Treatment of Metastatic Disease

Introduction

If OM spreads beyond the eye, it is metastatic and approximately 50% of OM patients go on to develop metastatic disease. 80-90% of the time, the liver is the first site of this metastatic disease given the hematologic nature of OM. In other words, OM spreads via the blood and not via the lymphatic system such as with cutaneous melanoma, and the liver is thus affected in this propagation.  

In general, prognosis is poor after an ocular tumor has metastasized. Without treatment, the median survival time is 2 to 8 months. We encourage you, though, to think of this as one data point, however. Many OM patients, even those with metastatic disease, have gone to live long, active lives.  Stephen Jay Gould wrote an excellent article entitled "The Median Isn't the Message" on this topic, and Cancerguide.org has a fantastic set of resources around cancer and morbidity statistics. 

Standard chemotherapies, overall, have not proven to be effective in treatment of metastatic OM. Today, there are no approved treatments for OM once it has spread but there are several palliative treatments and many new, promising clinical trials are being offered.

Liver Directed Treatments

Resection (surgical removal)
Only a small percentage of patients have this option (~10% are typically eligible) and many doctors advise against it if there are multiple tumors and because the tumor has a high likelihood of recurrence. However, new research is showing better outcomes if tumors are caught early and are able to be resected. Therefore, if resection is deemed to be an option, it is something to consider seriously. It may also be a good idea for the surgeon to be prepared to do radio-frequency ablation (RFA or other ablative technique similar to this) on any small tumors they might find that the scan missed and that might make surgical resection impossible once the surgery is in process. Some surgeons will recommend a laparoscopic "look-see" prior to the surgery to ensure it can go forward without surprises.

Immuno-embolization / Chemo-embolization
The liver is isolated and infused with either immunotherapy drugs or chemotherapy drugs. The side effects are less than with systemic treatments. Interventional radiology doctors typically perform these procedures. Although doctors all around the country perform chemoembolization, often different chemotherapy drugs are used depending on the team performing the procedure. At this point, no particular chemotherapy has been shown, in research trials, to be more beneficial than another.

Radio-embolization (SIR-Spheres or "SS")
The liver is isolated and infused with radioactive Yttrium beads in solution. See http://sirtex.com for more info on the process and to find practitioners in your area. Although this treatment is still "off-label" for OM, the response seems to be good and the side effects relatively minimal (depending on how advanced the disease is). Although it is different for different patients, a person can have up to approx. three treatments, due to the lungs' capacity to tolerate the radiation as they receive some "spill-over" from the liver. As with other types of embolization, this procedure is typically performed by an interventional radiologist and is performed at many centers.

Percutaneous Hepatic Perfusion (PHP)
PHP involves isolating the liver and "bathing" the liver in a particular chemotherapeutic agent. A clinical trial is being done by NIH's NCI (National Cancer Institute) and you can receive this treatment at several locations around the country. The liver is isolated and infused with the chemo drug Melphalan.

Systemic Treatments

Standard chemotherapy agents targeting the entire body have proven to be generally ineffective when it comes to OM.  Today, there is no approved systemic treatments for metastatic OM but many providers do recommend treatment with systemic agents that have been approved for cutaneous melanoma already. 

Dacarbazine, or DTIC, is the one most encountered by OM patients. It is the only FDA-approved chemotherapy agent for the treatment of Stage IV cutaneous melanoma and even though its applicability to ocular melanoma has yet to be demonstrated, it may still be recommended in some cases. It is administered via an intravenous (IV) infusion, but is also available in oral form under the name Temozolomide.

Other chemotherapy agents that may be used in OM treatment include taxanes (e.g. docetaxel or paclitaxel), platinum agents (e.g. cisplatin or carboplatin) and other drugs that have yet to be approved. Patients are encouraged to regularly check for current Clinical Trials being offered.

Immunotherapy is another type of systemic therapy that attempts to "kick start" a patient's own immune system and activate the cancer "killer cells." Caroline Bosch-Voskens, MD gave an excellent overview of immunotherapy at the 2012 EANA Patient Retreat.

As with chemotherapy, however, the response rate within the OM population has been significantly lower than with cutaneous melanoma. The most talked about drug in this category is YERVOY™ (ipilimumab, also commonly called "Ipi"). Relatively expensive but approved for melanoma treatment as of March 2011, YERVOY is a monoclonal antibody that binds to CTLA-4, an inhibitory molecule on T lymphocytes. According to the Melanoma Research Foundation, "T lymphocytes are blood cells that may be highly effective in inhibiting cancer growth. When YERVOY binds to CTLA-4, it releases the 'brake' from the immune system and T cells can become activated to destroy tumor cells. Unfortunately, response rates in OM are not well documented."

Other approved immunotherapy agents include cytokines which are used in the treatment of cutaneous melanoma (Interleukin-2; Interferon-alpha), dendritic cells such as those used in the treatment of prostate cancer (Provenge®).

Targeted therapy is where drugs are developed specifically with the goal of destroying cancer cells while (hopefully) leaving normal cells intact. These bespoke and often expensive drugs are custom cocktails designed to interfere with the specific molecules driving tumor growth. Since they are custom crafted to the tumor, these types of therapies are generally more effective and have fewer side effects versus chemotherapy. Taking a targeted approach to systemic OM treatment also allows the classification of the disease into different subtypes based on the tumor's genetic profile, allowing personalized drug treatment. As an example, 50% of cutaneous melanomas have a BRAF mutation and respond to BRAF inhibitors but, unlike melanomas on the skin, OM does not express a BRAF mutation and so will not respond to a BRAF inhibitor. About 80% of ocular melanomas express either the GNAQ or GNA11 mutations and studies are ongoing to identify what targeted therapies will work in these mutations. 

Navigating Treatment

For any of the above options, you would need to send a CD of your scans and reports to the treating physician. You may want to send scans to several at once to get opinions about which treatment to go with first (i.e. trying to make sure not to eliminate a treatment option down the road by the decisions you make now).

Numerous complications can result from the treatments outlined above, so it is important to have regular follow-up with an ophthalmologist and medical oncologist and to have open, frank discussions with your doctors.