Clinical Trials Target Brain Metastases

We are currently collaborating on three clinical trials. The first is an investigative trial looking at the use of immunotherapy in conjunction with antiangiogenic drugs for treatment of non-irradiated brain metastases. Antiangiogenic drugs are medications that prevent the growth of new blood vessels, which tumors need to survive. The second is a pre-operative versus post-operative radiosurgery trial that examines whether administering radiation before surgery significantly reduces the risk of the cancerous cells spreading during surgery. The third trial studies the safety of delivering drug therapy and radiation simultaneously to the brain.

In the past, because most drugs that treat cancer don’t get into the brain very well, the standard of care treatment for brain metastases was radiation—today in the form of radiosurgery, which we here at Yale call Gamma Knife.

Immunotherapy, in theory, gives patients the possibility of curing their cancer without surgery. Initial studies showed about 30% to 50% of patients with brain metastases could be successfully treated with single agent immunotherapy, meaning no radiation. We’re just over a decade removed from those studies and we now have what’s called dual-immunotherapy, which is a combination of two different immunotherapies that work via two different immunological pathways. The combination of these two drugs results in anywhere from 50% to 70% of brain cancer patients having a response in the central nervous system without the need for radiation or surgery.

The problem we’re facing with this non-radiation, immunotherapy-only approach is that patients can develop swelling in the brain, or edema, around their cancerous lesions. Depending on the size and location of this swelling, we may have to stop administering the drugs prior to completion of their course.

Bevacizumab is a non-steroidal antiangiogenic drug often used to treat gastrointestinal and primary brain cancers that can also work well to reduce brain edema. Our trial is looking at combining immunotherapy with bevacizumab to see if we can stop the swelling associated with immunotherapy, so the full course of immunotherapy can be completed.

There are two arms to the trial: the melanoma arm and the lung cancer arm. We almost have all the data from the melanoma arm and are still working on the lung cancer arm at this time.

Traditionally, craniotomy for removal of brain metastases is done because the lesions are usually large and causing symptoms. That creates an urgency to surgery. We also know that 70% of these lesions will regrow if not treated with radiation, which is why we administer the radiation post-operatively.

One of the risks of performing a craniotomy to remove brain metastases is something called leptomeningeal spread. The surgery involves making a hole in the skull and opening the lining of the brain to expose the tumor. That makes it possible for the tumor cells to spread to adjacent, exposed areas of the brain. Our clinical trial is testing the idea that if you give radiation to the lesion before it’s removed, you lessen the risk of leptomeningeal spread.

There are other potential benefits of using radiation pre-operatively. It makes the lesion easier to see, which makes it easier to target with radiation. It also may help from a wound-healing standpoint because the radiation is delivered before incisions are made.

Yes, it’s a concurrent therapy trial looking at breast cancer brain metastases. We typically do not give radiation and drug therapy together because a long time ago, if you gave chemotherapy and whole brain radiation together, it was too toxic for patients. Because of that history we have since always given radiation first, then the patient receives chemotherapy.

The trial looks at delivering the latest drug combination for HER2-positive breast cancer treatment at the same time as radiosurgery. We know that the latest three-drug combination for this type of breast cancer does penetrate the brain and can work there to shrink tumors.

Previously, we’ve been performing radiosurgery first, then administering this drug combination and that has resulted in very good brain control. The question now is, does administration of the drug have to wait until radiosurgery is completed, or can they all be administered safely together? In other words, can we give the drug and radiation concurrently?

This is our newest trial and we’re still in the process of recruiting patients.