By Paul T. Finger, MD

Description

Chemotherapy commonly refers to the use of drugs to treat cancer of the eye, lids and orbit. Some of these drugs are also used to treat benign ocular tumors caused by inflammation.

Though this review tends to focus on the side-effects of chemotherapy, it is important to note that most patients are able to tolerate treatment, are helped by chemotherapy, and go on to enjoy their lives.

Clearly the use of chemotherapeutic drugs have cured patients and extended lives. Chemotherapy also offers a method to control inflammatory diseases and provide an alternative or adjunct to surgery and radiation.

How Chemotherapy Drugs Are Given

Systemic chemotherapy drugs can be infused into a patient’s vein (intravenous – IV) or by mouth (per oral – PO). These methods can expose the entire body to significant doses of chemotherapy.

In ophthalmology, we also give chemotherapy topically (ointment or drops) onto the eye. This places the drug on top of the tumor or affected area and limits the possibility of systemic (whole body) side effects. In ophthalmology, certain drugs are also given by periocular injection. The physician’s choice of delivery method depends on the type of chemotherapy drug and the reason why it is given.

Why Chemotherapy Drugs Are Given

Chemotherapy drugs are typically prescribed to attack or destroy a patient’s tumor or cancer. They can also be used to change a patient’s immune system. They can be used alone or in combination with radiation and/or surgery. In general, systemic chemotherapy is given when a patient needs a systemic (whole body) therapy, or when the risks of chemotherapy are less than those associated with radiation or surgery.

Side Effects & Complications

All drugs can have side-effects (unwanted effects). It is important to ask your doctor or nurse about the potential risks (side-effects) and benefits associated with your chemotherapy. This is important because each drug can have slightly different types of side-effects.

There are common side-effects associated with many chemotherapy drugs. Since these reactions may or may not be associated with your chemotherapy, you may want to ask if they will apply to your case.

A partial list of side effects includes: allergies, bone marrow depression, hair loss, mouth and throat problems, nausea and vomiting, sexual and reproductive problems, and skin changes.

Allergic Reactions

Allergic reactions can occur after taking almost any drug (including chemotherapy). They can occur immediately or can be delayed. If severe, the drug will be discontinued. If mild, allergy treatments – e.g. suppression agents (typically more drugs) can be used to proceed with chemotherapy.

Common allergic symptoms include:

• Rashes on the skin
• Swelling
• Shortness of breath
• Rapid heart beat

Rare allergic symptoms include:

• Decreased blood pressure
• Shock
• Kidney failure

Since most chemotherapy is given in a clinic or hospital, patients are typically watched for reactions after drugs are administered. In these controlled environments, prompt treatment is administered and allergic reactions are treated.

When at home after treatment, patients can notice late allergic reactions. If you notice skin rashes, weakness while standing or sitting, progressive swelling or any unusual changes you should contact your physician immediately.

Bone Marrow Suppression

Bone marrow depression (suppression) is a side effect caused by certain chemotherapy drugs. When it occurs, it typically happens 7-10 days after the chemotherapy is started and usually recovers after 3 weeks. There are biotherapy medications that can speed bone marrow recovery.

Blood cells and other blood components are made in the bone marrow. Therefore, bone marrow depression results in decreased numbers of white blood cells, red blood cells, and platelets.

When the body loses white blood cells (leukopenia), it is a greater risk for infection.
When the body loses red blood cells (anemia), it can be associated with fatigue.
When the body loses platelets (thrombocytopenia), the blood has trouble clotting and the patient is at greater risk for bruising and bleeding.

Symptoms suggestive of bone marrow depression?

• Fever or chills
• Fatigue
• Bruising or Bleeding

If you have fever, chills, fatigue, bruising or bleeding call your doctor immediately. In most cases your physician can give you medicines to treat bone marrow depression. These drugs can treat infections and compensate for low levels of white blood cells, red blood cells, and platelets.

Hair Loss – Alopecia

Hair loss (alopecia) is a common side effect of chemotherapy, but not all chemotherapy drugs cause hair loss.

Not all hair loss is total. It can affect the head or all parts of the body. It can be gradual. Typically hair loss does not happen immediately. It starts several weeks after the first chemotherapy, then hair can thin or come out in clumps. Some people also experience scalp sensitivity.

It makes sense to use a mild shampoo, a soft hair brush, and low heat when drying your hair. Avoid dyes, perms and hair relaxers. In general, a short hair cut looks fuller. If you don’t cover your head, you may need to use sun screen on your scalp.

It is normal to feel angry or depressed when you lose your hair. You should speak with your doctor or nurse about your feelings. There may be a support group or mental health professional who can help you. But remember, hair loss is usually a temporary side-effect. The hair will grow back.

Hats and Wigs

Most sources say you should shop for a wig before you lose most of your hair. That way you can match your usual style and hair color. Consider getting a wig with tape-tab materials called “stickies.” This will allow you to comb and style the wig without worrying about sliding. Most sources also suggest you buy two wigs so you can have one on while the other is being cleaned.

Check to see if your insurance company will cover its cost. If not, it is a tax-deductible expense (keep your receipt). Have the establishment write, “hair prosthesis as prescribed by doctor” on the receipt.

When buying a hat, make sure it will block the sun from hitting your scalp. Women also prefer to wear hats or turbans when at home. Don’t forget your sunglasses.

Mouth and Throat Problems

Chemotherapy can cause sores, red areas or white patches to form on the mouth and throat. This is particularly true for systemic methotrexate and 5-fluorouracil.

Since mouth and throat care are known to improve, stabilize or prevent progression of mouth sores, patients should call their doctor if mouth sores or soreness occurs.

Typical Mouth Care Instructions May Include:

• Regular, gentle cleaning of your teeth or dentures.
• Also, rinse your mouth with a mixture:
  • 1/2 teaspoon of salt in 8 ounces of water or
  • 1/2 teaspoon of sodium bicarbonate (baking soda) in 8 ounces of water.
  • This should be done after every meal and at bedtime.
• Avoid alcohol containing mouthwash.
• Avoid acidic or spicy foods.
• Avoid drinking alcohol and smoking.

