Iluvien and the Future of Ophthalmic Drug Delivery Systems

I was recently sent a news release from Alimera Sciences, who have filed an NDA requesting priority review for its Iluvien sustained release drug delivery system for treating diabetic macula edema, which if granted could result in an action letter granting approval for marketing before the end of this year.

This got me thinking that I hadn’t written about ophthalmic drugs (except for Avastin and Lucentis) since I wrote about “Site Specific” Ophthalmic Drugs in June 1990, for the old Ophthalmology Management magazine. I followed that up with a series of three articles titled, On the Pharmaceutical Front – parts 1&2 appearing in the March and April 1991 issues of that same magazine, and the 3rd (and final) part began my ten-year plus run of writing a regular column (Technology Update) for Ocular Surgery News in December 1991.

Back in 1990, the key words were “site specific”, i.e., drugs that were activated at the site where they were needed, under development by Xenon Vision, based on the drug delivery patents of Dr. Nicholas Bodor of the University of Florida. Then in 1991, I wrote about Alza and its Ocusert sustained delivery system. It was a drug-filled rod inserted under the lower lid to dispense drugs. Also, Escalon Ophthalmics obtained rights to a rod-shaped sustained drug release device from the Institute of Ophthalmology in London, that apparently was inserted into the conjunctiva. And, at the time, Chiron Ophthalmics and Bausch & Lomb were investigating the release of drugs from collagen shields and contact lenses.

At that time, I was not aware of anyone developing drug delivery systems that could be inserted into the vitreous to deliver drugs to the retina, and I stopped writing about drugs and delivery systems until my new interest in drugs and devices for treating AMD upon my retirement in December 2005.

I have recently written about a new drug delivery system, the On Demand Therapeutics device, from the Dr. Robert Langer labs at MIT, that supposedly can hold several cells of drugs in a reservoir and have each cell activated to release its contents via a laser beam. (AMD Update 11: Potential Breakthrough Drug Delivery System for AMD) But, this development is in a very early stage and may or may not ever reach commercial development.

So, I began some research into current thinking and developments in ophthalmic sustained release drug delivery systems and I quickly learned that I’ve missed a lot, and as my friend Jerry Helzner wrote in a recent issue of (the new) Ophthalmology Management, “I have seen the future of medical ophthalmology and its name is sustained-release drug delivery.”

What I would like to relate in this opus is what Iluvien is all about, how it was developed, and a little about what others are doing in this field.

The Iluvien Story

Iluvien is a tiny, extended release intravitreal insert, that is being developed by Alimera Sciences as a way to deliver fluocinolone acetonide (FA), a corticosteroid, to the retina for up to three years of treatment for diabetic macular edema (DME).

The Iluvien intravitreal insert (see picture 1), is a tiny cylindrical polyimide tube, 3.5mm in length and 0.37mm in diameter, that contains 180 μg of fluocinolone acetonide (FA). It is about the size of a grain of rice, and is designed to provide a low daily dose of FA, a non-proprietary corticosteroid with a history of treating ocular disease. Iluvien is inserted into the patient's eye using a proprietary inserter with a 25 gauge needle, which allows for a self-sealing wound. Iluvien is placed in the back of the eye, in the vitreous (see picture 2), to take advantage of the eye's natural fluid dynamics to deliver FA to the retina. A single Iluvien insert is designed to provide sustained therapy for 24 to 36 months. By combining FA and a delivery device that provides for a unique long term, low dose delivery of FA to the back of the eye, it is believed that Iluvien has the potential to improve vision of those suffering from diabetic macular edema, while reducing common side effects of corticosteroids.

Picture 1 Comparison to grain of rice

Picture 2 Insertion into the vitreous

The Iluvien insert uses the Medidur delivery platform, licensed from pSivida in 2005. (For more on the Medidiur technology and pSivida’s role in the development of the sustained release delivery system, see The Back Story below.)

Addressing Diabetic Eye Disease

Diabetic retinopathy is the most common eye disease affecting people diagnosed with diabetes mellitus and is a leading cause of blindness in adults. The term "diabetic retinopathy" refers to a variety of disorders characterized by changes in the eye's retina that can occur in people diagnosed with diabetes. Diabetic eye diseases cause damage to the retina through swelling, fluid leaks, or abnormal growth of blood vessels, resulting in severe vision loss or blindness. Usually affecting both eyes, diabetic retinopathy may not be noticeable for some time, developing so gradually that serious retinal damage may take place before any changes in vision are noticed.

