My husband is finishing up cycle 4, our medical provider (Kaiser) does six rounds, so I'm curious if there's any benefit to seeing if more is better.
I know this was discussed in 2017 - Stephen posted a link to an Indian study/review article that said 12 cycle had improved PFS/OS but with big caveats about how more studies were needed. I've now seen a more recent study looking at the comparison between 6 and 12 Extended Dosing (12 Cycles) of Adjuvant Temozolomide in Adults with Newly Diagnosed High Grade Gliomas: A Review of Clinical Effectiveness, Cost-Effectiveness, and Guidelines seem to draw similar conclusions, though a couple of studies in Spain say that 12 cycles is a better choice for older patients or patients with AA (not GBM).
At the time Stephen's thoughts were to 1) go for 12 rounds (or possibly more if tolerated) if the tumor is methylated and if there weren't financial means to pursue immunotherapy, and 2) with an unmethylated tumor and financial resources, stop at six rather than continue to build toxicity to bone marrow and blood counts. Since we fit in the latter category I'm thinking that the six is fine, but I wanted to see if anyone here had additional thoughts or concerns. We have no additional tumor tissue (biopsy surgery only) and didn't have the right markers for the CAR-T treatment at City of Hope, so I'm not even sure if there are vaccine options to realistically pursue.
Thoughts?
If I am reading this correctly, you are addressing an unmethylated GBM? There is a Clinical Trial showing success with unmethylated GBM, at MD Anderson. I do not know what the requirements are. It is VAL-083. I have seen it discussed here in the past.
ReplyDeleteBoth the VAL-083 trial at MD Anderson
ReplyDeletehttps://clinicaltrials.gov/ct2/show/NCT02717962
as well as the expanded access protocol
https://clinicaltrials.gov/ct2/show/NCT03138629
both require that the tumor be recurrent.
The largest (although retrospective) study of this question was published in Neuro-Oncology in 2017.
ReplyDeletehttps://academic.oup.com/neuro-oncology/article/19/8/1119/3084493
The progression-free survival advantage of more than 6 cycles versus 6 cycles was statistically significant only for patients with methylated MGMT promoter (hazard ratio = 0.65, p= 0.0019). Progression-free survival difference was not statistically significant for the MGMT unmethylated group (p = 0.43).
Given the cumulative toxicity of TMZ, I wouldn't feel it necessary to extend TMZ cycles beyond 6 for MGMT-unmethylated tumors, unless there is a clear benefit shown on MRI images.
After 5 yrs from original GBM tumor resection, 77 yr old hubby had recurrence this Jan. After full resection of MGMT methylated tumor, he'll be starting his 8th rd of TMZ. MRI's look good and blood tests holding. Seattle NO wants to take him thru 12 rds, whereas 2nd opinion NO at UCSF is suggesting he stop now saying studies show doesn't do much good after 6 rds. Hmmm? Normally I go w/UCSF NO but not sure this time. Choice is ours. Whatcha think Stephen?
DeleteThanks,
Candy
There were two retrospective studies addressing this question for newly diagnosed GBM, both published in March 2017.
DeleteOne was a German study (by Gramatzki, Weller, et al.), that found a significant progression-free survival benefit with extended cycles (more than 6), but no overall survival benefit. They also found that the significance of the progression-free survival benefit disappeared in a multivariate analysis adjusted for various prognostic factors.
https://www.ncbi.nlm.nih.gov/pubmed/28298550
A second study, which I've discussed before (Blumenthal, Stupp, et al. - interestingly Michael Weller is also an author on this paper) was a much larger study with patient datao collected from several large phase 3 trials. It found a significant progression-free survival benefit of more than 6 TMZ cycles, especially for the MGMT-methylated group.
https://www.ncbi.nlm.nih.gov/pubmed/28371907
Neither of these studies were comparing 6 versus 12 cycles. They both compared 6 cycles versus any number over 6 cycles.
My belief is that when TMZ is working (mostly in MGMT-methylated tumors), more than 6 cycles is most likely beneficial. After a total resection, it's harder to say whether the chemo is "working" because it's no longer possible to observe a response. I would probably decide based on how well he is tolerating the chemo, how much it's impacting his quality of life and healthy blood counts.
The question of 6 versus 12 cycles still hasn't been answered definitively. I've only seen one completed prospective clinical trial, and that trial oddly didn't include information on MGMT status, so was not adequate to properly answer the question. However the results did show a significant benefit of more than 6 cycles.
https://www.ncbi.nlm.nih.gov/pubmed/28658891
Another consideration is hypermutation risk. Prolonged and exclusive chemotherapeutic reliance on TMZ is in a sense asking for a hypermutated recurrence later on down the line. For low grade gliomas, I would say that is a bad thing. For glioblastomas, I'm not so sure that is always a bad thing as it could make the tumor more visible to the immune system and more responsive to immune therapies such as checkpoint (PD-1, PD-L1 etc.) inhibition.
DeleteI would re-iterate stephen's last line -- unless there is a clear benefit shown on MRI images. Especially if you are doing the cocktail approach and the MRI's are improving then could even consider changing cocktails for a few rounds to reduce any risk that part of the cocktail was actually reducing chemo impact. Certainly watch blood counts carefully though if going past 6.
ReplyDeleteThe other thought is that biopsy only seems surprising for HGG. Kaiser is a lot more conservative with surgery than others top centers, and so hope you got second opinions.
Oh yes, we checked with UCLA and with Duke for second opinion on surgery. It's butterfly occipital lobe and no one would touch it.
ReplyDeleteHGG means what, btw?
The VAL-083 trial requires confirming unmethylated status of the recurrent tumor at MD Anderson. If you're having resection surgery anyway for the recurrence/progression that's one thing, but having a second biopsy only in order to take part in a trial when there's availability through compassionate use...I'm not seeing the value in that.
HGG - High Grade Glioma
DeleteHi Jo,
ReplyDeleteUCSF recently published an article on butterfly Glioblastoma.
https://www.researchgate.net/publication/325510543_Safety_and_outcomes_of_resection_of_butterfly_glioblastoma
If you are willing, maybe you can seek a third opinion from them especially Dr.Berger of UCSF in terms of possibility of Resection.
Hope this helps.