Oncology ScandHead and Neck Cancers

Summary: The Groupe d'Oncologie Radiotherapie Tete et Cou (GORTEC) 99-02 study (1) randomized 840 patients with stage III and IV head-and-neck squamous cell carcinoma to 1 of 3 therapy arms: standard chemoradiation, chemoradiation with accelerated radiation therapy, and very accelerated radiation therapy (VART). Subsites included the oropharynx, oral cavity, hypopharynx, larynx, and unknown primary. Radiation therapy was delivered with the 3-dimensional technique. The standard chemoradiation arm consisted of 3 cycles of carboplatin-fluorouracil given concurrently with 70 Gy of radiation therapy delivered over 7 weeks. The chemoradiation-accelerated arm consisted of 2 cycles of carboplatin-fluorouracil given concurrently with 40 Gy of radiation therapy over 4 weeks, followed by another 30 Gy in 1.5- Gy fractions delivered twice daily for 2 weeks. VART was spec- ified as 64.8 Gy given at 1.8 Gy per fraction on a twice daily schedule, completed in 3.5 weeks, without any chemotherapy. Follow-up computed tomography scans were performed every 3 to 6 months. The primary endpoint of the trial was progression- free survival (PFS), analyzed by intention to treat, and the study was powered to allow 2-by-2 comparisons of the treatment arms. Enrollment started in 2000 and ended in 2007, with a median follow-up of 5.2 years. Twenty-two centers participated. Ninety percent of the patients had stage T3 to T4 primary disease, and 79% had at least N1 nodal disease. Compliance with study procedures was generally high, except that only 73% of patients in the standard chemoradiation arm received the third cycle of chemotherapy. The 3-year PFS rates were 37.6%, 34.1%, and 32.2% for the standard, chemoradiation-accelerated, and VART arms, respectively, and rates of locoregional control (LRC) were 41.7%, 45.4%, and 49.9%, respectively. For PFS, LRC, and overall survival (OS) rates, standard chemoradiation was signifi- cantly better than VART (PZ.041, PZ.045, PZ.040, respec- tively). The chemoradiation-accelerated arm was only better than VART for LRC (PZ.033) but not PFS (PZ.060) or OS (PZ.169). The chemoradiation-accelerated arm did not produce any signifi- cant differences from the standard chemoradiation arm (PZ.88 for PFS, PZ.81 for LRC, PZ.60 for OS). VART resulted in significantly higher rates of acute toxicity. Among VART patients, 84% had Radiation Therapy Oncology Group(RTOG)grade3to4mucositisversus76%intheaccelerated arm and 69% for the standard arm (PZ.0001). For VART, 70% of patients had feeding tubes versus 64% in the accelerated arm and 60% in the standard chemoradiation arm (PZ.045). At 5 years, 25% of VART patients still had a feeding tube. Thus, convention- ally fractionated chemoradiation remains the GORTEC standard. Comment: If you experienced a bit of dejavu reading these results, it was warranted. The RTOG 01-29 study was conducted in a similar population with conventional radiation therapy tech- niques and compared an accelerated concomitant boost schedule to standard fractionation, both in combination with concurrent cisplatin therapy. There was no radiation-only arm. At 3 years, the OS and PFS rates in the RTOG study did not statistically differ between the 2 arms (2). Therefore, based on these 2 large randomized trials, we must conclude that 1 week of radiation therapy acceleration in combination with 2 cycles of concurrent chemotherapy does not improve PFS or OS compared to conven- tionally fractionated chemoradiation. It is faintly possible that the lack of a third chemotherapy cycle in the accelerated arm could have masked a benefit from moderate acceleration, but from a practical perspective, this cannot be meaningfully tested, as both studies showed reduced compliance with a third cycle of chemo- therapy, even in combination with only standard fractionation. Meanwhile, the landscape of these questions has shifted. The increasing prevalence of human papillomavirus (HPV) infection-related oropharyngeal cancers means that additional ef forts at radiochemotherapy intensification will only be needed for less common cancer subtypes, probably in smaller trials with restrictive selection criteria. In addition, from a technical perspec- tive, the now common practice of the simultaneous integrated boost used in intensity modulated radiation therapy (IMRT) means that many head and neck cancers are already treated with mildly accel- erated regimens. Finally, for diehard aficionados of radiation therapy fraction- ation, a surprising finding of the GORTEC trial is that a very accelerated schedule of radiation therapy treatments cannot compensate for a lack of concurrent chemotherapy. The VART arm was the worst not only for all oncologic outcomes, including LRC, but also for toxicity. Mucositis and feeding tube rates were highest in the VART arm, and long-term feeding tube dependence was higher than with either standard or moderately accelerated chemoradiation.