Alk lung Cancer Brain Mets Treatment - 1262866

Hi Alicia,

Welcome to GRACE, and congratulations on your good response to crizotinib.

Some oncologists and radiation oncologists tend to favor focused radiation (gamma knife or cyberknife) rather than WBR when there are only a few brain mets. Focused radiation has fewer neurological side effects than WBR, and using it first leaves open the possibility of using WBR later. As Dr. Loiselle wrote:

"An alternative to whole brain irradiation in some circumstances is stereotactic radiosurgery – a focused approach targeting known areas of brain metastases. Stereotactic radiosurgery can be accomplished with multiple devices – Gamma Knife and Cyberknife are examples of dedicated stereotactic radiosurgery platforms. For patients that present with a solitary or limited brain metastasis, there is a fifty percent chance they will develop other brain metastases and may eventually benefit from whole brain irradiation. There does not seem to be a detriment to initially deferring whole brain irradiation in favor of stereotactic radiotherapy for these patients. For patients with more extensive brain metastases, the risk of developing additional brain metastases is likely higher." - http://cancergrace.org/lung/2011/09/11/brain-metastases-in-lung-cancer-… The remainder of his post describes the circumstances in which stereotactic radiosurgery may be appropriate, and your situation is consistent with his principles - no more than 3-4 brain mets, disease control elsewhere in the body.

An alternative viewpoint is presented by Dr. Mehta, who provides evidence that suggests that WBR, although it can cause some cognitive defects, actually results in higher cognitive function by preventing progression in the brain. His discussion can be found here: http://cancergrace.org/radiation/files/2011/04/dr-minesh-mehta-preventi…

JimC
Forum moderator

Alicia,

I think you got a good discussion of the pros and cons and have a good understanding of the issues. There isn't a clear consensus, but a growing majority of lung cancer experts consider the brain a separate compartment and, knowing that XALKORI (crizotinib) doesn't penetrate into the CNS, don't consider it a failure of the drug if the cancer is very well controlled elsewhere but you see a few brain metastases. While LDK378 (now named ceritinib) and other second generation ALK inhibitors do have activity in the brain, there is reason to not rush into a treatment that may not be needed if patients can do well for a long time on ongoing crizotinib combined with focal radiation as needed. Many patients can go for many months, sometimes even years, after gamma knife (stereotactic radiosurgery) for limited brain metastases. Then the second generation ALK inhibitor can still be associated with a good probability of subsequent response, but you don't start the clock any earlier than needed.

As for whole brain radiation (WBR), I do think that the risks of WBR tend to be overstated, but they are more of a concern in patients who have a potential survival of years rather than what we historically saw in patients with advanced lung cancer and brain metastases, which was months. I have had patients do very well for years after WBR, but particularly if patients have a very limited number of metastases, I think it makes good sense to pursue a focal radiation approach and reserve WBR for more diffuse disease as needed.

Good luck.

-Dr. West

aliciauk,

The bad news is that brain mets are the Achilles heel of the 1st generation ALK inhibitor Xalkori. Despite the general view that brain mets are difficult to control, the hopeful news for ALK patients with brain mets is that they do have some options to consider trying (with a wide range of odds of benefit and side effect risks). Here’s my list of options you can discuss with your oncologists and radiation oncologists:

1. Targeted radiation (of various kinds and brand names)* to eliminate limited numbers of brain mets. Although USA radiation oncologist following today’s standards will limit this to patient with few brain mets, there is some research suggesting usefulness for 5 or more brain mets and there there are also anecdotes of its use for as many as 32 brain mets in the USA and 45 to 112 brain mets in Japan.

2. Whole brain radiation (WBR).* This makes a lot of sense when there are many brain mets, to try to clear the field for a number of months, especially if there are few options for brain mets control. Usually WBR won’t be repeated due to lifetime limits on how much radiation can be tolerated at any one spot, but targeted radiation might be used for subsequent control.

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3. WBR with hippocampus sparing* might reduce the small risk of the worst (debilitating) of the potential side effects that sometimes appear in the months following WBR . . . if there are no mets near the hippocampus and the risk of spread there seems less likely than elsewhere (as is often the case according to some research). I think this is considered experimental, though, so it may be very difficult to find radiation onologists willing to try it (and of course there is a risk that cancer cells could be harbored there and later grow or re-seed elsewhere).