Your doctor may have different methods of mouth care. So contact your doctor if you develop mouth sores, white patches, mouth pain or difficulty swallowing.

Nausea and Vomiting

Nausea and vomiting are the body’s defenses against eating too much and its mechanism to get rid of toxic food and poisons. During vomiting, the muscles that normally push food down the gastrointestinal tract, reverse direction and send back the partially digested material.

Nausea and vomiting may occur within the first hour of chemotherapy and can last up to a week. Most of the time nausea goes away shortly after these drugs are given.

In severe cases, anti-nausea medications may be necessary.
That is because the vomiting patient may lose too much fluid and necessary minerals. When a patient is at risk of dehydration and blood chemical (electrolyte) imbalance, your doctor or nurse can prescribe medication to help you prevent or lessen nausea.

Other causes of nausea that cancer patients may be experience include stress, radiation of the brain, and anesthetics (associated with surgery).

Treatment of Nausea and Vomiting 

The primary treatment for nausea is anti-nausea drugs. Since they work best taken before chemotherapy, discuss this with your doctor before your next treatment (particularly if you were nauseated after your last treatment).

Other methods include: acupressure wrist bands which are available at most drug stores, fasting (do not eat) for a couple of hours before your treatment, try to keep your eyes open, and slowly deep-breathing through your nose.

If you are already nauseated from chemotherapy, do not eat a large meal or drink carbonated beverages. You may try to eat crackers, pretzels, or dry toast. Avoid foods with a lot of residue, salads, high fiber cereals or fatty and fried foods.

Sometimes, right after chemotherapy patients are only able to suck on ice chips, sip ice water, or mild herbal tea. Once patients are feeling better, they may benefit from chicken soup.

If nausea and vomiting persist, call your doctor. Some patients need to receive intravenous (IV) fluids and electrolytes (minerals).

Sex and Reproduction

Chemotherapy-related sexual and reproductive problems can occur in both men and women.

Since certain chemotherapy drugs may have harmful effects on an unborn child, genetic counseling should be made available to the chemotherapy patient in order to discuss the effects of drug therapy on current and future pregnancies.

Studies & Research

1. Wilson MW, Czechonska G, Finger PT, Rausen A, Hooper ME, Haik BG. Chemotherapy for Eye Cancer Survey of Ophthalmology 45:416-444, 2001.
2. Calabresi P, Chabner BA. Chemotherapy of Neoplastic Diseases: Introduction. In: Goodman and Gilman’s: The Pharmacological Basis of Therapeutics. Tenth Edition Hardman JG, Limbird LE, Gilman AG (eds.) McGraw-Hill, New York, 2001, Section IX, pp.1381-1388.
3. Chabner BA, Ryan DP, Paz-Ares L, Garcia-Carbonero R, Calabresi P. Antineoplastic Agents. In: Goodman and Gilman’s: The Pharmacological Basis of Therapeutics. Tenth Edition Hardman JG, Limbird LE, Gilman AG (eds.) McGraw-Hill, New York, 2001, Chapter 52, pp.1389-1460.

Proton Beam Radiotherapy

By Paul T. Finger, MD

Proton beam radiation therapy is a form of teletherapy, where the radiation is directed into the eye from a machine outside the eye.

In order to aim the tube-shaped proton beam, surgical clips are sewn (surgically placed) on to the eye, around the tumor’s base. Then the patient returns for 3 to 5 daily outpatient treatments. During treatment, the eye must not move. Eye movement displaces the column of radiation away from the tumor, causing unnecessary radiation of normal ocular structures. Therefore, the eye must be open and closely monitored for movement while the radiation beam is traveling through the eye. If the patient closes their eye, it naturally rotates up “Bell’s Phenomenon” changing the position of both the eye and its tumor.

Eye cancer specialists commonly suggest protons or other external beam treatments when the tumor is touching (juxtapapillary) or surrounding (circumpapillary) the optic nerve. Since beam therapy can include the entire tumor (plus a tumor-free margin), beam therapy is likely to destroy the tumor. However such treatment places the optic nerve within the targeted radiation zone that also results in radiation-related optic nerve damage and loss of vision (in that eye).

Proton beam typically involves directing a column of radiation through the front of the eye (anterior segment, eye lids and/or orbit) in order to reach the intraocular tumor. Since the radiation typically enters the front of the eye, eyelash loss, eyelid excoriation, corneal neovascularization and ulceration, dry eye, neovascular glaucoma, and cataract are more common after treatment with proton beam radiation therapy (compared to low-energy plaque radiation therapy). Some of these effects may occur within weeks of treatment, others may take years to develop.

VS. Eye-Plaque Radiotherapy

In contrast, Plaque Therapy typically involves attaching a dish-shaped radiation source beneath the tumor and leaving it there for 5-7 days.

Compared with proton-beam, the front of the eye usually receives much less radiation with plaque radiation therapy, but parts of the back of the eye may receive more. This is why anterior “front of the eye” complications (eye lash loss, severe dry eye, neovascular radiation glaucoma) are unusual after low-energy palladium-103 or the older iodine-125 type ophthalmic plaque radiation therapy.

Tumors that touch the optic nerve are more difficult to treat with ophthalmic plaque radiation therapy. Over 12 years ago, Dr. Finger developed specialized “Finger’s slotted plaques” for treatment of tumors the touch or encircle the optic nerve (see below). Due to the advent of super-sized 24 mm (for extra-large tumors) and Finger’s slotted eye plaques (for tumors around the optic nerve), fewer than 6% of patients require enucleation (removal of the eye) as initial treatment for choroidal melanoma (at The New York Eye Cancer Center). Clearly, ophthalmic plaque radiation therapy is the most widely available and most commonly used eye and vision-sparing treatment for choroidal melanoma.

