Preventative Brain Radiation for Lung Cancer

[gpawelski]

A new study is taking a closer look at the benefits versus risks for lung cancer patients to undergo preventative brain radiation therapy as a means to stop cancer from spreading to the brain.

Study results show that while preventative brain radiation for patients with non-small cell lung cancer – the most common form of lung cancer – does reduce the chance of developing brain metastases, it impacts some short-term and long-term memory.

The study also reveals that preventative brain radiation does not increase survival and has no significant impact on quality of life, says study co-investigator Benjamin Movsas, M.D., chair of the Department of Radiation Oncology at Henry Ford Hospital in Detroit.

“These findings offer a more complete perspective regarding this intervention for patients with non-small cell lung cancer,” Movsas says. “We now need to develop strategies to help shift the benefit-risk ratio for this treatment.”

Dr. Movsas presents study results Nov. 2 at the plenary session for the 51st annual American Society for Radiation Oncology (ASTRO) meeting. Out of nearly 1,000 abstracts submitted, only a handful of study abstracts, including the one from Henry Ford, were selected for the ASTRO plenary session.

The study is part of a national Radiation Therapy Oncology Group (RTOG) analysis of prophylactic cranial irradiation for patients with stage III non-small cell lung cancer.

Previous studies have found this preventative type of external beam radiation therapy that treats the entire brain – known as prophylactic cranial irradiation (PCI) – can reduce the risk of cancer spreading to the brain in patients with non-small cell lung cancer, as well as its sister disease, small-cell lung cancer. The risk of cancer developing in the brain increases as people with non-small cell lung cancer live longer with more effective treatments.

To learn more about how PCI impacts a patient’s quality of life and cognitive function, Dr. Movsas and his colleagues tracked the progress of 340 patients with stage III non-small cell lung cancer for one year after receiving PCI, a 10-minute treatment that occurs once a day for two to three weeks.

The study finds that patients with non-small cell lung cancer treated with PCI have a significantly decreased risk of developing brain metastases by 10 percent (from 18 percent to 8 percent), compared with those who did not receive the treatment.

Although there was no significant impact on quality of life, patients who underwent PCI had a greater decline in immediate memory recall and delayed memory recall than patients who did not have PCI.

“This study offers patients a look at both sides of the coin with this treatment, allowing them to make an informed decision about their care,” says Dr. Movsas. “Now that we have a more complete perspective and know the challenges, we need to move forward to develop strategies to reduce the risk of neurocognitive changes after brain radiation.”

Already a RTOG study is underway to test memantine, a medication approved for Alzheimer’s disease, to see if it may help improve memory following brain radiation.

Dr. Movsas notes the potential for exploring other strategies, such as using newer radiation technologies like intensity modulated radiation therapy, for a more precise treatment that will spare parts of the brain associated with memory.

About Non-Small Cell Lung Cancer

Non-small cell lung cancer is a disease in which cancer cells form in the tissues of the lung. With non-small cell lung cancer, cancer tends to spread in the earlier phase of the disease to other organs, including the brain.

According to the American Cancer Society, about eight to nine out of 10 cases of all lung cancers are the non-small cell type. There are three main sub-types of non-small cell: Squamous cell carcinoma, which make up about 25 percent to 30 percent of all lung cancers; adenocarcinoma, which accounts for about 40 percent of lung cancers and is usually found in the outer part of the lung; and large-cell carcinoma, which accounts for about 10 percent to 15 percent of lung cancers.

Smoking tobacco is the major risk factor for developing lung cancer. Possible signs of lung cancer include a cough that doesn't go away and/or shortness of breath, according to the National Cancer Institute.

Reference: “Phase III Study of Prophylactic Cranial Irradiation versus Observation in Patients with Stage III Non-Small Cell Lung Cancer: Neurocognitive and Quality of Life Analysis of RTOG 0214.” ASTRO 2009.

[gpawelski]

The idea that systemic therapies can be as effective as PCI, WBR or even stereotactic radiosurgy has been looked upon for a number of years now, with agents like Temodar and EGFR inhibitors against brain metastases.