A Progressive Condition

Retinopathy progresses through four stages:

1. Mild Non-proliferative Retinopathy - This is the stage in which small areas of balloon-like swelling occur in tiny blood vessels in the retina.

2. Moderate Non-proliferative Retinopathy - At this stage, blood vessels that supply nutrients to the eye become closed off and blocked.

3. Severe Non-proliferative Retinopathy - More and more blood vessels cease to function, cutting off blood supply to the retina. The retina signals the body to grow new blood vessels.

No treatment is required for mild Non-proliferative Retinopathy, other than through control of levels of blood sugar, blood pressure, and serum cholesterol to retard early disease progression. (Diabetic Macular Edema can occur between moderate and severe non-proliferative, all the way through proliferative, and it is treated by lasers, see below.)

4. Proliferative Retinopathy - New blood vessels appear, but they are abnormal and weak. They grow along the clear gel that fills the eye (the vitreous). When the thin, fragile walls of the blood vessels begin to leak blood, severe vision loss or blindness can occur.

Treatment options for Proliferative Retinopathy include forms of laser surgery called scatter photocoagulation and focal photocoagulation. In photocoagulation, tiny burns are placed on the retina with a special laser. These burns seal the blood vessels and stop them from growing and leaking. In scatter photocoagulation, abnormal blood vessels are shrunk by a retinal specialist who applies as many as 2,000 laser burns in a polka dot pattern in areas of the retina away from the macula. While some loss of side vision may occur, scatter photocoagulation can save the rest of a person's sight. However, it is only effective before bleeding or detachment has progressed very far. In focal photocoagulation, specific leaking blood vessels in a small area of the retina, usually near the macula, are addressed. The retinal specialist identifies individual blood vessels for treatment and makes a limited number of laser burns to seal them.

Eye disorders attributable to diabetic retinopathy include: diabetic macular edema, cataracts, and glaucoma

Diabetic Macular Edema

Macular edema occurs when blood vessels in the retina begin to leak into the macula, the part of the eye responsible for detailed central vision. When this occurs in a patient with diabetes, it is referred to as diabetic macular edema or DME and is the major cause of vision loss in people with diabetic retinopathy. The lifetime risk for diabetics to develop DME is about 10%.

These leaks cause the macula to thicken and swell, progressively distorting acute vision. While the swelling may not lead to blindness, the effect can cause a severe loss in central vision. DME is classified into two types; focal and diffuse. Focal macular edema is caused by vascular abnormalities, primarily microaneurysms, which tend to leak fluid whereas diffuse macular edema is caused by dilated capillaries in the retina. This condition, at the moment, is treated with local focal coagulation as there is presently no FDA approved drug treatment.

Disease Prevalence

Diabetic retinopathy and vision loss Diabetic retinopathy is the leading cause of vision loss among working age adults in developed countries. For people with diabetes, the risk of blindness is more than 3 in 100,000 people. The disease affects nearly half of all Americans diagnosed with diabetes, and is the leading cause of new cases of blindness among adults between the ages of 20 to 74. Over 12,000 to 24,000 new cases of blindness occurring each year are attributed to diabetic retinopathy.

When the blood vessel leakage of diabetic retinopathy causes swelling in the macula, the part of the eye responsible for central vision, the condition is called DME. The Wisconsin Epidemiologic Study of Diabetic Retinopathy found that over a ten-year period approximately 19% of diabetics studied were diagnosed with DME. Based on this study and the current U.S. diabetic population, Alimera estimates there to be a prevalence of close to one million people and an incidence of approximately 300,000 new cases of DME annually in the United States. As detection of diabetes increases, the company expects its current estimates of the annual incidence of diagnosed DME to also increase.

Results to Date

Alimera is currently conducting two Phase 3 pivotal clinical trials (collectively known as the FAME Study) for Iluvien, involving 956 patients in sites across the United States, Canada, Europe and India, to assess the efficacy and safety of Iluvien with two doses, a high (an approximate initial 0.45 micrograms (µg) per day) dose and low (an approximate initial 0.23 micrograms (µg) per day) dose, in the treatment of DME.

In December 2009, the 24-month clinical readout from the FAME Study was completed and announced. The primary efficacy endpoint for the FAME Study is the difference in the percentage of patients whose best corrected visual acuity (BCVA) improved by 15 or more letters from baseline on the ETDRS eye chart at month 24 between the treatment and control groups. The study will conclude later this year with the final patient visits at the three-year data point.

