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Avastin Treats Stage 3+ ROP

Bevacizumab was FDA-approved for colon cancer, but the anti-VEGF drug may have found its true calling in treating stage 3+ retinopathy of prematurity. “This is a disease that bevacizumab is really made for,” said Helen A. Mintz-Hittner, MD. She recently reported the findings of a multicenter, randomized trial in which the recurrence rate for eyes treated with laser, the conventional therapy, was far greater than in eyes treated with bevacizumab. 1

The point of the treatment is to stop abnormal vessel growth, while giving normal retinal vessels a chance to finish growing in eyes that never fully developed in utero.

In the trial, BEAT-ROP (Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity), 150 infants with either zone I or posterior zone II ROP were randomly assigned to intravitreal bevacizumab or conventional laser therapy.

All the infants had stage 3+ ROP, the only stage at which bevacizumab should be used, said Dr. Mintz-Hittner, professor of ophthalmology and visual science at the University of Texas Health Science Center at Houston.

In stages 1 and 2, when the immature retina has few blood vessels and VEGF levels are relatively low, beva- cizumab could stop normal retinal development and induce retinal dystrophy. At the other end of the spectrum, stages 4 and 5, when VEGF is also down and scar-ring is occurring, treatment could accelerate retinal detachment. “In between is when it really works,” she said, referring to stage 3+.

In addition to staging, ROP is defined by severity, with zone I being the worst. For that subset, recurrence in eyes treated with laser was significantly higher than in bevacizumab-treated eyes. Specifically, ROP recurred in one or both eyes in 6 percent of the bevacizumab-treated patients, compared with 42 percent in the laser-treated patients. While the results were not significant for posterior zone II patients, the trend favored bevacizumab. The findings were so robust that an editorial in the New England Journal of Medicine recommended bevacizumab become the treatment of choice for zone I ROP.2

One caveat: Recurrence, if it happens, occurs further out with bevacizumab than with laser—at 16 weeks compared with 6.2 weeks. Therefore, doctors must carefully follow infants treated with bevacizumab to be sure vascularization is complete.

Dr. Mintz-Hittner said bevacizumab was chosen over ranibizumab because the molecule is three times larger and less likely to escape the eye and cause systemic problems. It also has multiple advantages over laser, including cost and ease of use, and it doesn’t destroy the peripheral retina.

Finally, she said re-treatment is not an issue. “There’s a natural endpoint for ROP, and that’s the completion of vascularization.” One shot is generally all it takes, with the exception of very early term babies, who may need one more.

—Miriam Karmel   

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1 Mintz-Hittner, H. A. et al. N Engl J Med 2011;364(7):603–615.
2 Reynolds, J. D. N Engl J Med 2011;364(7):677–678.

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Herpes Zoster Ophthalmicus 

Ninefold Risk of Cancer After HZO

For more than 50 years, leading physicians have noted an association between herpes zoster (HZ)—an activation of latent varicella—and a subsequent diagnosis of cancer. HZ is reported to affect 10 to 20 percent of the U.S. population. Now, a retrospective cohort study based on the entire population of Taiwan reports a ninefold increase in the risk of cancer the year following a diagnosis of herpes zoster ophthalmicus (HZO), a form of HZ that affects the ophthalmic nerve.1

As with a previous study linking HZO to stroke,2 this study used one of the largest nationwide, population-based datasets in the world, a database released by Taiwan National Health Research Institutes. “This provides a unique opportunity for studying these kinds of phenomena,” said Sudha Xirasager, MBBS, PhD, study coauthor and associate professor of health services policy and management at the University of South Carolina in Columbia.

The study compared a series of 658 HZO patients diagnosed in 2003 and 2004 with 5,264 randomly selected outpatients matched on age, gender, monthly income and residential urbanization level. The majority of the patients were age 50 or older.

In the year following diagnosis of HZO, a wide range of cancers were diagnosed in 4.86 percent of patients with HZO, compared with 0.53 percent of patients in the comparison cohort, yielding a 9.25 greater risk of cancer diagnosis among patients with HZO.

“The major contribution of this study is that it unequivocally confirms a clinical connection between herpes zoster ophthalmicus and cancer,” said Dr. Xirasager. “We cannot say that it is a causal connection, however.”

Until further research is done, a kind of chicken-and-egg debate still persists about their relationship. Several scenarios are plausible: HZO might signal early immune system impairment that accompanies malignancy. Alternatively, reactivation of the virus might trip certain immunologic mechanisms that could lead to cancer. Or, a host immunity compromise may be setting the stage for either HZ or cancer to emerge, according to the authors.

The implications of this study? “One, of course, is the opportunity to screen these patients very carefully for early stage cancers when the cancer is more treatable,” said Dr. Xirasager. HZO’s salient symptoms—severe eye pain, redness, tearing, and decreased vision— almost invariably send patients hurrying to the doctor’s office, where the diagnosis is very unlikely to be missed. “A diagnosis of HZO should serve as a trigger to refer the patient to a general internist or general surgeon for a comprehensive assessment.” Today’s sophisticated screening tools make this even more efficacious, she said.

