"The
The "mean" in the Google translation of the German language news report actually refers to the median (mittlere), as confirmed at the SNO 2017 presentation.
Although this was small for a phase 3 trial (only ~140 patients), a gain in median survival of over 16 months is unprecendented.
This will undoubtedly become the new standard of care for MGMT-methylated GBM.
https://clinicaltrials.gov/ct2/show/NCT01149109
https://forum.hirntumorhilfe.de/neuroonkologie/breaking-news-fortschritte-in-der-glioblastombehandlung-12606.html (news article in German)
Please find some additional information on mOS after 1-5 years below. The 50% OS improvement after 4 years and in median OS decreases to 20% after 5y, which is nevertheless a remarkable improvement. A larger patient cohort would probably level out these figures to a certain extent. More details are expected to be released with the upcoming SNO conference in November.
ReplyDelete1y OS(m): 84 vs. 89
2y OS(m): 65 vs. 71
3y OS(m): 42 vs. 57
4y OS(m): 31 vs. 49
5y OS(m): 28 vs. 34
Thanks for the additional info Malte!
DeleteThis is incredibly exciting news for Methylated patients!
ReplyDeleteDid they follow the 5/23 schedule and did they include CCNU exclusively with TMZ?
CCNU/TMZ combination was given in six 42 day courses. CCNU 100mg/m² on day 1 and TMZ 100 mg/m² on days 2-6. In courses 2-6 TMZ was stepwise adjusted to 200 mg/m² according to the hematotoxicity observed in the previous course
DeleteFirst CCNU application was already during first week of radiotherapy.
As stated in the listing for this trial on clinicaltrials.gov
ReplyDelete"Six 42-day courses of oral CCNU 100 mg/m2 (day 1) and oral TMZ 100 mg/m2 (day 2-6), first CCNU application during the first week of RT[.] CCNU/TMZ and radiotherapy start 2-5 weeks after diagnosis (day of surgery for glioblastoma (GBM). In courses 2-6, TMZ dose are adjusted according to the hematotoxicity observed in the previous course and can be increased stepwise up to 200 mg/m2/day"
6 week (42 day) cycles
Day 1: CCNU 100 mg/m2
Day 2-6: TMZ 100 mg/m2
So this is different from the standard 5 in 28 day cycle of TMZ in that the cycles are 6 weeks instead of 4 weeks (but both groups get 6 cycles total), and the starting dose of TMZ is lower in the combination groups (100 mg/m2 rather than 150). Also CCNU starts during the radiation+TMZ phase of treatment.
https://clinicaltrials.gov/ct2/show/NCT01149109
Notably, the reason why so few patients were recruited to this phase 3 trial is because they were expecting a large survival benefit based on the phase 2 results, so fewer patients would be needed to detect statistically significant benefit.
ReplyDelete"Assuming that CCNU/TMZ therapy increases the median overall [one year] survival (mOS) from 48.9% (standard TMZ) to 70% (CCNU/TMZ; 75% in the previous phase II trial, Glas et al., 2009), 2 x 68 patients have to be accrued"
In my experience, it is still sometimes very toxic for the platelets. That is why the cycles are each 6 weeks
ReplyDeleteGood to see a progress based a cocktail approach of existing drugs while most other promising drugs are in an orphan/early trial stage. I understand it so that this protocol could be applicable asap with GBMs with methylation?
ReplyDeleteQuestion: CCNU as I understand it has been part of PCV treatment for especially Oligos for years, whilst solely TMZ has been the preferred drug for astrocytomas? Would this discovery also have an possible influence on treatment of DA2 and AA3 with e.g. IDH1 and methylation? So would you expect a CCNU/TMZ combo as standard treatment of methylated AA3´s in the future?
Astrocytomas were also treated with PCV before the approval of TMZ. I expect with these GBM trial results, we'll see new trials testing this CCNU + TMZ combo in lower grade gliomas very soon.
DeleteNice to see such an improvement in survival. What do you think is the cause of this? Do CCNU and TMZ have different mechanisms of action?
DeleteYes they do have different mechanisms. There was an in vitro study published recently showing that mismatch repair deficient tumors that are resistant to TMZ are more sensitive to CCNU, and even more sensitive to TMZ + CCNU. Mismatch repair defects often occur in recurrent MGMT-methylated tumors as a form of TMZ resistance, so if you combine CCNU and TMZ from the start, you could prevent this form of resistance.
Deletehttps://link.springer.com/article/10.1007%2Fs12094-017-1743-x
This is very interesting. What's the next step on these findings, is it at the stage where oncologists would start recommending this as the standard of care rather than TMZ alone? My wife has just finished the third round of TMZ and about to start the fourth.
ReplyDeleteCCNU is already an approved drug for brain tumors, so that should facilitate this becoming the new "standard of care", as set by organizations such as NCCN, for newly diagnosed MGMT-methylated GBM. Even before official standards are changed, some institutions could change their practice on the basis of results presented at oncology meetings. For example, what came to be known as the Stupp regimen: "This regimen was first used routinely at the Johns Hopkins Medical Institutions in June 2004, following presentation of the regimen at the 2004 annual meeting of the American Society of Clinical Oncology" though TMZ was not approved by the FDA for newly diagnosed GBM until March 2005.
DeleteFirst presentation of these results to an international audience will take place at the SNO meeting in San Francisco in November. So far they were only discussed at a NOA meeting in Germany. I don't imagine many changes to standard practice will happen until after the presentation at SNO.