The 24-month analysis demonstrated statistical significance with 26.8% to 30.6% of the low dose patients having an improvement in BCVA of 15 letters or greater over baseline and 26.0% to 31.2% of the high dose patients having an improvement in BCVA of 15 letters or greater from baseline. In addition, both the low and high dose Iluvien showed greater numerical efficacy at month 24 than at month 18, a requirement for NDA submission with 24 month data in the United States.

Safety was assessed for all patients treated in the study. Intraocular pressure (IOP) increases of 30 millimeters of mercury (mmHg) or greater at any time point, a key adverse event studied in the trial, were seen in 16.3% of the low dose patients and 21.6% of the high dose patients. Over the 24 month period, 2.1% of patients receiving the low dose and 5.1% of the patients receiving the high dose had undergone a trabeculectomy (filtration procedure) to reduce their eye pressure.

A 30-month analysis of the FAME date was presented at the Citi Investment Research Global Health Care Conference on May 27th, 2010. The analysis focused on the primary efficacy variable of the number of patients who improved by 15 letters or more, based on observed cases. At month 24, 31% of the low dose patients had improved vision of 15 letters or more and at month 30, with a sample size of 123 patients, an improvement in visual acuity of 15 letters or more was seen in 40% of the patients. (See Graph 1). Statistical significance versus control was seen by three weeks among the observed cases, and this significance was maintained through month 30. The complete 36-month dataset will be presented at the fall AAO Meeting after the trial concludes in October 2010.

Graph 1. Percent of patients achieving greater than or equal to15 letters of visual acuity improvement using the observed cases method.

Based on these and other data, Alimera, on June 29, 2010, filed a New Drug Application (NDA) to the FDA for the low dose of Iluvien for the treatment of DME. In the submission, Alimera requested priority review, which, if granted, could result in an action letter from the FDA in the fourth quarter of 2010.

On July 8, 2010, the company also submitted a Marketing Authorization Application (MAA) to the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom (UK). The MAA is being submitted through the Decentralized Procedure with the UK MHRA as the Reference Member State (RMS). Applications have also been submitted to the following other Concerned Member States (CMS) in the European Union: Austria, France, Germany, Italy, Portugal and Spain..

Alimera's Future Focus On Diabetic Eye Disease

Alimera Sciences Inc. is a public biopharmaceutical company that specializes in the research, development and commercialization of ophthalmic pharmaceuticals. The company is currently in the process of completing two 36 month Phase 3 pivotal clinical trials with Iluvien for diabetic macular edema (DME). Combined enrollment of 956 patients was completed in October 2007 and a preliminary 24 month readout of the studies occurred at the end of 2009. As incidences of diabetes and diabetic retinopathy escalate, Alimera Sciences is in the forefront of research and development to meet the increasing need for reliable, effective treatments.

While dedicating much of its early resource allocation to the study of DME, the company looks forward to applying its efforts with the Medidur delivery platform (used with Iluvien), for super-antioxidants, and other therapies under investigation for the management and control of other retinal diseases.

As shown in the Pipeline graphic below, Alimera is developing Iluvien devices for the treatment of wet (as an adjunct to Lucentis) and dry (for geographic atrophy) AMD and retinal vein occlusion. In addition, the company is in the pre-clinical stages of development of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase inhibitor, also for treating geographic atrophy in dry AMD.

The Back Story

As I have related in the introduction, there have been many attempts at using sustained release in treating various eye diseases, including gels, rods, loaded contact lenses, and impregnated devices placed in the conjunctiva.

However, it wasn’t until the ganciclovir implant was developed by co-inventors Paul Ashton, Andrew Pearson, Thomas Smith and David Blandford at the University of Kentucky in 1989, in response to the AIDs crisis of the 1980s and 1990s, that a long-acting implantable device became available. That device, now known as Vitrasert, became available after Paul Ashton left Kentucky to start a small drug delivery development company in the Boston area called Control Delivery Systems, and partnering with Chiron, now Bausch & Lomb, got Vitrasert approved for marketing by the FDA in 1996 to treat cytomegalovirus (CMV) retinitis, a condition associated with late-stage AIDS that often leads to blindness.Vitasert releases ganciclovir (Cytovene) directly to the diseased area of the eye over a period of six to eight months and has been a successful treatment for thousands of patients over the past 14 years.

