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Alimta for Brain Metastases in NSCLC?
Brain metastases from NSCLC is almost a field of its own. This is because of the relatively high frequency with which metastases appear, the fact that they may return, even after treatment with whole brain radiation therapy (WBRT), and that our chemotherapy has long been considered to be ineffective against them. In fact, the extent of them as a problem is reflected in the number of thread questions on this subject in the GRACE forum. At the same time, there has also been work devoted to prophylactic whole brain radiation therapy (WBRT) in selected NSCLC patients considered to be at high risk. For unknown reasons, adenocarcinomas (ADC) seem to be the most likely to appear in the brain, at times the first/only site outside of the lung.
For this reason, a recent study of Alimta, published on-line in Lung Cancer, by Bearz and colleagues from several hospitals in Italy, may be of interest. Of a subset of 22 patients with brain metastases who either recurred after WBRT (11 patients) or had never received radiation (11 patients), and then received Alimta (pemetrexed), a remarkable 68% had what the authors called a “cerebral benefit.” Of the 22, 5 had a partial response, 9 had stable disease, while only 7 had progressive disease.
That being said, the study had several limitations. First, although half of the 22 had prior WBRT, the authors did not say how each of the 2 groups fared. The implication is that some of the 14/22 who benefited from Alimta had prior WBRT. Next, it would have been good to see how those few with squamous cell carcinomas (SCC) responded. In the entire group of 39 patients, only 4 had SCC, a subtype not generally felt to respond well to Alimta. Finally, this was a small study, with presumably a relatively homogeneous population, and the results may not reflect what might happen elsewhere. On the other hand, of the 39 patients with brain mets treated with Alimta, the median survival was 10 months, a pretty encouraging result considering what we had historically expected.
Clearly, more pre-clinical work needs to be done to determine the factors leading to central nervous system penetration by this drug. However, since we are loath to re-radiate the brain in such patients, this may be a strong alternative for those who progress after prior radiation. Also, since these patients are often somewhat frail, and Alimta is often quite well tolerated, the drug is appealing (it is already approved as second-line and maintenance chemotherapy as a single agent). Finally, in patients with locally advanced disease receiving combined radiation and chemotherapy, one might consider Alimta to go along with a platinum, at least in those with ADCs.
We hope to see further work on this subject, since it certainly represents an unmet need in lung cancer management.
18 Responses to Alimta for Brain Metastases in NSCLC?
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Although thankfully it is a relatively rare occurence, treatment of brain recurrence after WBRT represents a real unmet need. Other than repeating the WBRT, or trying gamma knife if there are only a few spots, there are not a lot of options for these patients. I have seen people use Temodar, but with little success. It would be encouraging to find a systemic therapy that would have a reasonable chance of working, but it occurs to me that most patients with adenocarcinoma will now be getting Alimta in first or second line therapy anyway, so I’m not sure how often it will still be available as an unused drug in this setting.
Dr. Garfield -
Thank you for providing this information. Brain mets are among my greatest fears as I battle Stage IV NSCLC. I still work full time, but the nature of my career is such that the side effects of brain radiation might end that part of my life. Work adds purpose and a sense of “normalcy” that I value greatly. So far, I have no symptoms of brain involvement and my oncologist prefers to wait to see if symptoms occur before ordering an MRI. I’m taking Alimta and Zometa (for bone mets) as maintenance after 6 sessions of taxol and carboplatin. Although I realize this is only one study with a small number of patients, it’s encouraging to read that Alimta MIGHT possibly play a role in combating brain mets. I hope someone somewhere is pursuing additional research on this unmet need.
- Catharine
My main concern reading this was the same one that Dr. Pennell raised. We all see that the majority of people with brain metastases have an adenocarcinoma, and most will be getting Alimta as a first or second line therapy. I strongly suspect that the majority of patients who have progression/recurrence of brain metastases after whole brain radiation will have already received and then progressed on Alimta. Still, it’s a lead we should follow up on.