A second implication of the study, she said, would be to initiate molecular biological and hematological studies to understand the biological mechanisms that link these two conditions. A direct carcinogenic effect of herpes zoster would imply the need for interventions to avert cancer and for research on a targeted boosting of host immune mechanisms.

—Annie Stuart   

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Dr. Xirasager reports no related financial interests.
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1 Ho, J-D. et al. Ophthalmology Published online Jan. 12, 2011.
2 Kang, J-H. et al. Stroke 2009;40:3443–3448.

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Compounding Problems 

Handle Avastin and Lucentis With Care

Improper shipping and storage of bevacizumab (Avastin) and ranibizumab (Lucentis) can cause microdroplets of silicone oil to form in the liquid medication, a phenomenon that could explain sustained intraocular pressure spikes after one or more injections of the anti-VEGF drugs, according to a report by Colorado researchers.1

“Silicone leaching from syringes can happen either with Lucentis or with Avastin. This is not a medication-related phenomenon, but rather an issue with compounding, shipping and packaging of fluid within syringes,” said Malik Y. Kahook, MD, a glaucoma subspecialist and coauthor of the paper. He is associate professor of ophthalmology and bioengineering for the University of Colorado Hospital Eye Center, Denver.

The researchers began looking for subvisible particulate contaminants in the two anti-VEGF drugs after physicians reported several cases of high IOP and ocular inflammation in injected eyes. “Sustained elevation in IOP has been noted in some patients after one or more injections of either Avastin or Lucentis. I know that it has been seen in clinics around the country, but only in small numbers and usually in clusters of patients,” Dr. Kahook said. He reported that in his own patients this complication of intravitreal injections of Genentech’s anti-VEGF drugs was more likely with bevacizumab than with ranibizumab.

The group’s evidence pointed at silicone oil, which lubricates the barrels of insulin syringes in which bevacizumab commonly is stored for up to 90 days. Such syringes are not labeled for storage of biologic agents beyond 14 days, the authors note.

They tested the contents of syringes shipped by four compounding pharmacies and compared the results to samples deliberately mishandled in the lab. There were similar baseline particulate levels in fresh drug solutions in glass vials, the researchers reported. But particulates began forming under certain conditions:

  • If the bevacizumab was stored in plastic insulin syringes lubricated with silicone oil—a common practice.
     
  • If the syringe contents were poorly cooled.
     
  • If the contents alternately froze and thawed during shipping, or while stored in a refrigerator.
     
  • If individual syringes were not wrapped in multiple layers and oriented vertically, to attenuate mechanical shocks during shipping.

Syringes from three pharmacies (not identified by name) suffered from such deficiencies, Dr. Kahook noted. The fourth compounder packaged syringes carefully, and fewer silicone particles formed during shipping.

In the lab simulations, medication froze within minutes of direct contact between syringe and a frozen gel pack. The amount of leached silicone varied between syringe brands, and between batches of the same brand. (Doses kept in tuberculin syringes, without an attached needle, were less problematic.)

Dr. Kahook recommended that clinicians ask compounding pharmacies about the age of filled bevacizumab syringes (preferred: less than 14 days between filling and use); inspect packages to assure the syringes were protected from shocks and freeze-thaw cycling; and ask if the syringes used are more or less likely to leak silicone into the barrel than others.

—Linda Roach   

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Dr. Kahook is a consultant for Genentech. The current research was not funded by outside sources.
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1 Liu, L. et al. Invest Ophthalmol Vis Sci 2011;52(2):1023–1034.

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Strongly Resistant Bugs Found Before IVT

Even before the first anti-VEGF intravitreal injection, your patient’s conjunctiva and nasopharynx might be harboring bacteria resistant to several antibiotics, including fourth-generation fluoroquinolones.1

This worrisome discovery emerged from baseline data collected by Vanderbilt University researchers at the beginning of a study that will track changes in resistance in 24 patients’ eyes after four monthly, unilateral intravitreal injections accompanied by one of four topical antibiotics: ofloxacin 0.3 percent, azithromycin 1 percent, gatifloxacin 0.3 percent or moxifloxacin 0.5 percent.

Even before the first injection, there was 50 percent resistance to three fluoroquinolones (ofloxacin, levofloxacin and gatifloxacin) by conjunctival cultures of Staphylococcus lugdunensis, a particularly virulent coagulase-negative species (CNS) organism that has been associated with endophthalmitis. In this study, about 60 percent of the CNS isolates were resistant to at least three antibiotics and 30 percent were resistant to five or more antibiotics.

A third of the nasopharyngeal cultures grew S. aureus. Of the eight isolates, one was resistant to all 16 antibiotics tested.

—Linda Roach   


1 Kim, S. J. et al. Ophthalmology 2010;117(12):2372–2378.

EyeNet thanks K. David Epley, MD, for his help with this issue’s News in Review.

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