An Overview of Plaque Radiation Therapy in Treatment of Choroidal Melanoma (1,2)

*Note* These results were published largely prior to the discovery of intraocular anti-VEGF therapy for radiation retinopathy and optic neuropathy. To see Dr. Finger’s current results, go to his results page on this web site.

Summary

Currently eye cancer specialty centers should be able to offer radiation as an eye and vision-sparing alternative for 95% patients with intraocular melanoma. The two main types of radiation are eye-plaque brachytherapy (iodine-125, ruthenium-106, palladium-103) and external beam (Proton-Beam, stereotactic radiosurgery). Radioactive plaques are more commonly used and available in more centers throughout the world.

Side effects/complications

An Overview of Plaque Radiation Therapy in Treatment of Choroidal Melanoma (1,2)

Related links

• Scatter laser photocoagulation has been used in an effort to prevent radiation related vision loss.
• Information about the “Finger Classification of Radiation Retinopathy.”
• Compare results using different types of radiation plaques
• About radioactive plaque construction
• Read about Finger’s Slotted Plaques for Tumors Around the Optic Nerve
• Intravitreal Anti-VEGF Therapy For Radiation Retinopathy

References

1. Finger PT. Radiation Therapy for Choroidal Melanoma. Survey of Ophthalmology (Review Article) 42:215-32, 1997.
2. Finger PT., Berson A, Ng T, Szechter A. Palladium-103 Plaque Radiotherapy for Choroidal Melanoma: An 11-year study. Int. J Radiation Oncology Biol. Phys. Vol 54, No. 5, pp. 1438-1445, 2002.

By Paul T. Finger, MD

Radiation Retinopathy: Prevention and Suppression

Benjamin Franklin once wrote, “an ounce of prevention is worth a pound of cure.” ¹ Although he was referring to fire prevention, this adage also applies to radiation maculopathy.

Over the years, I have relentlessly sought ways to decrease therapeutic radiation to the fovea and optic nerve. For example, in the 1980s, I studied adding intraocular microwave hyperthermia to lowered doses of plaque radiation therapy for the treatment of choroidal melanoma.²

In 1990, I published on the use of radio-opaque vitreous substitutes to act as an internal shield during plaque radiation therapy.³ This strategy is being pursued today with silicone oil.⁴

However, it was not until the mid-1990s that I discovered a simple, low-risk opportunity to improve plaque radiation therapy.^5-7 Compared to iodine-125, the use of lower-energy palladium-103 photons shifted the intraocular dose distribution.⁸ It increased the dose within the tumor, while decreasing irradiation of most normal ocular structures.⁹

25 Years of Evidence

Since then, the dosimetric advantages of palladium-103 have been demonstrated in many published studies and affirmed in guideline publications from the American Association of Physicists in Medicine and the American Brachytherapy Society.^10-15

With more than 20 years of clinical experience, palladium-103 plaque therapy has offered superior local tumor control and among the lowest rates of metastatic disease (linked results).^7,16,17 The palladium-103-related decreased dose to the fovea and optic nerve has offered a simple method to prevent or delay radiation maculopathy and optic neuropathy.

There is strong clinical evidence that radiation maculopathy is dose-dependent.^18,19 In 2000, I first reported that there was less radiation maculopathy after ophthalmic plaque therapy for anterior vs posterior uveal melanomas.²⁰

Subsequently, Yousef reported a total lack of radiation maculopathy after palladium-103 plaque therapy for iris and iridociliary tumors.²¹ These clinical observations clearly linked radiation dose to fovea to the incidence of radiation maculopathy.

However, not all radiation maculopathy is preventable. The fovea dose depends on the size of the tumor, its intraocular location, and the radiation source (palladium-103, iodine-125, ruthenium-106, strontium-90, and proton beam). Each source and method of ophthalmic radiation therapy offer unique intraocular dose distributions and thus equally unique patterns of side effects.^11,22

Suppression of Radiation Retinopathy

Before 2005, there was no effective treatment for radiation maculopathy. Prior to the advent of anti-VEGF therapy, virtually all published studies of radiation for choroidal melanoma found that the resulting vision at three to five years was typically 20/200 or worse.⁶

This outcome should not be surprising. Macular radiation vasculopathy evolves from vascular incompetence (macular edema, hemorrhage, and cotton-wool spots) to an obliterative endarteritis (ischemia) with secondary neovascularization, vitreous hemorrhage, and preretinal fibrosis.²³

To this day some eye cancer specialists question the treatment of radiation maculopathy because it “burns itself out” or is “self-limited.” However, one look at the history of medicine demonstrates that untreated diseases (diabetes, hypertension) also exhibited a fulminant course, leaving significant morbidity in their wake. It was not until the discovery of insulin that the natural course of diabetes was suppressed, allowing patients to lead longer and more normal lives.²⁴

Laser Photocoagulation

Prior to anti-VEGF therapy, I would use laser to destroy the extrafoveal areas of diseased “ischemic” retina. Panretinal photocoagulation laser either prevented or slowed the progression of radiation retinopathy. When this strategy prevented radiation foveopathy, retinal neovascularization, and glaucoma, the patients typically maintained useful vision.

However, in 2005, I published the first evidence that laser demarcation of the posterior 180º around the tumor was effective for preventing or delaying radiation maculopathy.²⁵

This type of laser typically extinguished fluorescein evidence of intrinsic tumor circulation. In retrospect, demarcation laser likely decreased the tumor and peripheral retinal ischemia associated with VEGF production. The efficacy of demarcation laser was confirmed by Materin et al.²⁶ I currently use early (six to 12 months after plaque therapy) laser demarcation in an effort to avoid intravitreal anti-VEGF injections.

Anti-VEGF Suppression

There exists worldwide evidence that suppression of radiation maculopathy can be achieved with periodic intravitreal anti- VEGF therapy.^27-38 However, increasing anti-VEGF doses are typically required over time.²⁹ This goal has been accomplished by shortening time intervals between injections or increasing the dose (in milligrams) per injection.