In 1989, Pearson, Smith, Blandford and Ashton were all at the University of Kentucky working on a device to deliver drugs for glaucoma filtering surgery. (Smith was the principal investigator and a glaucoma surgeon; Ashton had just completed post doctorate work, – his Ph.D. is in drug delivery, and Pearson and Blandford were doing their residencies in ophthalmology). According to Ashton, Pearson had the idea to adapt the drug delivery system for the back of the eye and put ganciclovir in it in order to help treat AIDS patients who were then going blind due to CMV Retitis. The first person to be implanted was an AIDS patient from Texas who received the implant in 1990. Smith went into private practice around 1992 as did Blandford, when he qualified as an ophthalmologist. Ashton moved to Boston  to take a position with New England Eye Center. Pearson, however, remained at the University of Kentucky and is now chairman of the Department of Ophthalmology.

Control Delivery Systems was acquired by the Australian company pSivida Ltd. in 2005 and was re-named pSivida Corp. in 2008 when the company reincorporated as a Delaware company. It is headquartered in Boston and Ashton is CEO. CDS also developed, and pSivida now owns, the technology used for the Retisert fluocinolone acetonide (FA) intravitreal implant, marketed by Bausch & Lomb and currently approved for the treatment of chronic noninfectious uveitis affecting the posterior segment, and the Medidur implant technology, licensed to Alimera Sciences and used in the Iluvien FA intravitreal insert. pSivida has also licensed the underlying Medidur technology for all ophthalmic indications not licensed to Bausch & Lomb or Alimera, to Pfizer for all other ophthalmic indications.

pSivida, as shown in Graph 2 below, has several other products in its pipeline in addition to Vitrasert, Retisert and Iluvien. For more information about pSivida and its products and technology, please visit the company’s website: http://www.psivida.com/products.html.

Graph 2 pSivida Pipeline of New Implantable Drugs

In addition, an article by Glenn J. Jaffe, MD, “Sustained Drug-delivery for Retinal Disease: Current technologies include implanted and injected devices”, in the June 2010 issue of Retina Today (2) explains more about the development of Vitrasert, Retisert, and Iluvien by CDS and pSivida and its licensee, Alimera Sciences.

Other Sustained Release Ophthalmic Drugs

As stated by Dr. Robert Avery in his editorial comments introducing the June 2010 issue of Retina Today, “As evidenced by the number of abstracts and posters on drug delivery that were presented at the 2010 ARVO meeting, the science of delivery of pharmaceuticals to the back of the eye is clearly a burgeoning field in the subspecialty of retina. Goals in drug delivery research include targeting therapy for maximum or minimal effect on collateral tissue, creating a depot system that would offer sustained therapy with single administration, reducing the physical burden on patients and physicians (eg, frequent intravitreal injections), and reducing associated costs.”

Dr. Avery further stated, that as of the date of his preparing the editorial commentary, “...there are three FDA-approved therapies that provide sustained posterior- segment drug delivery. The first is the ganciclovir implant (Vitrasert, Baush & Lomb), approved for cytomegalovirus retinitis; the second is approved for uveitis (intravitreal fluocinolone acetonide 0.59 mg implant (Retisert, Bausch & Lomb) and the third is intravitreal dexamethasone 0.7 mg, approved for the treatment of retinal vein occlusion (Ozurdex, Allergan, Inc.). Additionally, several modes of delivery are being evaluated in the preclinical and clinical trial setting to determine safety and efficacy. “

In the same issue of Retina Today, Dr. Szilard Kiss stated, “Retina practices are becoming overwhelmed with the ever-increasing burdens of repeated intravitreal injections for the treatment of age-related macular degeneration (AMD) and macular edema associated with retinal vein occlusion (RVO) and diabetic retinopathy. The need for frequent intraocular injections and the potential side effects associated with those injections has focused attention on the development of alternative systems for the delivery of ophthalmic medications. A variety of methods have been proposed that achieve longer duration of pharmacologic effect with lower administration frequency and minimal side effects.”

I would like to briefly describe some of the sustained release ophthalmic drug systems that 1) have been approved for marketing, and 2) are being developed for use in treating retinal and other ocular diseases.

FDA-Approved Systems

Vitasert (B&L, pSivida) – is a ganciclovir implant tht provides an antiviral release into the eyes of patients with AIDS for the treatment of cytomegalovirus retinitis. It is an ethylene viny acetate and polyvinyl alcohol polymer, sutured into the eye wall to deliver the drug over a 5-8 month period.

