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Accelerated hyperfractionated chemoradiation (C-HART) plus 5-FU/MMC is superior to HART for inoperable locally advanced head and neck cancer. Final results of the German ARO 95-06 Multicentre Trial

Reviewer: Neha Vapiwala, MD
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 8 de junio del 2004

Presenter: V.G. Budach
Presenter's Affiliation: ARO
Type of Session: Scientific

Background

The use of combined modality therapy in locally advanced head and neck cancer, specifically concurrent chemoradiation, is accepted by many clinicians as a superior regimen to standard radiation therapy alone. Further gains in locoregional control have been acheived with the use of altered fractionation radiation therapy, ranging from hyperfractionated regimens of twice-daily treatment to accelerated regimens delivered over shorter time periods, and various combinations thereof.  One of the standard regimens favored in Germany for locally advanced cancers of the head and neck is radiation dose escalation through hyperfractionated regimens, or HART. This trial was designed to evaluate if standard dose, hyperfractionated RT with concurrent chemotherapy (C-HART) was superior to dose-escalated, hyperfractionated RT alone. The overall treatment package time, which is a well-established prognostic factor, was maintained at 6 weeks for both arms. 

Materials and Methods

• Eligible patients had stage III/IV head and neck cancer
• 384 patients were randomized to one of two arms:
•     1) C-HART: 70.6 Gy/6 weeks + 5-FU 600 mg/m2 infusion days 1-5 + mitomycin-C (MMC) 10 mg/m2 on weeks 1 and 5
•     2) HART: 77.6 Gy/6 weeks
• Overall patient characteristics were as follows: 84% male, 59.5% oropharynx, 32.4% hypopharynx, 8.3% oral cavity, and 93.8% stage IV
• Patients were stratified by institution, tumor site, and nodal stage
• Both arms were well-balanced for age, gender, performance status, histology, and subsite
• All analyses were intent-to-treat
• Study endpoints included locoregional control (LRC), progression-free survival (PFS), overall survival (OS), and toxicity. 

Results

• All results are reported for C-HART vs. HART:
• 5-year OS = 28.6% vs. 23.7%, p=0.023
• Median survival period = 23 months vs. 16 months, HR=0.71
• 5-year PFS = 29.3% vs. 26.6%, p=0.009
• Median PFS period = 16 mos vs. 11 mos
• 5-year LRC = 49.9% vs. 37.4%, p=0.0009
• Median LRC period = 48 months vs. 15 months
• Freedom from distant metastases = 51.9% vs. 54.7%, p=0.58
• No significant differences were noted in acute and late toxicities between the two arms, including skin reactions, mucositis, dysphagia and xerostomia.

Author's Conclusions

• C-HART achieves higher LRC, PFS and OS than HART in patients with locally advanced head and neck cancers.
• There is an acceptable toxicity rate, both acute and late, with C-HART.
• There remains an unacceptably high metastatic rate in these patients, and optimization of distant control is still needed.

Clinical/Scientific Implications

This large study demonstrates that the use of chemotherapy concurrently with hyperfractionated RT, when delivered within an acceptable "treatment package time", is superior to dose-escalated, hyperfractionated RT delivered over the same time period but without chemotherapy. Furthermore, the relatively comparable tolerablity and side effect profiles of the two regimens show that concurrent chemoradiation is indeed feasible. Almost all of the clinical endpoints of interest, namely progression-free and overall survivals, were statistically significantly improved. However, the non-significant impact of treatment on the rate of distant metastases highlights the unfortunate reality that better systemic therapy is desperately needed, especially as locoregional control rates improve and alter the natural history of this disease to one with increasing distant spread. The continually growing body of research on targetted agents may help offer some of this badly needed systemic control. In addition, a future ARO trial is presently accruing patients to evaluate cisplatin-based chemotherapy against the 5-FU/MMC winning arm from this study.

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