Since my original paper, clinical research has demonstrated reductions in radiation-induced macular edema, retinal hemorrhages, and cotton-wool spots and relative preservation of vision.

A scientific report on our 10-year experience using anti- VEGF therapy for radiation maculopathy is available in the European Journal of Ophthalmology.³⁷ Download a PDF of This Study

Practical Questions and Clinical Pearls

Which Anti-VEGF Agent Is Best?

There have been no published clinical trials comparing intravitreal bevacizumab (Avastin, Genentech, South San Francisco, CA), ranibizumab (Lucentis, Genentech), and aflibercept (Eylea, Regeneron, Tarrytown, NY). However, at the New York Eye Cancer Center, we have found that all three anti-VEGF therapies are able to suppress radiation maculopathy.

When Should We Start Anti-VEGF Therapy?

Not all patients will develop radiation maculopathy, so we must select those who need close serial observation, early intervention, or prophylactic treatment. As physicians, we are in the business of risk mitigation. Therefore, we must balance the relative risks of intravitreal injection and ocular and systemic drug-induced side effects vs radiation-induced (typically monocular) vision loss.

At the New York Eye Cancer Center, we divide our patients into three risk groups. While this grouping is clinically based (by tumor size and location), we also rely on the preoperative calculation of radiation dose to the fovea.

Patients at low risk

For eyes at high risk (>50 Gy) or those that are certain to develop radiation maculopathy (tumors within 2 mm, touching or beneath the fovea), I discuss the relative risks and potential benefits of delayed vs immediate treatment.

When Should We Stop Anti-VEGF Therapy?

Anti-VEGF therapy suppresses and thus prolongs the evolution of radiation maculopathy. I have found that almost all patients who significantly delay or stop anti- VEGF treatment develop “off-treatment” recurrent macular edema. Although these cases respond (a second time) after restarting anti-VEGF therapy, measurable damage has typically occurred in the interim.

These cases have cemented my conviction that anti- VEGF treatment works, but it merely suppresses radiation vasculopathy. The more consistent we are with treatment, the more likely it is that vision will be preserved. The bottom line is that we do not stop therapy until there is no useful vision.

What Anti-VEGF Dose Is Best?

Anti-VEGF strength makes a difference. In our Genentech-sponsored IST testing 2.0 mg/0.05 mL ranibizumab radiation maculopathy trial, higher doses decreased radiation-associated macular edema in recalcitrant cases.²⁹

We also found that external beam radiation therapy (EBRT)–treated patients often require higher doses to suppress their radiation maculopathy.³⁰ I suspect that this relationship is due to a more generalized radiation-induced retinal ischemia, with more resultant VEGF requiring more anti-VEGF therapy.

Finally, we have used up to 3.0 mg/0.12 mL bevacizumab when lower doses have failed.³⁷ The only current way to increase anti-VEGF dose is to shorten the time between intravitreal injections or to increase drug volume. Additionally, self-sealing “angled” injections allow for more drug (the prescribed amount) to be retained within the eye.³⁹

As a general rule, we should use the lowest dose and longest time interval that best restore the normal “optical coherence tomography” anatomy of the macula and that preserve visual acuity.

Conclusions

Radiation dose can be used to predict the incidence of radiation maculopathy.¹⁸ Therefore, the prevention of radiation maculopathy can be achieved by selecting radiation sources that limit the dose to the macula and fovea via preoperative comparative simulations.⁹

Plaque Radiation-induced Radiation Maculopathy

At the New York Eye Cancer Center, we perform pretreatment mathematical modeling to compare the intraocular dose distribution of iodine-125 vs palladium-103 plaque therapy for each patient.^9,10 In general, source selection (for an equivalent tumor dose) focuses on which isotope will relatively spare the macula and/or optic nerve.

In general, if both sources produce doses that are suprathreshold for radiation maculopathy or optic neuropathy, we will use the source that offers the lowest organ dose (as measured at the opposite eye wall). Using these parameters, most plaque patients have been found to be better off being treated with the palladium-103 radionuclide.^9,40

External Beam Radiation-induced Radiation Maculopathy

In the treatment of primary orbital and metastatic tumors to the eye and orbit, most patients are treated with 6-MV photons using an external beam linear accelerator. Here, we discuss our concerns with the treating radiation oncologist. Strategies to decrease radiation maculopathy include limiting daily dose fractions to 180-200 cGy, macula-sparing radiation fields, and the use of the lowest possible therapeutic dose.⁴⁰

Laser Photocoagulation

For select posterior choroidal melanomas that are at high risk for radiation maculopathy, I continue to prefer laser demarcation to suppress the ischemic drive likely contributing to elevated intraocular VEGF.²⁵ Demarcation argon laser can be delivered in one or two sessions and may avoid or delay the need for periodic intravitreal injections.

However, in cases in which laser does not work or is not possible (eg, when the tumor is too near or beneath the fovea), anti-VEGF therapy will offer the patient the best chance for vision preservation.

Anti-VEGF Therapy

Anti-VEGF drugs can be used for radiation maculopathy related to the treatment of ocular lymphoma, uveal metastasis, and cancers of the lacrimal gland, sinus, and ocular adnexa.³⁰

Regardless of the source, our current strategy is initial monthly dosing to determine the degree of the clinical response (normalization of macular thickness with slow resolution of intraretinal hemorrhages and cotton wool spots). Then, we titrate the number of injections, week intervals, and drug dose needed to stabilize patients over time. Since 2005, there have been only two cases in which we have been able to completely discontinue maintenance anti-VEGF dosing without significant loss of vision.

We suspect that the level of VEGF may be too high for standard doses of intravitreal anti-VEGF agents. These patients benefit from 2.0, 2.5, and even 3.0 mg of monthly bevacizumab. However, the physician should be aware that high-dose therapy requires increased drug volume, leading to transient postinjection vision loss.

