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Significance of persistent Epstein-Barr virus DNA remains unclear
This abstract addresses the role of chemotherapy if there is persistent EBV DNA detectable after a patient with virus-related nasopharynx cancer has been treated with definitive chemoradiation.
The first demonstration of the curative effects of chemoradiation by Al-Sarraf and colleagues included three subsequent cycles of doublet chemotherapy, and that has been accepted as the standard of care for a long time.
However, there has been concern that these three subsequent cycles of chemotherapy are toxic and difficult to deliver.
Also, a somewhat underpowered noninferiority study from Sun Yat-sen University compared chemoradiation for nasopharynx cancer with chemoradiation followed by chemotherapy, and results did not appear to show an advantage for the subsequent cycles of chemotherapy.
Researchers reported these data again with long-term follow-up showing the same finding, although the concern is that, because the noninferiority boundary in that trial was extremely permissive, it was really a small trial to answer the question.
Researchers at The Chinese University of Hong Kong have demonstrated that patients with EBV-related cancers with elevation of EBV DNA persistently at 6 to 8 months after definitive treatment have a much higher risk for recurrence.
Further, a meta-analysis by Blanchard and colleagues, published in 2015 in The Lancet Oncology, showed more chemotherapy — whether as neoadjuvant therapy before chemoradiation or adjuvant therapy after chemoradiation — appeared associated with a significant improvement in outcome.
In the United States, researchers are evaluating patients with EBV-related cancers and measuring EBV DNA in their blood following treatment with chemoradiation in the cooperative group trial NRG-HN001.
Patients with persistent EBV will be randomly assigned to conventional chemotherapy or an alternate regimen of gemcitabine-paclitaxel. If there is no EBV, patients will be randomly assigned to observation or doublet chemotherapy.
If measuring EBV DNA immediately after chemoradiation is informative, that should be an important trial. However, it may be superseded by some reports that seem to show chemotherapy before chemoradiation is particularly effective.
In this study, researchers from The Chinese University of Hong Kong evaluated patients who had completed their radiation — in whom the EBV DNA remained detectable — and randomly assigned them to observation or a novel chemotherapy regimen of cisplatin and gemcitabine. This regimen has shown survival improvements in the metastatic recurrent setting, but there are no data in the adjuvant setting.
This trial was small; it included 52 patients per arm. Not everyone assigned chemotherapy accepted their treatment, so the intent-to-treat and per-protocol results appeared a little different.
Three-year and 5-year PFS and DFS looked no different between the observation group and the chemotherapy group. Looking at 3-year OS, it appeared chemotherapy had a detrimental effect compared with observation, although that result flipped by 5 years.
Instability of the data in the 3- to 5-year timeframe highlights a couple of reservations one might have about this study.
First, nasopharynx cancer can be a somewhat indolent disease, so 3-year results might be considered premature in the locally advanced setting. Second, with 52 patients per arm and a substantial number not accepting chemotherapy, this study was somewhat underpowered.
We remain uncertain about the meaning of EVB DNA that has not gone down to zero immediately after chemoradiation. It appeared in this trial that the OS for this group is good at 66% to 67% at 5 years. However, it would be premature to look at the results of this small trial for persistent EBV DNA and conclude there is no role for chemotherapy after chemoradiation given the long-term results with Al-Sarraf, the findings of the meta-analysis and the inconclusive results of the prior trial from Sun Yat-sen University.
References:
Al-Sarraf M, et al. J Clin Oncol. 1998;16:1310-1317.
Blanchard P, et al. Lancet Oncol. 2015;doi:10.1016/S1470-2045(15)70126-9.
Chen L, et al. Eur J Cancer. 2017;doi:10.1016/j.ejca.2017.01.002.
For more information:
Barbara A. Burtness, MD, is professor of medicine, disease-aligned research team leader of the head and neck cancers program, and codirector of the developmental therapeutics research program at Yale Cancer Center. She also is a HemOnc Today Editorial Board Member. She can be reached at barbara.burtness@yale.edu.
Disclosure: Burtness reports she has no relevant financial disclosures.