UPFRONT

Has the Fat Lady Sung?

Peter K. Kaiser, MD

“The opera ain't over till the fat lady sings.”
— attributed to Dan Cook

The fat lady is Brunnhilde from Wagner's Ring Cycle, which often lasts over 14 hours. When Brunnhilde appears and begins her 15-20 minute final aria, there's only one line left in the opera, sung after her death. Thus, the endless opera is truly over when she sings.

Dan Cook was a broadcaster who uttered these words during the 1978 NBA playoffs to illustrate that the series wasn't over, and its use to describe sports has been cemented over the years. With all due respect to Brunnhilde, radiation therapy in AMD ain't over till the fat lady sings.

Radiation is firmly established in managing tumors, so it was natural to attempt to use it in AMD, as the neovascular target is similar. Unfortunately, we've heard the results of numerous clinical trials using radiation therapy in the management of wet AMD. Most of these trials failed or were equivocal at best.

Recently, Neovista gained EU approval for its Vidion ANV system, in which after vitrectomy, a special probe is placed on the retinal surface delivering radiation directly to the CNV membrane, minimizing radiation to surrounding by-stander areas. Theoretically, if placed correctly, the device delivers 2.3 MeV of beta radiation over a 5-mm area and at a depth of around 3 mm.

The reason everyone was excited about this approach, compared to proton beam or plaque brachytherapy, was that minimal radiation is used, targeted to the CNV. This should minimize off-target effects but allow the radiation's effects on the CNV. Early studies of the device were very promising, with a dramatic reduction in the need for anti-VEGF injections and good VA results.

The results of the pivotal phase 3 CABERNET study of 494 treatment-naïve patients were recently announced. The combination of Vidion and Lucentis was not equal to Lucentis (10% noninferiorty margin) in the percentage of patients losing ≤15 letters of vision. Although the combination group only required on average one additional anti-VEGF injection over 24 months, the visual results were not great. Many would argue that the fat lady has now sung.

But there are issues with this study that may have confounded the results. Foremost was the requirement for the probe to touch the retina for around five minutes. Even for very experienced surgeons, this is a difficult maneuver and, I'd guess, not universally followed. If the probe doesn't touch the retina, the radiation delivered to the CNV is dramatically reduced. Thus, many patients may have been undertreated.

Moreover, this protocol required vitrectomy in the combo group, suggesting that many patients would have had accelerated cataract formation. I'm sure the folks at Neovista are parsing their data to see how pseudophakic patients performed.

In any case, I'm not so sure the fat lady has sung. Later this year, another company will deliver its trial results using a different radiation delivery system. As Yogi Berra put it best, “It ain't over till it's over.”