Retisert (B&L, pSivida) – is a flucinolone acetonide (FA) implant for release of this corotocosteroid into the eye to treat uveitis. It uses a silicone-polyvinyl alcohol combination polymer, and like Vitasert, is sutured into the back of the eye, for delivery of the drug for up to 30 months.

Ozurdex (Allergan) – is a dexamethasone biodegradable implant for treating macula edema following branch or central retinal vein occlusion. The Novadur system is composed of a poly D,LSustained lactide-co-glycolide (PLGA) polymer matrix that slowly degrades to lactic acid and glycolic acid, enabling extended release of dexamethasone over thirty days, with the expectation that patients can go six months without the need for additional treatment.

Sustained Delivery Systems Under Development

Alimera/pSivida – Iluvien – wet AMD (adjunct to Lucentis)

– Iluvien – dry AMD/geographic atrophy

– Iluvien – retinal vein occlusion

Alimera/Emory Univ. – NADPH – dry AMD/geographic atrophy

Allergan – brimonidine implant. A selective alpha 2 adrenergic agonist as an IVT implant for GA in dry AMD

Genentech/Surmodics – Lucentis for 6-8 month treatment of wet AMD

Glaukos – drug eluting stent

Icon Biosciences – Verisome (IBI-20089) – sustained release drug delivery system that injects a liquid into the vitreous that coalesces into a single spherule. It delivers a titrable drug for up to 1 year for the treatment of edema associated with retinal vein occlusion

Jerini Ophthalmics/PR Pharmaceutical – JSM 6427 –integrin anatagonist injectable sustained release technologies

Lux Biosciences – Lumiject (LX201) – an episcleral implant for delivery of cyclosporine A for prevention of corneal transplant rejections.

MacuCLEAR/Mystic Pharmaceuticals – Versidoser (MC1101) – delivers an anti-hypertension drug to prevent dry AMD from progressing to the wet stage, by preventing the rupture of Bruch’s membrane.

Macusight/Sirolimus – Perceiva – subconjunctival injectable immunosuppressant that uses the sclera for sustained release

Merck/Surmodics – I-Vation – triamcinolone acetonide helical implant for delivery of TA for up to 2 years for DME. The trial has been suspended, data supported focal/grid photocoagulation over the drug delivery. Further, Merck has pulled out of its licensing deal with Surmodics.

Neurotech – NT-501 – encapsulated cell technology (ECT) to deliver ciliary neurotrophic factor (CNTF). For treatment up to 12 months in treating progressive loss of photoreceptors in retinitis pigmentosa, AMD, and related retinopathies, including geographic atrophy in dry AMD

Novagali Pharmaceutical – Cortiject (NOVA63035) – injectable emulsion containing a proprietary tissue-activated corticosteroid, acting for 6-9 months in treating DME

On Demand Therapeutics/InterWest Partners – a unique drug delivery reservoir that can hold multiple cells of a drug and have each cell release its contents by puncturing the cell with a laser beam, for example, Lucentis or Avastin could be placed in the reservoir and released “on demand” using an ophthalmic laser.

Potentia/Alcon – POT-4 – depot forming properties of the cyclic peptide compstatin that functions as a complement factor C3 inhibitor that forms gel-like IVT deposits for slow release in treating wet AMD

QLT – latanoprost coated punctal plug to treat open angle glaucoma for up to 3 months

Regeneron – VEGF Trap-Eye – protein blocks of VEGF-A, VEGF-B and Pl GF (placental growth factor) for wet AMD, CRVO and DME

References:

1. Sustained-Release Drugs: Heralds of the Future, Jerry Helzner, Ophthalmology Management, March 2010.

2. Sustained Drug-delivery for Retinal Disease: Current technologies include implanted and injected devices, Glenn Jaffe, MD, Retina Today, June 2010.

3.Sustained- release Corticosteroid Delivery Systems, Szilard Kiss, MD, Retina Today, June 2010.

A New Laser-based Diagnostic to Detect Malignant Breast Cancer Tumors

It has been some time since I last addressed a medical laser application not connected with ophthalmology on this site. As many of you who visit this Journal regularly know, the vast majority of my consulting time was spent in ophthalmology, including applications involving ophthalmic lasers. I did, however, do a considerable amount of consulting work (and writing) about medical and surgical lasers.

