Targeted Therapy ...Ocular/unveal Melanoma ..Jim Breitfeller

As I continue my series on Targeted Therapy, I was contacted and was asked to put the word out for Ocular Melanoma Patients. Well I did not know very much about this cancer. So, I decided to research it before I said anything.

About 2000 people get diagnosed with Ocular Melanoma a year. Ocular melanoma is a lethal and very rare disease. Many people die from it, especially when it spreads to the liver, a common complication. There are other types of eye cancers, but melanoma is the most common.

Ocular melanoma, a rare cancer, is a disease in which cancer (malignant) cells are found in the part of the eye called the uvea. The uvea contains cells called melanocytes. When these cells become cancerous, the cancer is called a melanoma. The uvea includes the iris (the colored part of the eye), the ciliary body (a muscle in the eye), and the choroid (a layer of tissue in the back of the eye). The iris opens and closes to change the amount of light entering the eye. The ciliary body changes the shape of the lens inside the eye so it can focus. The choroid layer is next to the retina, the part of the eye that makes a picture. If there is melanoma that starts in the iris, it may look like a dark spot on the iris. If melanoma is in the ciliary body or the choroid, a person may have blurry vision or may have no symptoms, and the cancer may grow before it is noticed. Intraocular melanoma is usually found during a routine eye examination, when a doctor looks inside the eye with special lights and instruments.1

The chance of recovery (prognosis) depends on the size and cell type of the cancer, where the cancer is in the eye, and whether the cancer has spread.

What are the Symptoms?
“Ocular melanoma may not cause any early symptoms. It is sometimes found during a routine eye exam when the doctor dilates the pupil and looks into the eye. The following symptoms may be caused by intraocular melanoma or by other conditions. A doctor should be consulted if any of these problems occur:”2


• A dark spot on the iris.
• Blurred vision.
• A change in the shape of the pupil.
• A change in vision.

If it is caught early, it is curable. Left untreated this melanoma usually metastasizes to the liver and onto other sites. It is very difficult to treat once it has metastasize. Uveal melanoma can be effectively treated, but once it metastasizes to
the liver, survival can be less than 6 months.



What are the Known Treatments?
A good web site to go for information from Patients like us is:
http://www.lafn.org/~bc534/OcularMelMets.htm

Uveal Melanoma Metastatic to the Liver


There are at least five different treatments for Ocular (uveal) melanoma patients who have liver metastases.

Immunoembolization

“Immunoembolization is a variation of chemoembolization, which involves infusing a
cytotoxic agent into a tumor after mechanically or surgically disrupting the tumor's
blood supply. The advantage of immunoembolization is that it
could attract and stimulate antigen-presenting cells in liver tumors and improve the
uptake of tumor antigens released from necrotic tumor cells, as well as potentially
facilitate a systemic immune response against tumor cells and thereby suppress the
growth of extrahepatic metastases.”3


Stereotactic Body Radiosurgery

“Stereotactic body radiosurgery(SBR) is a novel treatment that can be employed in the treatment of metastatic melanoma. Stereotactic body radiosurgery is a treatment that uses multiple high powered beams aimed very precisely at tumors in the body. The Elekta frame immobilizes the patient and decreases the movement of the liver and lung tumors due to breathing. The treatment spares normal tissue because of its extreme precision. The treatment is completely non invasive and is given in 1-3 outpatient treatments. Patients can continue there normal daily activites as there are often minimal side effects. Metastic melanoma, melanoma that has spread to other organs, is a difficult situation because there is not effective drug therapy. Occasionally, if possible, the tumors can be surgically removed. However, surgery is usually not possible and can be quite morbid with extensive recovery times. Much as surgery, Stereotactic body radiosurgery can eradicate treated tumors in the lung and liver 90 percent of the time. Unlike surgery, there is very little risk and minimal side effects. Patients are able to continue their daily activities without difficulty. The high tumor eradication rate is a result of its high dose per treatment.

