Purpose
To test the hypothesis that radiotherapy (RT) of head and neck squamous cell carcinoma (HNSCC) can be improved by hypoxic modification using nimorazole (NIM) in association with accelerated fractionation.
Patients and Methods
The protocol was activated in March 2012 as an international multicenter randomized trial in patients with HNSCC. Tumors were treated to a dose of 66–70 Gy, 33–35 fractions, 6 fractions per week. NIM was administered in a dose of 1.2 g per m2, 90 min before the first daily RT fraction.
The primary endpoint was loco-regional failure. The trial was closed prematurely by June 2014 due to poor patient recruitment. An associated quality assurance program was performed to ensure the consistency of RT with the protocol guidelines.
Results
The trial was dimensioned to include 600 patients over three years, but only 104 patients were randomized between March 2012 and May 2014. This was due to the inability to involve three major centres and the insufficient recruitment rate from the other participating centres. Twenty patients from two centres had to be excluded from the analysis due to the unavailability of follow-up data. Among the remaining 84 patients, 82 patients were evaluable (39 and 43 patients in the RT + NIM and the RT-alone arms, respectively). The treatment compliance was good, with only six patients not completing the full planned RT course, and 31 patients (79%) out of 39 allocated for NIM, achieving at least 90% of the prescribed drug dose. At the time of evaluation, 40 patients had failed to achieve persistent loco-regional tumor control, and a total of 45 patients had died. The use of NIM improved the loco-regional tumor control with an 18-month post-randomization cumulative failure rate of 33% versus 51% in the control arm, yielding a risk difference of 18% (CI 3% to 39%; P = 0.10). The corresponding values for overall death was 43% versus 62%, yielding a risk difference of 19% (CI- 3% to 42%; P = 0.10). Sixteen out of 55 patients analysed for hypoxic gene expression were classified as having more hypoxic tumors. Such patients, if treated with RT alone, had a higher loco-regional tumor failure rate than the rest of the patients with known hypoxic status (P = 0.05).
Conclusion
Although the trial was incomplete and impeded by a small number of patients, the results suggested an improvement in loco-regional tumor control and overall survival in patients with advanced HNSCC given the hypoxic modifier NIM in addition to accelerated fractionation RT. However, the trial also revealed that conducting multicenter and multinational studies combining drug and RT in developing countries may face uncontrolled and unsolvable problems.
The results of the CRP were published in: J. Radiotherapy and Oncology 116 (2015) 15–20. ? 2015 by European Society for Radiotherapy and Oncology
Researchers from Denmark, Pakistan, Estonia, Egypt, Slovenia and the IAEA participated in this CRP.
For more information, please see the CRP description:
http://www.dgdingfa.net/projects/crp/e33030
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