If I recall correctly, your wife was diagnosed with a lower grade astrocytoma rather than a GBM, so a bit more convincing might be required to get a prescription for CCNU on top of TMZ.
my 25 year old son was diagnosed with a stage 4 Astrocytoma this past May and after undergoing surgery (took large part of left side of brain} the suggested treatment was 6 weeks of radiation and TMz, we just finnished and begin the solo chemo for 6 months...Im searching for better suggestion??
ReplyDeleteThe first question that comes to mind is: what was the result of testing for MGMT promoter methylation status and IDH1 mutation status? Did you get a copy of the pathology report and was there mention of these tests? 25 is very young for GBM, so there's a higher chance his tumor would have either the IDH1 mutation, or possibly a mutation in the H3F3A gene, which is also more common in young adults.
DeleteAs for the CCNU+TMZ results we've been discussing, this applies to tumors with methylation of the MGMT promoter, which is common in IDH1-mutant tumors, but not as common in other types.
In other words, more information on pathology is required before any detailed suggestions can be given.
Could this also benefit people with recurrent methylated GBM? My dad is on TMZ again but there is some progression again. Should we consider adding CCNU?
ReplyDeleteYes, as shown in this study https://link.springer.com/article/10.1007%2Fs12094-017-1743-x
Deleteif a tumor has acquired resistance to TMZ through mismatch repair defects, then such a tumor should be especially sensitive to CCNU, and perhaps even more sensitive to the combination of TMZ + CCNU. Caveat: this study was only in vitro. I don't suppose his recurrent tumor was tested for hypermutation, but if the tumor is hypermutated, more TMZ as a single agent could end up not giving any benefit and perhaps even make the situation worse. I would consider it a good idea to either add CCNU, or switch over to CCNU and drop the TMZ.
The way forward is of course dependent on his ability to tolerate CCNU or CCNU + TMZ which can be hard on blood counts.
DeleteThat is very interesting. our NO definitely doesn't suggest CCNU (Lomustin) as a great alternative to TMZ, but the release of these studies might change his mind.
ReplyDeleteOn a separate note, could somebody guide me as to how I can start a new post on the Blog, rather than simply replying to an existing?
My wife started off with a Grade 2 astrocytoma but throughout the years has now progressed to a Grade 4 GBM that isn't responding well to TMZ. We are looking into clinical trial options but there aren't many options where we live, so we are exploring options in the US.
Has anybody else had the experience of travelling to the US to access clinical trials? I understand that it will be extremely expensive, and a logistical challenge to organise. We are willing to take on the expense if it is a trial that is worth it. Really wanted to hear from anybody else who have gone down this path.
We are also only starting to look through trial options, primarily in the US. If anybody has any recommendation as to the most promising trials that are happening at this point, we would really appreciate any guidance and advice.
I've added you to the author list. You should get an invite by email. If you don't see it in your inbox, check in the spam folder. After you've accepted the invite, you should see the words "New Post" at the top right corner when looking at the blog.
DeleteMy mother is a glioblastoma patient, and her tumor is methylated. She is 3 weeks into the radiotherapy and temozolomide. Two questions:
ReplyDelete1. How can we make use of this paper right now? Is it safe to shift from temozolomide to temozolomide+CCNU?
2. Are there any side effects that we should be aware of just in case we switch?
The main risk with the combination treatment is more severe myelosuppression - bone marrow toxicity leading to declines in healthy blood counts. In the prior phase 2 trial, with the standard dosing regimen (100 mg/m2 of both CCNU and TMZ), the rate of severe (grade 4) myelo/hematological toxicity was 16-19% depending on which paper you're looking at. 42% of patients experienced grade 3 or 4 hematologic toxicity.
DeleteNon-hematological adverse events were rare: out of 31 patients, there was one case of grade 2 lung fibrosis, one case of grade 3 elevation of liver enzymes (ALT/AST), and one case of grade 4 drug-induced hepatitis.
This toxicity data comes from a 2006 paper:
http://ascopubs.org/doi/full/10.1200/jco.2006.06.9104
There was also a separate paper showing "that late
and prolonged pseudoprogression may be in fact a common phenomenon in patients with glioblastoma with a methylated MGMT promoter and treated with a more intensive alkylating chemotherapy."
http://ascopubs.org/doi/full/10.1200/jco.2011.40.9565
There will likely be safety and toxicity data for the phase 3 trial presented at this year's SNO conference in November.
The main thing to watch out for is severe drops in healthy blood counts (leukocytes, platelets). Also it's likely stronger anti-nausea measures would be required.
It usually takes at least 6 weeks for healthy blood counts to recover from one standard dose of CCNU. You'd have to discuss with her oncologist whether her bone marrow is in good enough condition to tolerate the combined regimen and whether doing a dose of CCNU now would risk having to delay the start of follow-up chemo after radiation.
Note doing TMZ + CCNU may provide bigger benefit after radiation. During RT the TMZ is fairly low dosage and is acting more as a radio sensitizer and CCNU generally isn't thought to do the same thing.
DeleteDuring RT w/ TMZ switching to a very aggressive ketogenic diet has some good data for improving efficacy. At 3 weeks in though, it would have to be taken very seriously, very soon to actually get to a ketogenic state quickly enough. Roughly would mean a 100% water only fast for 4 days, then eating almost no carbs, mostly fats and modest proteins.
It's a little odd. I haven't heard much talk about this trial since it was presented on Friday. But it's probably the most significant news to come out of this year's SNO conference: the first phase 3 trial for newly diagnosed GBM (MGMT-methylated subgroup only in this trial) to meet its primary endpoint since the EF-14 trial results were announced in 2014, and only the second since the pivotal 2005 trial that led to approval of TMZ for newly diagnosed GBM.
ReplyDeleteI'm working on a summary of this trial presentation now.