Patient with recurrent metastatic melanoma or diagnosed initially with metastatic melanoma are potential candidates. Patients need to have relatively few liver or lung metastasis and have good funtional status. Some doctors have arbitrarily set the limit to 5 tumors.”4




Radiofrequency Ablation

“Radiofrequency ablation (RFA) is an exciting technique used to treat malignant liver tumors. An electrical current is transmitted through a small needle placed directly into a liver tumor, to destroy cancer cells with heat. An array of hook electrodes are deployed from the tip of the needle after it's placed in the tumor. The hook electrodes look like the ribs of an umbrella, with a diameter of 3.5 centimeters (slightly greater than an inch) when fully deployed (figure 1). An ultrasound probe is used to guide placement of the needle, and after the needle is in the correct area, the hook electrodes are deployed into the liver tumor. The treatment is started by applying electrical current from a small, briefcase-sized device called a radiofrequency current generator. The amount of power supplied by the generator can be controlled precisely, and the generator is also used to monitor the treatment until complete heat-induced destruction of the tumor being treated occur.”
“The key in each of these patients is that the liver was the only cancer site. We do not perform RFA in patients with cancer that has spread to other areas or organs, because treating only the liver will not improve these patients’ chances for survival. We also have learned that it is difficult, and probably not helpful, to treat patients with more than eight tumors, or if more than half of their liver is replaced by tumors. Lastly, we find that the RFA equipment currently available does not reliably destroy all the tumor if it is larger than six centimeters in diameter. These larger tumors should be removed when possible. Thus, we do not recommend RFA for these larger liver tumors, but we, and others, are working to develop RFA systems that will effectively treat larger tumors. 5”


Chemoembolization.

A procedure in which the blood supply to the tumor is blocked surgically or mechanically and anticancer drugs are administered directly into the tumor. This permits a higher concentration of drug to be in contact with the tumor for a longer period of time. Unlike conventional systemic chemotherapy, the drugs injected through the hepatic artery are confined to the liver. Side effects of chemotherapy are minimized as a result.




Isolated Liver Perfusion

This treatment for liver tumors was first described over thirty years ago but has had limited clinical use until now. The basis of this treatment is to expose the liver to high doses of chemotherapy in order to achieve maximal tumor shrinkage. The blood supply to the liver is completely isolated from the systemic circulation so that the body is not exposed to the high dose of drugs. It requires a lengthy operation to completely mobilize the liver and to insert catheters into the hepatic artery, portal vein and hepatic veins.
Recently, initial results using different drugs have been encouraging and work continues with this modality. This is experimental therapy and should only be used in a clinical trial.





Patients with isolated hepatic metastasis from Ocular Melanoma are indeed rare. In the largest prospective data base on melanoma in the world (the combined experience of The John Wayne Cancer Institute and Sydney Melanoma Unit) only 24 of 1750 patients (1.3%) with hepatic metastasis were found to have disease that was resectable6

Since the most of the patients would have non-resectable with hepatic metastasis, I have been contacted by Delcath Systems that is the sponsor of the trial.

“I oversee Delcath Systems' National Cancer Institute-led Phase III clinical trial for metastatic melanoma to the liver. As you know, there are few effective treatment options for patients once melanoma has metastasized to the liver, however, we are highly encouraged by our current clinical trial, which showed tremendous response rates in its corresponding Phase I study. We are treating patients at a number of cancer centers throughout the country using a minimally invasive procedure that targets the liver for high dose drug treatment. In addition to overseeing the operations of this trial, I am also trying to increase the awareness of its availability to patients, medical oncologists, surgical oncologists, dermatologists and other physicians.”


Phase I Study of Hepatic Arterial Melphalan Infusion and Hepatic Venous Hemofiltration Using
Percutaneously Placed Catheters in Patients With Unresectable Hepatic Malignancies



Delcath Systems Granted Orphan-Drug Designations for Cutaneous and Ocular Melanoma
NEW YORK, November 18, 2008 – Delcath Systems, Inc. (Nasdaq: DCTH), a medical technology company testing its proprietary liver cancer treatment for melanoma metastatic to the liver, announced today that the United States Food and Drug Administration (“FDA”) granted to Delcath two orphan-drug applications for the drug melphalan. Delcath was granted designations of the drug melphalan for the treatment of patients with cutaneous as well as ocular melanoma. Approximately 65,000 cases of these melanomas are diagnosed annually in the United States.
Delcath is actively enrolling patients in a Phase III clinical trial testing its proprietary drug delivery system, known as Percutaneous Hepatic Perfusion (“PHP”), with melphalan for the treatment of ocular and cutaneous melanoma metastatic to the liver. This NCI-led trial is enrolling patients at leading cancer centers throughout the United States. Commenting on these orphan-drug designations, Richard L. Taney, President and CEO of Delcath, stated, “These favorable designations are important steps in our efforts to secure Delcath’s commercial position upon conclusion of our pivotal Phase III trial for metastatic melanoma. We remain steadfast in our commitment to become the leader in the regional treatment of liver cancers and we continue to enroll patients in this study, and advance our technology and the promise that it offers to patients with these deadly forms of melanoma and other cancers of the liver, all with limited treatment options.”
Orphan drug designation, when granted by the FDA’s Office of Orphan Products Development, allows for up to seven years of market exclusivity upon FDA approval, as well as clinical study incentives, study design assistance, waivers of certain FDA user fees, and potential tax credits.
Source: Delcath Systems Inc.