The brain is the most common site of metastatic spread of lung cancer. Accumulating evidence suggests that systemic chemotherapy may play an important role. There have been clinical observations of frequent brain metastasis responses with systemic chemotherapy.

With a brain metastasis indicated or not, small molecule intervention can be beneficial by dissolving through the capillary cell membranes and absorbed into the brain. Systemic brain chemotherapy can also treat coexistent systemic disease.

Clinical data suggests that patients benefit both in terms of response and survival from drugs and drug combinations found to be "sensitive" to cancer cells rather than "resistant" to those cells.

The leading edge of research today is determing how a patient's tumor cells work and hitting those pathways with multiple drugs, simultaneously or sequentially, each chosen because it targets one of those growth, replication and angiogenesis pathways. Matching tumor type to drug.

A drug like Temodar is small molecule. Empirically, it has been shown to cross the BBB to affect cell death in circulating tumor cells. Exciting results have come from studies of multitargeted tyrosine kinase inhibitors, small molecules that act on multiple receptors in the cancerous cells, like Tykerb and Sutent.

What may be another alternative is high doses of 2 small molecule EGFR pathway drugs, erlotinib (Tarceva) and gefitinib (Iressa), given together. These might cross the blood brain barrier and some patients get a long lived remission. High dose tamoxifen could then be given continuously as a potentiator.

It makes me wonder, if they radiate just the whole brain but not the spinal cord, how does PCI benefit the patient? Any theoretical cancer cells in the spinal cord would eventually infiltrate the brain.

The problem of penetration into the CNS is not as nearly as severe for small-molecule drugs. Large molecules cannot permeate through the narrow spaces, however, fat soluble (lipophilic) molecules can dissolve through the capillary cell membranes and are absorbed into the brain. A few brain diseases consistently respond to lipid-soluble small molecules.

Source: Cell Function Analysis

[Outrider1]

This is interesting reading. They did a study to back up the what the doctors are already practicing confirming that they are doing the right things. Most Onc.s do not recommend PCI for nonSCLC patients and WBR is only used after mets are found in the brain.

As I have ext-sclc and have had PCI (twice Mar09 and then again Jul09) and am considered in the minority of that type of LC at the VA where I go, I have yet to see any of the Non-Sclc patiients sent down to RadOnc for PCI. They usually only have radiation to their brain(WBR) when mets are found and it is targeted to the the tumor itself and not to entire brain.

When I asked some of them about it, they tell me they are sent for radiation to shrink or destroy (hopefully) their tumors only and not as a preventative and the radiation is only to the location of the tumor directly. My Onc.s (I see several different ones) all have said the same thing. Dr. West over at Grace says the same thing as my Onc.s about the relationship of radiation in the preventing future mets with Non-sclc.

I also asked about the radiation to the spinal cord in relation to the fluid and was told that the larger molecules of the chemo are thought to be able to pass through via the capillaries surrounding the cord as they (the capillaries) are larger than the ones surrounding the brain and once the fluid reaches the brain the molecules are too large to pass through the smaller capillaries. Radiation to the spine is usually only used to treat for pain management or to remove actual tumors and not to treat the fluid for floating cells in the fluid for that reason. They think that the chemo can reach the the fluid surrounding the spinal cord.

I am no Dr. so this is only the stuff I have been told by the Dr.s and what I have been able to pick up through researching on the internet and at the library.

It is nice to know that someone (People doing the research) is back stopping what the Onc.s are practicing with the studies that they are doing the right things.

Thanks for the information and interesting read.

Dawn

[ginnyde]

Dr. Movsas was Earl's radiation oncologist at Fox Chase Cancer Center. As some of you know, I have had my problems over the care Earl received at Fox Chase. This does not apply to Dr. Movsas. He was professional, caring and knowledgable. He never let the ball drop or give bad information as others there did.

Knew he was no longer at Fox Chase (smart man). Glad to see this article. Thank you.

[gpawelski]

Outrider1

I've asked this question to Dr. West on the Grace forum. "If they radiate just the whole brain but not the spinal cord, how does it benefit that patient? Any theoretical cancer cells in the spinal cord would eventually infiltrate the brain." This was in regards the SCLC.