So, when I read this story about a new hand-held device for detecting breast cancers using laser diagnostics, I decided to look further into the invention, and discovered that it is was an important story that should be brought to your attention.

The original story appeared on the University of California-Irvine (UCI) website, and the version I read appeared in the Spring 2010 issue of the Beckman Laser Institute Newsletter (BLI), LASER I have incorporated portions of both writeups in my version below, along with a synopsis of the journal article, based on this technology, that appeared in the January 2010 issue of Radiology, all presented with the permission of the Director of the BLI, Dr. Bruce Tromberg and Tom Vasich of UCI.

Using Lasers to Improve Cancer Care

In 2003, UC-Irvine Beckman Laser Institute (BLI) researchers received a $7 million grant from the National Cancer Institute (NCI) to standardize the use of a laser imaging device they had created for better breast cancer detection and treatment. This effort is beginning to bear positive results.

In January 2010, the researchers reported in the journal Radiology (Radiology 254: 277-284, 2010) that this hand-held laser breast scanner (LBS) can accurately distinguish between malignant and benign tumors, potentially providing an easy-to-use, non-invasive technique to see whether breast tumors warrant further aggressive treatment. The study involved 60 subjects and will be replicated with a larger test group.

The team’s approach is based on a sophisticated new analysis method developed by UCI Biomedical Engineering Professor Enrico Gratton and M.D./Ph.D. student Shwayta Kukreti, that produces a spectral “fingerprint” or signature for each patient. Their technique was developed specifically for the hand-held laser breast scanner (LBS) developed by Beckman Laser Institute (BLI) Director and grant Principal Investigator, Professor Bruce Tromberg, and BLI Professor Albert Cerussi.

Bruce Tromberg (right), director of the Beckman Laser Institute, and UCI oncologists John Butler, David Hsiang and Rita Mehta (from left) are evaluating a breast imaging device that produces metabolic "fingerprints."

The scanner works by measuring metabolism in breast tumors and normal breast tissue. Unlike mammography, the LBS provides detailed functional information by measuring hemoglobin, fat and water content, as well as tumor oxygen consumption and tissue density. In the study, the researchers found that potentially dangerous malignant tumors have a different metabolic fingerprint compared to benign tumors.

“The LBS spectral signature method has the potential to help improve detection and diagnosis in women with dense breast tissue who don’t do well with mammography,” according to co-author and UCI surgical oncologist Dr. David Hsiang.

“Unlike with other technologies, the laser breast scanner provides a metabolic fingerprint of tumors without the use of added contrast agents,” says Tromberg, who worked with a multidisciplinary team of biomedical engineers and oncologists on this effort. “This can help make diagnosis more exact and treatment more focused.”

Younger women typically have dense breast tissue, and since breast cancer in that demographic is often more deadly, early detection is critical.

In a second area, the UCI laser breast scanner is being used to evaluate the effectiveness of chemotherapy treatments. The scanner is proving beneficial for providing detailed information on changes in breast tumor metabolism during chemotherapy. This information, which can be accessed quickly at the bedside, allows oncologists to target chemotherapy treatments more effectively and safely, tailoring them to how the patient responds.

“The use of chemotherapy for tumor reduction prior to surgery is an important approach for certain types of breast cancer,” says surgical oncologist Dr. John Butler, who works with medical oncologist Dr. Rita Mehta and the BLI team. “The metabolic fingerprint the laser breast scanner provides gives detailed clues on how the chemotherapy is working and allows doctors to adjust treatments as needed.”

Currently, the BLI/UCI researchers are also working with colleagues at the University of Pennsylvania, Dartmouth College, UC San Francisco and Massachusetts General Hospital in Boston to start a five-center clinical study, coordinated by the NCI and the American College of Radiology Imaging Networks (ACRIN), for monitoring and predicting the effectiveness of chemotherapy treatments in breast cancer patients. In addition, the San Francisco Bay Area biotechnology company FirstScan has licensed the technology for commercial applications.

“This is an important opportunity to standardize our approach and determine, in a national multi-center trial, how this new technology can help improve the treatment and quality of life for breast cancer patients,” Tromberg added.

Characterization of Metabolic Differences between Benign and Malignant Tumors: High-Spectral-Resolution Diffuse Optical Spectroscopy

To provide further insight, the following information was taken from the article describing the new technology, published in the January 2010 issue of Radiology.

