

  • This was a prospective multicenter randomized trial, and analysis was via intention-to-treat
  • The primary endpoint was overall survival (OS), and secondary endpoints included local control (LC), distant metastasis (DM), and toxicity
  • Patients were stratified by treatment center and primary site
  • Eligibility criteria included pT3 R1 tumors or pT4 tumors or ≥ 3 involved LN or ECE as well as lack of macroscopic residual tumor; both squamous cell carcinoma and undifferentiated histologies were allowed
  • Chemotherapy consisted of cisplatin 20 mg/m 2 d1-5 and 29-33 and 5-FU 600 mg/m 2 continuous infusion d1-5 and 29-33
  • RT doses included 50 Gy for N0 patients, 56 Gy for pN+ patient without ECE, and 64 Gy for pN+ patients with ECE


  • Between May 1997 and December 2004, 440 patients were randomized to either post-operative RT (n=214) or post-operative RCT (n=226)
  • median follow-up was 36 months
  • the treatment arms were well-balanced with respect to primary site, gender, pT stage, and pN stage; patients in the RCT arm were slightly younger, and ECE was slightly increased in the RCT arm
  • there was significantly increased compliance in the RT versus RCT arms (96.4% vs. 73%, p<0.001)
  • there was significantly increased 5-year LC in the RCT arm (83.3±3.0% vs. 61.9±4.2%, p=0.0006)
  • there was significantly increased 5-year disease-free survival (DFS) in the RCT arm (62.4±4.4% vs. 50.1±4.0%, p=0.0023)
  • there was no significant difference in 5-year OS between the RCT and RT arms (58.1±4.6% vs. 48.6±4.4%, p=0.11)
  • however, on multivariate analysis, a significant difference in 5-year OS was seen favoring the RCT arm (p=0.034), with primary tumor site and treatment arm as significant factors
  • there was no significant difference in freedom-from-distant metastasis (FFDM) between the RCT and RT arms (70.0±4.6% vs. 68.4±4.3%, p=0.73)
  • however, on multivariate analysis, a significant difference in FFDM was seen favoring the RCT arm (p=0.031), with completion of chemotherapy (2 courses) and ECE as significant factors
  • there was increased grade 3/4 mucositis (20.8% vs. 12.6%, p=0.038) and grade 3/4 leucopenia (4.4% vs. 0%, p=0.007) in the RCT arm; additionally, more patients on the RCT arm demonstrated creatinine levels ≥ 1.5X the normal value (p=0.034)

Author's Conclusions

  • post-operative RCT improves LC and DFS in the setting of an acceptable acute toxicity profile
  • post-operative RCT demonstrated a statistically significant OS and FFDM advantage versus post-operative RT on multivariate analysis

Clinical/Scientific Implications

This trial demonstrated a significant increase in LC and DFS at 5 years in patients treated with cisplatin/5-FU chemotherapy concurrent with RT versus patients treated with RT alone following surgical resection. Additionally, statistically significant differences regarding OS and FFDM at 5 years were demonstrated on multivariate analysis, again favoring the RCT arm. It is puzzling, however, that the authors would report estimated 5-year data when the median follow-up of the study was only 36 months. For this reason, these results should be considered exceedingly preliminary, and little value should be placed in them at this time. Furthermore, caution should also be used when considering the results yielded by multivariate analysis, as neither the abstract nor presenter provided details on information regarding potential patient and treatment factors utilized in the analysis. This study also suggests somewhat different guidelines for defining high-risk disease, making comparisons with earlier similar trials more difficult.

When all trials are considered together, RCT has been shown to improve locoregional control, to have no impact on distant metastases, and to yield spotty and inconsistent results across trials with respect to OS. Ultimately, a consensus definition of high-risk disease in head & neck cancer is needed. This will aid in allowing more applicable comparisons between trials and serve to lessen confusion regarding treatment indications.