His answer was "the benefit of PCI is that the vast majority of CNS occurrences are in the brain rather than the meninges, so while there is some theoretical benefit to treating the spinal cord, there is also greater risk, and the volume at risk is probably low enough that it isn't worth the added risk." Cute answer. Isn't worth the added risk.

One of his colleagues, Dr. Goldberg, stated that "PCI doesn't include the whole spine because it doesn't need to do that. So, while theoretically true that all disease in the brain could contaminate the spinal length, it doesn't seem to do that in reality very often, and certainly not often enough to warrent the widespread use of craniospinal radiation for brain mets or PCI." Even a cuter anwser.

What I gathered from both of them is that the larger the volume treated, the greater the "effect" from radiation. The patterns of recurrence along the spine do not support it. It doesn't seem to recur there very often (on average). So why do it, even if it could contaminate the spine? Still doesn't make a lot of sense to me.

In regards to NSCLC, Dr. West said "there is no proven value of PCI for NSCLC yet." As the above study afirms. He agreed that the question of whether systemic therapies can be as effective as PCI with a more favorable side effect profile is an interesting one, and one that might be done if the value of agents like Temodar and/or EGFR inhibitors against brain metastases can be established more clearly.

I think they can be established more clearly, if you "test the tumor first" with cell function analysis. The leading edge of research today is determing how a patient's tumor cells work and hitting those pathways with multiple drugs, simultaneously or sequentially, each chosen because it targets one of those growth, replication and angiogenesis pathways. Matching tumor type to drug.

Some six and a half years ago, an old high school classmate contacted me because of reading my material about cancer on the internet. Her husband had stage 3a NSCLC. They choosed to go to the University of Pennsylvania rather than our infamous regional cancer center, who said his cancer was inoperable and wanted to just give him chemotherapy and radiation.

She had read of my experiences with our regional cancer center and did not want to experience the same consequences. She told me that our regional cancer center radiation oncologist wanted to do prophylactic whole brain radiation for NSCLC clinical trial. They absolutely said NO to it! As the clinical trial turned out, there is no proven value of PCI for NSCLC.

ginnyde

I empathize with your experiences at Fox Chase.

My wife had an extrapleural lobectomy for a metastatic recurrence at Fox Chase in 1996 by one of the finest thoracic surgical oncologists in America. It was a metastatic transdiaphragmatic tumor from the original ovarian cancer (1972), with attachment to the lung, liver and other midline structures of the chest.

The surgeon was known for her "shark-bite" stitches (some surgeons are known for their Mercedes Benz symbol stitches). And she placed Gore Tex where my wife's diaphragm used to be.

Thanks to Taxol, when I called Fox Chase two years later because of a metastatic tumor on her cerebellum, they didn't have any neurosurgeons on staff. The thoracic surgical oncologist also left.

[Outrider1]

So what's the rub here?

From what you stated about the Grace Dr.s responses to your question; 1. it was in relation to SCLC not to NSCLC as your original post was and 2. That they agreed that in regards to NSCLC that PCI/WBR showed no added benefit just as the study suggested. Those two posts had responses about questions of spinal fluid and cord which had nothing to do with the original study information that you posted. The original post was that the study was conducted to determine the effectiveness of PCI/WBR as a preventative for NSCLC to the brain. I found both of the responses not "cute" but informative and well thought out but I did not take them as "gospel" on the subject.

My PCI was 8 days both times and the actual radiation to the brain lasted maybe 30 seconds not the ten minutes as suggested in the study information. The whole time from on the table being adjusted to strapped down to unstrapped, and off the table was 10 minutes or less, every time. Ten minutes of radiation seems excessive to me and woulds certainly cause cognitive damage and memory loss problems.