Program Objective/Purpose: The objective of the study was to develop a near-infrared spectroscopic method to identify breast cancer biomarkers and to retrospectively determine if benign and malignant breast lesions could be distinguished by using this method.

Through the application of a spectral analysis method that accounts for interpatient variability, it was discovered that metabolic differences occur between malignant and normal tissues that result from subtle changes in molecular disposition. The purpose was to demonstrate how absorption signatures, likely resulting from changes in lipid, hemoglobin, and water metabolism, rather than the abundance of molecules, help distinguish between benign and malignant breast tumors.

Materials and Methods: By using self-referencing differential spectroscopy (SRDS) analysis, the existence of specific spectroscopic signatures of breast lesions on images acquired by using diffuse optical spectroscopy imaging in the wavelength range (650–1000 nm) was established. The SRDS method was tested in 60 subjects (mean age, 38 years; age range, 22–74 years). There were 17 patients with benign breast tumors and 22 patients with malignant breast tumors. There were 21 control subjects .

Patients Studied: From a search of patient records dating from August 2004 to January 2007, DOS imaging data for 60 subjects were selected; there were 22 malignant tumors, 18 benign tumors (17 patients), and 21 control subjects. Selection criteria from the protocol were as follows: female, older than 21 years, not pregnant, not taking light sensitive medications, and had given written informed consent. In addition, for patients with lesions, the subject must have had a suspicious finding on a mammogram or sonogram prior to enrollment in the study. All subjects had palpable lesions. Patients were generally referrals from a physician.

Tumor disease was confirmed by using standard of care biopsy results, and control subjects had normal mammographic findings. All subjects were women (age range, 22–74 years). Within each group, mean age and range were as follows: malignant group (mean age, 39 years; range, 32–65 years), benign group (mean age, 33 years; range, 22–57 years), and normal group (mean age, 42; range, 22–74 years).

Instrumentation: The diffuse optical spectroscopy (DOS) instrument used a combined frequency-domain and continuous-wave tissue. The combined system was necessary to provide absorption and scattering spectra from 650 to 1000 nm (approximately 1000 wavelengths with 8-nm spectral resolution). The frequency-domain light sources are six independent laser diodes (660, 690, 780, 808, 830, and 850 nm), while the continuous-wave light source is a tungsten-halogen lamp. Frequency-modulated light was detected by using an avalanche photodiode detector, and continuous-wave light was detected by using a back-illuminated spectrometer.

The handheld probe, (as shown in use in Fig 1), incorporated source (i.e, optical fibers) and detector (i.e, avalanche photodiode detector and a spectrometer detector fiber) channels. Less than 20 mW of optical power was launched into the tissue at any time by using reflection geometry (28-mm source detector separation). Frequency domain measurements were calibrated with a tissue-simulating phantom with known absorption and scattering properties. Spectral response was calibrated by using a commercial reflectance standard (Spectralon, Labsphere, North Sutton, NH).

Figure 1. Photo of Device in Use

DOS imaging measurements were acquired by moving the handheld probe over the tumor in lines of discrete measurement points spaced 10 mm apart ( Fig 1 ). Tumor locations were known a priori from mammographic findings, ultrasonographic (US) findings, and/or palpation. Patients were measured in the supine position. Probe contact was similar to that as used with ultrasonography, by using gentle contact on the breast without compression. Full broadband absorption and reduced scattering spectra were measured at each spatial location, requiring less than 10 seconds per spatial location. Similar measurements were taken on the mirrored location of the contra lateral breast.

Results: Figure 2 shows the specific tumor components (STC) spectra acquired from 22 malignant breast tumors and the spatially equivalent normal tissue from the same patients, as well as normal regions from 21 control subjects. Despite the wide range in patient age and tumor size, the STC spectrum was present in all 22 tumors and was not found in the normal tissues of any subjects in this study. STC spectra were found in all malignant cases and displayed notable features in the following five wavelength regions: 650– 665, 730–800, 875–930, 930–960, and 980–1000 nm. We noted that the specific choice of normal region had little effect on the overall shape of the STC spectrum. The STC spectral shapes were similar to the original, and the tumors were classified as benign or malignant.

Figure 2. Spectra of Cancerous vs. Normal Tissue

In Figure 3, a comparison of STC spectra that have been normalized to the amplitude (thereby providing a ratio) to retrieve the differences in spectral shape, as opposed to magnitude, from both benign (fibroadenoma) (n = 18) and malignant (n = 22) tumors. Distinctive spectral differences exist between the STC spectra of these populations.