Summary

Ophthalmic radiation therapy continues to save the lives, vision, and eyes of cancer patients. However, we should all strive to decrease irradiation of the macular retina because prevention is the best way to “treat” radiation maculopathy.

We must also recognize that, despite our best efforts, cases of radiation maculopathy are inevitable. Eyes with tumors posterior to the equator or in the macula and large tumors are at the greatest risk.

Fortunately, we have found that demarcation laser and anti-VEGF therapy can suppress radiation maculopathy.. However, anti-VEGF dose escalation strategies may need to be employed to allow for vision preservation.³⁷

Like so many other diseases (diabetes, hypertension, heart disease, and arthritis) radiation maculopathy can be pharmacologically suppressed and transformed into a manageable event.

Paul T. Finger, MD, FACS was awarded US Patent #7553486, entitled, “Anti-VEGF Treatment for Radiation Induced Vasculopathy,” on June 30, 2009. He would like to acknowledge the assistance of his associates at The New York Eye Cancer Center: Drs. Kimberly Chin, Ekaterina Semenova, and Nadia Sachinski.

Related links

• The article above was written for Retinal Physician magazine.
• Scientific Article from the European Journal of Ophthalmology – Download the PDF
• Palladium-103 versus Iodine-125 Plaque Dosimetry – Download the PDF Here
• Treatment of Radiation Retinopathy caused by External Beam Radiation Therapy – Download the PDF Here
• Laser for Radiation Retinopathy – Download the PDF Here
• High Dose Lucentis for Radiation Retinopathy

References

1. Citizen O. Pennsylvania Gazette. February 4, 1735.

2. Finger PT. Microwave thermoradiotherapy for uveal melanoma: results of a 10-year study. Ophthalmology. 1997;104:1794-1803.

3. Finger PT, Ho TK, Fastenberg DM, et al. Intraocular radiation blocking. Invest Ophthalmol Vis Sci. 1990;31:1724-1730.

4. Oliver SC, Leu MY, DeMarco JJ, Chow PE, Lee SP, McCannel TA. Attenuation of iodine 125 radiation with vitreous substitutes in the treatment of uveal melanoma. Arch Ophthalmol. 2010;128:888-893.

5. Finger PT, Moshfeghi DM, Ho TK. Palladium 103 ophthalmic plaque radiotherapy. Arch Ophthalmol. 1991;109:1610-1613.

6. Finger PT, Chin KJ, Duvall G; Palladium-103 for Choroidal Melanoma Study G. Palladium-103 ophthalmic plaque radiation therapy for choroidal melanoma: 400 treated patients. Ophthalmology. 2009;116:790-796.

7. Semenova E, Finger PT. Palladium-103 plaque radiation therapy for American Joint Committee on cancer T3- and T4-staged choroidal melanomas. JAMA Ophthalmol. 2014;132:205-213.

8. Finger PT, Lu D, Buffa A, DeBlasio DS, Bosworth JL. Palladium-103 versus iodine-125 for ophthalmic plaque radiotherapy. Int J Radiat Oncol Biol Phys. 1993;27:849-854.

9. Finger PT, Zhou D, Kalach N, Semenova E, Choi W. Pd versus I ophthalmic plaque brachytherapy: preoperative comparative radiation dosimetry for 319 uveal melanomas. J Radiat Oncol. 2014;3:409-416.

10. American Brachytherapy Society – Ophthalmic Oncology Task Force. The American Brachytherapy Society consensus guidelines for plaque brachytherapy of uveal melanoma and retinoblastoma. Brachytherapy. 2014;13:1-14.

11. Chiu-Tsao ST, Astrahan MA, Finger PT, et al. Dosimetry of (125)I and (103) Pd COMS eye plaques for intraocular tumors: report of Task Group 129 by the AAPM and ABS. Med Phys. 2012;39:6161-6184.

12. Rivard MJ, Chiu-Tsao ST, Finger PT, et al. Comparison of dose calculation methods for brachytherapy of intraocular tumors. Med Phys. 2011;38:306-316.

13. Rivard MJ, Melhus CS, Sioshansi S, Morr J. The impact of prescription depth, dose rate, plaque size, and source loading on the central axis using 103Pd, 125I, and 131Cs. Brachytherapy. 2008;7:327-335.

14. Gagne NL, Rivard MJ. COMS eye plaque brachytherapy dosimetric sensitivity to source photon energy and seed design. Appl Radiat Isot. 2013;79:62-66.

15. Astrahan MA, Szechter A, Finger PT. Design and dosimetric considerations of a modified COMS plaque: the reusable “seed-guide” insert. Med Phys. 2005;32:2706-2716.

16. Semenova E, Finger PT. Palladium-103 radiation therapy for small choroidal melanoma. Ophthalmology. 2013;120:2353-2357.

17. Ophthalmic Oncology Task Force. Local recurrence significantly increases the risk of metastatic uveal melanoma. Ophthalmology. 2015. In press.

18. Finger PT, Chin KJ, Yu GP, Palladium-103 for Choroidal Melanoma Study G. Risk factors for radiation maculopathy after ophthalmic plaque radiation for choroidal melanoma. Am J Ophthalmol. 2010;149:608-615.

19. Tsui I, Beardsley RM, McCannel TA,et al. Visual acuity, contrast sensitivity and color vision three years after iodine-125 brachytherapy for choroidal and ciliary body melanoma. Open Ophthalmol J. 2015;9:131-135.

20. Finger PT. Tumour location affects the incidence of cataract and retinopathy after ophthalmic plaque radiation therapy. Br J Ophthalmol. 2000;84:1068-1070.

21. Yousef YA, Finger PT. Lack of radiation maculopathy after palladium-103 plaque radiotherapy for iris melanoma. Int J Radiat Oncol Biol Phys. 2012;83:1107- 1112.