I can understand your concern Doctor’s, about Alimta being used early and therefore perhaps not available when brain mets occur. However, as one who has been on Alimta for nearly a year (as second line), and showing no evidence of disease since January of this year, I have to credit Alimta for holding off any metastasis, including brain mets. My point is, this info makes me wonder should my cancer progress, perhaps brain mets will be less than it could have been because of this chemo, and I still have WBRT to fall back on. At least I’d like to think so….
I can’t resist this, especially since I think I see a couple of other people hinting at it, but maybe it’s possible that Alimta used as first line treatment is active in the brain where other treatments aren’t, and we’ll see a decrease in the incidence of brain mets in the years ahead.
Perhaps. The use of alimta in the first line setting has really only occurred very recently (it was approved as a first line treatment in October of 2008, I believe), so we haven’t seen the sequelae of this development.
-Dr. West
My thoughts are similar. So far I’ve had 12 third-line Alimta treatments — 3 as a single agent, 1 with Cisplatin, and 8 with Carboplatin. Though I haven’t had any measurable shrinkage, neither have I had any appreciable growth since starting on the Carbo-Alimta doublet. At our most recent meeting my oncologist said he would agree to a break in treatment if I so desired, but I said I’d prefer to continue since I’m tolerating the treatments reasonably well and my cell type is adenocarcinoma. We also discussed the Italian study and the fact that my recent brain MRI showed no change from the one in 2006, and while it’s too early to make a definite connection, we’re both comfortable with continuing the Carbo-Alimta on the same schedule.
Ned
I was asked via email if I’d been on Alimta since 2006. No, I’ve been on one treatment or another since October 2006, but Alimta only since early 2009. Here’s the summary I have in my profile/signature on the forums part of the site:
Dx NSCLC adenocarcinoma IIIb Sep 2006, now stage IV. Taxol/Carbo/Avastin 4 mo., Avastin 8 mo., Tarceva 16 mo., Alimta 2 mo., Cisplatin/Alimta 1 mo., Carboplatin/Alimta since Apr 2009. See My Cancer Journey: http://tinyurl.com/69argz
Ned
I get to respond to a comment by Ned!
What I based my first comment on was Dr. Garfield’s remark about determining the factors leading to CNS penetration, plus Terryl’s comment about being NED since starting Alimta. This is a bit of a stretch for a “civilian”, and it’s impossible to know with just the information supplied, but it’s possible that Alimta does cross the blood-brain barrier and doesn’t have to rely on tumors having established their own blood supplies before becoming effective; therefore, first line treatment with Alimta could POSSIBLY make the scenario of an otherwise “cured” patient relapsing with brain mets a thing of the past, or at worst, extremely rare…maybe just wishful thinking.
Could I ask whether any additional information about this has come to light in the past year? My mom has what we believe to be SCC and had multiple brain mets on presentation, so she was treated with gamma knife, WBR, and tarceva (since she has an exon 19 mutaion). She had a major response for over a year but then had a large growth in a femur met that required stabilization with a gamma nail. She was off systemic therapy for 6 weeks. She has subsequently gotten 2 cycles of Abraxane and we just learned (18 months out from WBR) that she has several small brain mets, 2 of which are in previously irradiated areas. If there is some additional evidence that Alimta might help the brain mets, even in SCC, we would push for this.
Many thanks.
Anna
An article from Current Drug Targets (http://www.bentham.org/cdt/) of March 2010 had some partially positive things to say on the topic.