Figure 3. Spectra of Cancerous vs. Benign Tumors

As noted in the results, three of the 40 tumors analyzed were misclassified. One benign tumor was misclassified as cancer, and two cancers were misclassified as benign, showing that more work on this method is needed.

Conclusions: On the basis of the wavelength dependence of the STC spectrum, it was hypothesized that the signature is due to changes in lipid metabolism. Recent studies have shown that cancers can alter the lipid metabolism. Benign lesions such as fibroadenomas display hemodynamic signatures similar to those of malignant lesions.

There were limitations to the study. Fibroadenomas were the only type of benign tumors measured. Furthermore, the lesions were not corrected for depth.

In conclusion, the SRDS method relies on the presence or absence of a spectral fingerprint that reports on molecular disposition and not molecular abundance. These changes in molecular disposition are on the order of parts per thousand and are possibly due to alterations in the lipid state. The SRDS technique subtracts for the unique metabolism of each individual patient and facilitates comparisons across patient populations. The observed molecular dispositions were converted into a simple index that stratified benign and malignant tumors in a population of 40 subjects with lesions. The observation of pathologic state-specific spectral signatures provided a potentially significant method for differential diagnosis and monitoring response to therapy.

Editors Note: For some perspective, I asked a noted breast cancer oncologist from the Dana Farber Cancer Institute in Boston for his thoughts on the technology and the paper in Radiology.

Basically, he said that “The technology will have to improve, since missing 2 out of 22 tumors is simply not good enough. That said, it is an interesting technology and has the ability to push the field forward. Since the researchers are evaluating whether a breast abnormality is benign or malignant, the technology can probably be evaluated in several hundred patients. If it is a useful test in that setting, there is potential to launch a large screening study, though such a study would have to be several orders of magnitude larger.”

Next Steps:

The 60 patient study reported in the Radiology article was completed in 2008. Currently, the BLI/UCI teams are working with colleagues at four other institutions, to undertake a five-center clinical study, being coordinated by the National Cancer Institute and the American College of Radiology Imaging Networks (ACRIN), for monitoring and predicting the effectiveness of chemotherapy treatments in breast cancer patients.

The four other institutions are: the University of Pennsylvania, Dartmouth College, UC-San Francisco, and the Massachusetts General Hospital in Boston.

I asked Bruce Tromberg about the follow-on study and learned that the ACRIN 6691 is a protocol recently approved by the NCI to assess how well the Diffuse Optical Spectroscopic Imaging (DOSI) technology works in monitoring and predicting patient response to pre-surgical neoadjuvant chemotherapy. BLI, which has published extensively on this topic, has been working on the protocol for about 3 years, and the NCI committee, CTEP, has just approved it as a national protocol for the five sites. DOSI instruments have been located at all sites and the teams hope to officially kick off the study this fall. It should take about 2-3 years to complete. The clinical endpoint is pathological complete response (pCR), and the teams will be looking at how its tissue optical index (TOI) correlates with and predicts pCR.

He also said, “Outside of neoadjuvant chemotherapy monitoring, our near term goal with this technology, in terms of detection/diagnosis, is to focus on younger and mammographically dense subjects. This population has no good alternatives, with sensitivity/specificity ranging from ~50% to "unable to determine"...so the standard of care "bar" we need to beat is quite a bit lower.”

In addition, a Bay area company called FirstScan has licensed the technology for commercial applications. In checking their website, I discovered it had not been updated since 2005 – so I asked the Dr. Tromberg how this company is involved and what are they doing with the technology?

His response: “FirstScan has licensed our technology, broadband DOS, from UCI, for breast cancer applications. This technology allows us to get full absorption and scattering spectra from thick tissues. They are developing a handheld breast scanner using optical imaging. They are a spinoff of Spectros which makes tissue oximeters.”

Further, as stated in the Radiology article, several of the authors hold patents related to the technology, are board members, and have licensed these patents to a company called Volighten, about which I could find very little information. I asked Dr. Tromberg how Volighten is involved and what were they were doing with the technology?

Again, he was kind enough to provide the answer. “This company has licensed the broadband DOS for applications, other than breast cancer. It was started by one of my former postdocs. Their goal is to develop portable prototypes and components for DOS, such as the scanning handpiece. It is a very early-stage company. I am one of the co-founders with less than a 5% interest.”