22. Finger PT. Radiation therapy for choroidal melanoma. Surv Ophthalmol. 1997;42:215-232.

23. Archer DB, Amoaku WM, Gardiner TA. Radiation retinopathy–clinical, histopathological, ultrastructural and experimental correlations. Eye (Lond). 1991;5(Pt 2):239-251.

24. Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA. Pancreatic extracts in the treatment of diabetes mellitus. 1922. Indian J Med Res. 2007;125:141-146.

25. Finger PT, Kurli M. Laser photocoagulation for radiation retinopathy after ophthalmic plaque radiation therapy. Br J Ophthalmol. 2005;89:730-738.

26. Materin MA, Bianciotto CG, Wu C, Shields CL. Sector laser photocoagulation for the prevention of macular edema after plaque radiotherapy for uveal melanoma: a pilot study. Retina. 2012;32:1601-1607.

27. Finger PT, Chin KJ. Intravitreous ranibizumab (lucentis) for radiation maculopathy. Arch Ophthalmol. 2010;128:249-252.

28. Finger PT, Chin K. Anti-vascular endothelial growth factor bevacizumab (avastin) for radiation retinopathy. Arch Ophthalmol. 2007;125:751-755.

29. Finger PT, Chin KJ. High-dose (2.0 mg) intravitreal ranibizumab for recalcitrant radiation retinopathy. Eur J Ophthalmol. 2013;23:850-856.

30. Finger PT, Mukkamala SK. Intravitreal anti-VEGF bevacizumab (Avastin) for external beam related radiation retinopathy. Eur J Ophthalmol. 2011;21:446-451.

31. Arriola-Villalobos P, Donate-Lopez J, Calvo-Gonzalez C, Reche-Frutos J, Alejandre-Alba N, Diaz-Valle D. Intravitreal bevacizumab (Avastin) for radiation retinopathy neovascularization. Acta Ophthalmol. 2008;86:115-116.

32. Shah SU, Shields CL, Bianciotto CG, et al. Intravitreal bevacizumab at 4-month intervals for prevention of macular edema after plaque radiotherapy of uveal melanoma. Ophthalmology. 2014;121:269-275.

33. Missotten GS, Schlingemann RO, Jager MJ. Angiogenesis and vascular endothelial growth factors in intraocular tumors. Dev Ophthalmol. 2010;46:123-132.

34. Loukianou E, Brouzas D, Georgopoulou E, Koutsandrea C, Apostolopoulos M. Intravitreal bevacizumab for macular edema due to proton beam radiotherapy: Favorable results shown after eighteen months follow-up. Ther Clin Risk Manag. 2010;6:249-252.

35. Kim SJ, Hubbard GB 3rd. Intravitreal bevacizumab (avastin) for radiation retinopathy 53 years after treatment of retinoblastoma. Retin Cases Brief Rep. 2007;1:198-201.

36. Gupta A, Muecke JS. Treatment of radiation maculopathy with intravitreal injection of bevacizumab (Avastin). Retina. 2008;28:964-968.

37. Finger PT, Chin KJ, Semenova EA. Intravitreal anti-VEGF therapy for macular radiation retinopathy: a 10-year study. Eur J Ophthalmol. 2015. In press.

38. Finger PT. Radiation retinopathy is treatable with anti-vascular endothelial growth factor bevacizumab (Avastin). Int J Radiat Oncol Biol Phys. 2008;70:974-977.

39. Mehta MC, Finger PT. Angled transscleral intravitreal injection: a crossover study. Eur J Ophthalmol. 2015;25:173-176.

40. Finger PT. Radiation therapy for orbital tumors: concepts, current use, and ophthalmic radiation side effects. Surv Ophthalmol. 2009;54:545-568.

By Paul T. Finger, MD

Description

When possible, many centers offer radiation as an eye and vision-sparing alternative for patients with intraocular cancer. The two main types of radiation are plaque radiotherapy and external beam.

External beam radiation was commonly used for retinoblastoma (a childhood eye cancer), choroidal melanoma (in several centers) and for metastatic tumors (that have spread from another part of the body to the eye).

Plaque brachytherapy is the most widely used treatment for choroidal melanoma and delivers a highly concentrated radiation dose to the tumor (with relatively less radiation to surrounding healthy tissues). The radioactive plaque can also be called a “radiation implant” or “radioactive source.”

Plaque brachytherapy is typically used in one definitive treatment. The radiation sources used for brachytherapy come in the form of small “rice-sized” radioactive seeds. These seeds are attached within a gold or steel bowl called a plaque.

The dose of radiation delivered to the tumor is determined by the type, number and strength of the seeds used and length of time of the implant. The dose will also depend on the size of the tumor and its location. Make sure your eye cancer specialist has performed a comparison between various types of available eye plaques (e.g. iodine-125, palladium-103 and ruthenium-106) before surgery. Though they all can destroy the tumor, the plaque that delivers least radiation to your macula, optic nerve and fovea will offer the patient his or her best chance of keeping your vision (over time).

Placement of the plaque is performed in the operating room. During the procedure, the eye cancer specialists will attach the plaque to the wall of the eye, covering the base of the intraocular tumor.

A comprehensive review of radiation therapy for choroidal melanoma showed that many forms or sources of radiation have been used to treat intraocular tumors. It is reasonable to assume that given a large enough dose, all of these radiation techniques can destroy intraocular tumors. They differ in the distribution of ocular and orbital radiation dose, and their resulting radiation side effects. For example, proton radiation will affect those tissues through which it travels to get to the tumor (typically the eyelashes, eyelid, conjunctiva, cornea, lens, iris and ciliary body), whereas plaque radiation travels throught the wall of the eye (sclera and cornea) in order to reach an intraocular tumor.

Dr. Finger’s review showed that external beam therapy resulted in more reported anterior complications than plaque therapy for choroidal melanoma.

These findings, and our desire to improve radiation safety, have driven an evolution in treatment techniques.