As to the spinal cord and fluid, it stands to reason that cancers cells travel in a fluid system, ei. lymphatic, circulatory, or cerebreo-spinal fluid just as all other things that affect are whole body do (drugs, infection, virus, etc.) So treating the fluid makes sense. The problem is that the closer you get to the brain and in the brain itself, the pathways for the fluid to travel get smaller and smaller so that the larger molecules of whatever drug they are using can not get in. The larger capillaries in the CNS surround the spine, so it stands to reason that you would treat the spine with treatment that would cause the LEAST amount of possible damage (ie. chemo v. radiation). Since most chemo will not cross the blood brain barrier and may not get rid of all of the cancer cells in the CNS, PCI/WBR is used to try to reach those cells. Although SCLC is extremely aggressive, it is an easy "kill" in that Chemo and radiation both work on it rather well which is not the case with NSCLC. There are several drugs out (navalbine comes to mind right off the top of my head used for NSCLC)that are thought to be able to cross the blood brain barrier and are being studied for use for SCLC. The ones you mentioned in the second part of the post are targeted to NSCLC and do not work as well or at all for SCLC. Since SCLC is less common the NSCLC more work is done in that area of research in order to reach the most people with any possible new breakthroughs.

The first part of the Hyppocratic Oath is "First do no harm" I see this in the post from the Grace site. Radiation is extremely damaging and the body can only take so much radiation in a lifetime, so why use that if something less damaging will do? Although most chemo currently destroys all cells, there is research on-going right now for new therapies and chemo drugs that target specific cancer cells and not good healthy cells. There are also new targeted radiation treatments being used for treatments to the brain as well as all other areas to minimize exposure and damage.

And please explain to me how one cancer drug can run a several different types surgeons away from a Hospital/Medical Center? It certainly isn't because the surgeons are out of business as they work on all things related to their areas of expertise not just removal or eradication of cancer. I realize this was in response to a similar experience shared by ginny but it sound like from the beginning of the response to me and then included to ginny that you were more angry at the Grace Dr.s posts and your experience with the Medical treatment center than in the fact that all things posted after the original study information you posted agreed with what the study said.

I am not trying to be confrontational at all, however I do not understand the rationale behind your reply post to me when I agreed with what you and the original two posts were saying. Although, I am no Dr. (as I have stated several times before) so my agreement is really immaterial, I did appreciate that you brought the information forward.

Maybe I am missing something fundamental here. If so please let me know.

Dawn

[gpawelski]

No rub Dawn. Whether SCLC or NSCLC, if they prophylactically irradiated just the whole brain but not the spinal cord, how does it benefit that patient? Any theoretical cancer cells in the spinal cord would eventually infiltrate the brain.

West and Goldberg gave their respective reasons that the larger the volume treated, the greater the effect from radiation. The patterns of recurrence along the spine do not support it. It doesn't seem to recur there very often (on average). But it does happen.

I knew of a physician (he posted his experience on the ACS discussion board back in 2003) who was diagnosed with late-stage NSCLC, with a brain met. He insisted on having his tumor screened before he began chemo and had a lymph node removed to provide the sample for the test.

He was going to have Gamma-Knife on the brain met. However, he did not need it. He had the right kind of synergistic combination (gemzar, carboplatin, navelbine, high-dose tamoxifen and iressa) working against his cancer cells, and it eliminated the brain metastasis also.

That is why I thought the idea of systemic therapies could be as effective as PCI, WBR or even stereotactic radiosurgy. Small molecule intervention can be beneficial by dissolving through the capillary cell membranes and absorbed into the brain, while also treating coexistent systemic disease.

[Outrider1]

Okay, I'm with you now.

I agree with you about the cells in the spinal fluid infiltrating the brain.

My hypothesis is that since there are less blood pathways (veins, arteries etc.) around the spinal cord than there is in the brain (which is a target rich environment, so to speak) is the reason that you see less cancer cells in and around the fluid and spine than the brain. Since cancer cells target the brain for that reason, it is the only reason I can see for targeting the brain only to minimize any damage that may occur from the radiation to the spine.(I hope that makes sense) (I am no Dr. but have gathered this from what I have gotten...I think I said that before.lol)

As far as the Grace Dr.s I think they are referring to the possible damage from the radiation in relationship to the actual good it might do in reference to the volume given. Most of their posts on the the subject point out that it is a tool to use when necessary, but feel their best options are for the chemo regimes you have noted.

I will note in the treatment of my SCLC I have had carboplatin. Of the other drugs you have listed I have been told they do not work nearly as well on SCLC as they do On NSCLC and are not normally used for SCLC. But, I will ad them to my list for if and when my SCLC shows back up.

Thank you for the discussion, I found it enlightening.

Dawn