So, I went out and tried to contact the Oncologists that are participating in the trial.


http://www.delcath.com/news/2008/treatmentcenters.html

Current Trial Centers



Oncologist’s Comments:

“We are participating in the percutaneous hepatic perfusion with melphalan trial. This treatment is for patients with melanoma metastatic to the liver (either from the eye or skin), with little or no melanoma elsewhere. The response rates so far are high (the majority of patients respond in the liver) and patients have tolerated the perfusion well. The main risks have to do with the thinning of the blood that occurs during the perfusion and the possibility of the chemotherapy escaping the isolated area and affecting other parts of the body, but problems have been rare. The main disadvantage is that the rest of the body is not treated, only the liver. This is fine if the areas of melanoma are restricted to the liver exclusively, or almost exclusively. Obviously there is a lot more to it, but I’d be happy to give more information if anyone had specific questions.”


“One good thing about the perfusion trial is that, though it is randomized, there is the potential for “crossover”. That is, patients are assigned to get the perfusion or get the best alternative care (almost any alternative is allowed), and if their liver disease grows on the other therapy, they can switch over to the perfusion. If it were me, I would do the perfusion trial if I had unresectable, liver only metastases.

The leakage is rare and has not happened at all to my knowledge since some protocol changes were implemented.

Every patient is different and I would encourage everyone to explore options and go to a melanoma center where the most options can be considered.”

“Because this is an active ongoing Phase III clinical trial there is no preliminary data to give. What I can tell you is that the technique and the phase I data was published in a the Journal of Clinical Oncology in May 2005. Because we did have some great responses in melanoma patients, we are testing this technique against the best available therapy. This technique is best used for patients with disease confined to the liver but there are exceptions to this.”


As usual, I was in contact with Dr. James Pingpank, author and principle investigator of:

Phase I Study of Hepatic Arterial Melphalan Infusion and Hepatic Venous Hemofiltration Using Percutaneously Placed Catheters in Patients With Unresectable Hepatic Malignancie.


He was encouraged with the results so far.


James F. Pingpank, Jr., MD, FACS
Associate Professor of Surgery
Division of Surgical Oncology
Suite 406, UPMC Cancer Pavillion
5150 Centre Avenue
Pittsburgh, PA 15232
412-692-2852 (Office)
412-692-2520 (Fax)
PingpankJF@UPMC.edu


My Take on the subject as I see it:

This very hard disease to treat.

This Therapy is not a cure all, but it seems to extend the survival for most patients while maintaining a good quality of life base on the disease.

As one Oncologist said “Every patient is different and I would encourage everyone to explore options and go to a melanoma center where the most options can be considered.”


References

1. http://www.kellogg.umich.edu/patientcare/conditions/intraocular.melanoma.html
2. http://www.cancer.gov/cancertopics/pdq/treatment/intraocularmelanoma/Patient#Keypoint3
3. Immunoembolization safe, promising for liver metastases from uveal melanoma October 24, 2008 American Society of Clinical Oncology
4. http://www.cancertreatmentgroup.com/metastatic_melanoma.shtml
5. http://www.mdanderson.org/departments/ltsg/display.cfm?id=6193B8E8-BC8D-11D4-80FB00508B603A14&pn=9DF6DAEE-7AAF-430F-8ADC4CAF62712136&method=displayfull

6. Rose DM, Essner R, Hughes TM, et al. Surgical resection for metastatic melanoma to the liver: the John Wayne Cancer Institute and Sydney Melanoma Unit experience. Arch Surg 2001; 136: 950–5.



Take care

Jimmy B
Melanoma_Missionary