Dr. Finger currently recommends the use of palladium-103 for plaque radiation therapy of most choroidal melanomas. Studies have shown that low-energy iodine-125 plaques have largely replaced cobalt-60 and ruthenium-106 for plaque radiation therapy.

In 1985, the Collaborative Ocular Melanoma Study chose iodine-125 ophthalmic plaque radiation therapy (iodine-125 seeds in gold ophthalmic plaques) to treat medium-sized choroidal melanomas. This decision resulted in both widespread acceptance and standardization of this technique.

Then, in 1990, palladium-103 became available for the treatment of cancer. Though there has been no randomized trial comparing palladium-103 versus iodine-125, the results of the largest studies can be seen in the detailed comparison of iodine-125, ruthenium-106 and palladium-103 plaques.

Table 5. ¹⁰⁵Pd. vs. ¹²⁵I results

Authors	Radiation	Mean apex dose (Gy)	Follow-up (mo)	Recurrence (%)	Enucleation (%)	Metastasis (%)	Visual acuity
Packer et al. (11)	125I results	91	64	7.8	17.2	15.6	45% better or 20/100
Fontanesi et al. (26)	125I results	79	46	2.3	9.7	5.5	41% better or 20/200
Giblin (27)	125I results	97	60	7.2	8.8	6.1	47% better or 20/200
Kreissig et al. (25)	125I results	70	60	10	0	15.7	100% “severe loss of vision”
Melia et al. (28)	125I results	Variable*	36	NA	NA	NA	57% better than 20/200
Lommatzsch (30)	106Ru results	100	80	15	26	20	NA
All 6 trials	Mean	86	67	8	11	11
Finger et al.	103Pd results	80.5	55	4	6	6	73% better than 20/200

* Minimum 5mm “apex dose.” Abbreviation: NA = not available.

Admission to the Hospital

After admission to the hospital, you will be asked to sign a consent form (if not done previously). Your doctor may order blood tests, an EKG, x-rays or imaging scans. The placement procedure takes a short time. The radiation is painless, but sometimes movement of the eye or stitches can cause discomfort. Medication is available if you experience pain.

Activity with the Implant in Place

Most patients will be allowed to stay at home during iodine-125 or palladium-103 plaque therapy. A lead patch or lead glasses must be kept over the operated eye while the plaque is in place.

Side effects/complications

Radiation works on cells by creating free-radicals (primarily hydroxyl OH-) in humans which can directly destroy cells and by breaking cellular DNA. This means that there are some immediate tumor killing effects and other effects which will not show up until the cell tries to divide (using its broken DNA). Cells that will die when they try to divide are considered sterile and incapable of metastasis. Radiation damages both the cancerous and normal tissues. This is one reason why tumors tend to shrink slowly, and why some radiation complications appear years after treatment.

Complications can occur after radiation therapy for intraocular and orbital tumors. The incidence of these complications is related to the amount (dose) given, how fast it is given (dose-rate), the age of the patient, other synchronous diseases, and the individuals tolerance for radiation therapy. In general, larger tumors require more radiation to kill them as do some tumors which are less radiation sensitive.

Large differences exist between plaque therapy which typically deliver radiation constantly for 5-7 days, as compared to external beam therapy, which typically delivers 5 daily doses of 1200-1500 cGy in 5 minutes (each). Both require surgery.

Above, this is an intraocular photograph of a patient treated with ophthalmic plaque radiation who later developed optic nerve neovascularization, intraretinal microangiopathy, chorioretinal atrophy, a ghost vessel, and perivascular sheathing. The dark tumor on the bottom of the photograph was inactive (sterilized).

Above, this patient was treated with proton-beam irradiation. He developed radiation-related eyelash loss, dry eye, cataract, and iris neovascularization. Notice the large conjunctival blood vessels. In contrast, eyelash loss, dilated conjunctival vessels and dry eye are unusual after plaque radiation therapy.

These cases were chosen as to include most of the known complications found after radiation therapy for intraocular tumors. It is important to note that many patients do not develop these complications and benefit from the most commonly used eye and vision sparing alternative to enucleation.

Summary

The two main types of radiation are eye-plaque brachytherapy (e.g. iodine-125, ruthenium-106, palladium-103) and external beam (proton-beam). In general, external beam therapies are more likely to be associated with external (lids, cornea, iris, lens) complications and plaques appear to induce earlier radiation retinopathy with few external radiation complications.

Post treatment care

After Treatment Is Over:

You may experience some fatigue for a few weeks following surgery. You may find it helpful to plan rest periods throughout your day. You may resume your normal diet after discharge from the hospital, unless directed otherwise by your doctor.

Skin Care Around the Eye

The following guidelines will help promote comfort and healing of the area involved.

• Wash the eye lids with mild soap and lukewarm water and gently pat dry.
• Avoid extreme temperatures (e.g. hot showers, hot water bottles, heating pads, or ice bags) on the affected area.
• Avoid any friction or eyelid rubbing or scratching.
• Radiation blepharitis (eyelid inflammation) can be treated with silvadine ointment, black tea soaks, or A&D ointment.

Studies/research

Dr. Finger suggests that clinical centers perform comparative dosimetry studies of iodine-125 versus palladium-103 prior to all plaque insertions.

1. Finger PT. Radiation Therapy for Choroidal Melanoma. Survey of Ophthalmology (Review Article) 42:215-32, 1997.
2. Finger PT, Berson A, Szechter A. Palladium-103 Plaque Radiotherapy for Choroidal Melanoma: Results of a 7-Year Study. Ophthalmology 106:606-613, 1999
3. Finger PT, Berson A, Ng T, Szechter A. Palladium-103 Plaque Radiotherapy for Choroidal Melanoma: An 11-Year Study. International Journal of Radiation Oncology Biology Physics 54;1438-1445, 2002.
4. Finger PT, Chin KJ, Duvall BS for The Palladium-103 for Choroidal Melanoma Study Group. Palladium-103 Ophthalmic Plaque Radiation Therapy for Choroidal Melanoma: 400 Treated Patients. Ophthalmology 2009;116:790-6.
5. Laube T, Fluhs D, Kessler C, Fiscia LE, Bornfeld N. Determination of Surgeon’s Absorbed Dose in Iodine-125 and Ruthenium-106 Ophthalmic Plaque Surgery Ophthalmology 107;107:366-369.