*[Regarding 1, 2, and 3 above be aware that a hammer may view every problem as a nail. Radiation oncologists who don’t do a lot of targeted radiation or hippocampus sparing may be more inclined to recommend their own WBR, and traditionally that would’ve made a lot of good sense (esp. back before today’s drugs when late-stage lung cancer survival for multiple years was rarer). Conversely, ones who only do targeted radiation might be more inclined to favor that even where WBR might (in hindsight) have been a better bet.]

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4. Even though lab experiments and clinical experience show Xalkori doesn't seem to penetrate into the brain (only about 0.25% of the blood level penetrates per one study, and about half of progression on Xalkori occurs in the form of brain mets), I have heard that there have been some rare surprising cases where Xalkori seemed to have caused some brain mets shrinkage nonetheless. This is rare enough that I assume nobody should rely on it, but sometimes it can be the only choice left and a low-odds gamble worth trying if (1) an ALK+ patient whose brain mets did not arise while trying an ALK-targeted drug and (2) that patient doesn’t have any other fair option available. If this unusual situation arises without other viable options, your oncologist might want to phone an ALK research expert like Drs. Shaw or Camidge for their opinion of the situation.

5. 2nd generation ALK-targeted inhibitor drugs that are still going through clinical trials like Novartis ceritinib (LDK378), Chugai alectinib (CH5424802), Ariad AP2611, which have each demonstrated at least some brain mets shrinkage in what seems like most patients with ALK-driven brain mets if the early results are upheld.** (There also might be other 2nd gen ALK drugs that aren't as far along in their clinical trials.) Novartis’ ceritinib (LDK378) seems closest to FDA approval for Rx use in lung cancer and already has an extended access program version of its trial for patients in the USA who come close to but don't quite meet all the eligibility requirements of their regular trial.

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6. 3rd generation ALK-targeted inhibitor drugs (also for ROS1).** The only one today is Pfizer PF-06463922. It was specifically designed to be able to cross into the blood brain barrier and also have effectiveness against known stubborn variants of ALK (and ROS1) which 1st and 2nd generation ALK inhibitors can’t control. Although lab experiments show its % penetration into the brain is about 20-30% of that in the blood, the potency and range of variants it controls makes it promising for ALK (and ROS1) brain mets control. The difficulties with this drug are (1) it is just starting its trials so it is only available in 2 USA locations (Boston & Nashville), 1 in Australia, 1 in France, and 1 in Spain, (2) it is still testing various doses (although I think early patients can up their dose after proven safe in other patients), (3) eligibility requires no more than two prior ALK inhibitors have been tried before, and (4) if any have been tried then an ALK inhibitor must be the last treatment tried (i.e., they want it to be clear that this drug improves patients more than their prior drug, but one can re-try one long enough to prove it isn’t helping).

**[Keep in mind that just as drug-resistant variants of ALK-driven lung cancer can emerge anywhere, even in the brain even if a drug can reach it. Some variants of Xalkori-resistant cancer might be invulnerable to a particular drug tried against it, and some might require a greater amount of the drug than can penetrate through the blood-brain barrier into the brain.]

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7. Usually not so, but some chemo drugs are believed to penetrate the brain. For example, Alimta (pemetrexed), Avastin (bevacizumab), or Camptosar (irinotecan), if I remember correctly. Even though the odds of benefit of a chemo drug might be lower than the odds for a newer ALK-targeted inhibitor drug, chemo is a readily available locally Rx-able option. (And there is some evidence that ALKies have better odds with Alimta than others, although some experts think that is only due to their usually never-smoker/light-smoker history.) Wherever in the world you are, your oncologist will have a great deal of experience with chemo options and I assume they will probably know if there are remaining chemo options for your case that might be worth trying against brain mets.

8. Brain port infused chemo. This is sometimes tried, for example using an Ommaya Reservoir with port directly into a large brain met or sometimes infusing a chemo infusion drug via a spinal port for leptomeningeal carcinomatosis (mets in brain lining) as speculated in this CNN report about Valerie Harper (“Rhoda”). I have only heard of these in a couple of lung cancer patients, so it must be rarely used. Your oncologist will probably be able to tell you if this is a viable option.

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9. Hopefully in a year or two we might see clinical trials testing whether one or another existing Rx-able drug might make the brain more permeable for an ALK inhibitor.

Best hopes,

Craig
In PA

P.S. -- If I missed some other options or important errors/limitations/caveats I hope someone else will add or elaborate.

Craig,

That was the most thorough discussion I've ever read. You should write review articles for medical journals.

It's truly a tour de force. I don't think the direct infusion of chemo into the brain is an approach I'd favor, but you did list it last...

-Dr. West