The Role of Pemetrexed in Advanced Non Small-Cell Lung Cancer: Special Focus on Pharmacology and Mechanism of Action
http://www.bentham.org/cdt/samples/cdt11-1.tar/0005J.pdf
Page 38
Pemetrexed and the Blood-Brain Barrier
… Several arguments have been put forward to emphasize the concept of the blood-brain barrier (BBB) as an explanation for the limited activity of most cytotoxic compounds in the treatment of CNS-metastases from lung cancer, including low concentrations of most anticancer drugs in the normal CNS, and the failure of systemic treatment strategies for preventing brain relapses… Especially for hydrophilic drugs, transport from blood to the CNS is limited by the presence of tight junctions between brain endothelial cells. For hydrophobic drugs, specific carrier-type systems such as P-glycoprotein (P-gp) are suggested to affect net brain uptake. …
The antifolate methotrexate has been routinely used for treating primary CNS-lymphoma, and there are some arguments for pemetrexed to have similar useful applications in the treatment of CNS tumors. The main argument is that pemetrexed – due to its promiscuous multitargeted enzyme blockade – can overcome drug resistance that is suggested to be a major drawback in treating CNS metastases from solid tumors. Accumulating data suggest drug resistance to be more important than mere mechanistic hindrance for intratumoural drug distribution in patients with CNS metastases from solid tumors. Therefore, overcoming drug resistance by using multitargeted drugs such as pemetrexed, or combining anticancer drugs with P-gp inhibitors might be promising. Pemetrexed pharmacokinetics were also assessed
in liquor in non-human primates after the intravenous application of pemetrexed 20 mg/kg … For this reason, CSF penetration of pemetrexed was less than 2%, suggesting that it might preferably be used in
conjunction with other CNS-targeting strategies. The distribution of pemetrexed to the CNS has been examined by Dai and colleagues in 2005 [52]. These animal experiments showed pemetrexed to have limited CNS distribution, with unbound brain drug concentrations being roughly 10% of plasma concentrations, and suggested the existence of a potent efflux transporter for pemetrexed clearance from the CNS. We recently described a first clinical case of a patient with CNS-metastases from lung adenocarcinoma and a tumor response to 3-weekly pemetrexed monotherapy, suggesting at least partial disruption of the BBB in patients with brain metastases, and possibly also after brain irradiation.
I had not heard of this, Joe. Good to know. Thank you.
Laya
Interesting timing for both this question and Joe’s response—new data was presented yesterday at the Chicago multidisciplinary thoracic tumor conference by my mentor and friend, Dr. Corey Langer, that are relevant to our discussion. He retrospectively analyzed data from two large phase III studies of pemetrexed in advanced NSCLC (Hanna study and Scagliotti study). Patients without known brain mets at study entry were analyzed to determine the rate of brain met as only site of progressive disease. In other words, the question was whether pem could prevent brain mets. Brain met recurrence rate was 3.2% in the pem-containing arms vs. 6.6% in the non-pem containing arms, giving an odds ratio of .49. The effect was confined to non-squamous patients–the rate was 3% for non-sqcc pts treated with pem and 7.3% for those not treated with pem. For squam patients treated with pem, the rate was 3.7%, compared to 4.8% for non-pem treatment. To me, these results generate an important and interesting hypothesis, that pem can prevent brain mets in pts w/non-sqcc; further confirmation will be needed to confirm these findings and they do not address the question of treatment of brain mets once they are there. It’s also worth repeating the histology comment—both pem and these results apply only to non-SqCC.
Continuing the topic of poster presentations by my friends relevant to your question on the topic of brain mets (who knew this could be a subject?) was a poster out of UNC. My new colleagues looked back on the patients they treated on the PASSPORT trial @UNC to see what the effects of the regimen (carbo/taxol/bev for patients with non-sqcc w/treated brain mets) were on brain mets. Of 115 patients enrolled, 12 patients with a total of 24 brain mets were identified with sufficient imaging and followup imaging to allow assessment of response. 13 mets (54%) were classified as complete response, 7 (29%) as partial response and 4 (17%) as stable; there was no progressive disease. These results fit in well with an existing literature about avastin having activity in the brain and promote the hypothesis that avastin should be studied, after radiation, as a treatment of brain mets. However, the retrospective nature of the study and the small numbers prevent the conclusion that avastin should be used for this indication prior to further study.
How rare of an occurence is treatment of brain recurrence after WBRT are brain mets in NSCLC?
Unfortunately, it’s not rare.
Dr. Weiss, getting back to the results of the study with Alimta: if this is true, this is great news for people with adenocarcinoma in general, and especially people like me, with N2 disease and pathologic complete response. We might not have to worry if we’re going to get over that final hurdle. It means that we’ll see more cures as time goes on!
If you can point to any literature on this, it would be appreciated very much.
Thank you Dr Garfiield for posting the study and these very interesting comments, we hope and hope and ever hope for good news!
may I know what is the latesst report on this. This post is December 15th 2010, It is now February 23, 2012. Has the jury given the verdict?
Thank you
Apra