Related links

• Iodine-125 and palladium-103 eye plaques
• Compare the results of Iodine-125, ruthenium-106 and palladium-103 eye plaques
• Compare Proton Beam Charged Particle Radiation Therapy to Ophthalmic Plaque Irradiation
• Palladium-103 and iodine-125 plaque construction
• Tumour location affects the incidence of cataract and retinopathy after ophthalmic plaque radiation therapy.

By Paul T. Finger, MD

Ocular Prostheses Can Offer an Excellent Cosmetic Result

Description

Enucleation is removal of the eye. It is a form of treatment that allows your eye-cancer specialist to remove the tumor from your body. Unfortunately, when the eye is removed there is no chance that vision can be restored. Fortunately, most patients can see with their fellow eye, almost all patients are able to do all the things they used to do (before losing their eye) and with ocular prosthetics people are typically happy with how they appear.

The most well organized studies of enucleation surgery were performed as part of the Collaborative Ocular Melanoma Study (COMS). The COMS medium-sized choroidal melanoma trial found no survival benefit to eye removal. That is, for similarly sized choroidal melanomas, survival was the statistically equivalent whether patients were treated with an iodine-125 plaque therapy or removal of the eye. In the second COMS arm, the large tumor study, researchers found no benefit from pre-enucleation external beam radiation therapy.

Currently, enucleation is most commonly used to remove eyes with extra large-sized tumors, large tumor-bearing eyes with little or no vision and those with severe glaucoma. However, in 2012, the vast majority of choroidal melanomas diagnosed in developed countries can be treated with eye and vision sparing radiation techniques (plaque and proton beam). Most patients prefer to keep their eye even if vision is severely limited.

Procedure

Most patients have their eye removed under anesthesia and can go home after surgery. Since your surgery will be performed under general anesthesia, you will not feel or see anything until you wake up. Dr. Finger gives an injection of local extra local orbital anesthetic at the end of your surgery, just before placing the pressure bandage over the wound. This injection of anesthetic allows for the least pain possible when you wake up in the recovery room. Most patients have a headache for 24-36 hours after surgery which goes away with two regular Tylenol every 4 hours. Many patients are concerned that the loss of the eye may hurt. But the eye is surrounded by bones, therefore it is much easier to tolerate removal of an eye as compared to loss of a lung or kidney.

At The New York Eye Cancer Center, we typically place a temporary prosthesis at the time of bandage removal. Thus, patients do not have to walk around without a temporary prosthetic eye. However, 6 weeks later patients typically start their ocular prosthesis fitting for a more permanent prosthesis. After a final prosthetic fitting 90% of our patients are happy with the way they look, and 80% say others can’t even tell they are monocular. It will take some time to adjust to using one eye, but most patients learn to compensate during the first year after surgery.

Side effects/complications

When an eye is removed, the patient loses all vision and the cosmetic use of the globe.

Reported complications include hemorrhage, infection and extrusion of the implant. In our review of Enucleation published in the Survey of Ophthalmology, we found that integrated implants were more likely to get infected or extrude. However, these complications are becoming less common and integrated implants offer less orbital migration and better cosmesis.

Post-operative hemorrhage is both rare and uncomfortable. Most patients who experience a significant post-enucleation orbital hemorrhage are either on blood thinners (e.g coumadin, plavix, heparin or aspirin) or are known to have a bleeding disorder. Such hemorrhages can be painful, but intervention is rarely helpful. Patients are typically treated with analgesic medications (pain-killers).

Orbital Infections are also rare. Most secondary orbital infections can be managed with antibiotics, covering or surgical removal of the orbital implant.

Implant extrusions can be managed by surgical replacement of the orbital implant.

Post treatment care

After your surgery you will have a pressure bandage over your eye. In our center, we ask patient to leave it in place for 5-days. On the 5th day, we remove the bandage and typically place a temporary prosthesis (plastic eye). In addition, we ask patients to take a topical antibiotic and steroid daily for up to a month. This helps the wound heal more safely and quickly.

After the patch has been removed, you may tear and the tears may contain a little blood. This is normal. You should gently wash the outside of your eyelid with a warm, clean, soapy wash cloth. Don’t let matter accumulate to form crust on your eyelids. During this time you should not rub your eyelids or run the shower on your operated eye for at least 10 days after surgery.

Returning to Work:

You will be able to return to normal activity soon after surgery. The orbit should heal quickly and you should be able to return to school or work within 2 to 6 weeks. You should not lift more than 10 pounds, strain, or rub your eye for at least 14 days after surgery. The enucleation patient should also not take aspirin or other blood thinners unless your internist says it is required. You will need to be examined at 5-7 days, 1 month and every 6 months after surgery. This is because there is an extremely small chance the tumor will regrow behind your prosthesis.

Follow up:

We recommend that you return for a complete ophthalmic oncology exam at least on a yearly basis. You should also have twice-yearly medical check-ups by your family doctor, internist, or medical or pediatric oncologist. Copies of your laboratory evaluations should be forwarded to your eye-cancer specialist’s office so they can be checked for metastatic disease. The law may require that you request this information in writing from your doctor.

After enucleation you will be a patient for the rest of your life. You must be followed by an eye-care specialist and may need a medical oncologist. You may want to take this into account in choosing your doctors and their location.

For additional information and support we suggest you read the book “A Singular View” by Frank Brady. It will help in your transition. This book was written by an airplane pilot who lost one eye.

Studies/research

• A Review of Enucleation By Moshfeghi DM, Moshfeghi AA, Finger PT. Survey of Ophthalmology 2000:44:277-301

Related links

• Ocular Prosthesis Care