I have been reading this message board for years and been impressed with the knowledge of many of the participants. I was hoping I would never need to post...
As posted by Stephen previously, my now 25 y/o son was diagnosed in 2011 with OA Grade 2 (now felt to be AA3) and treated with surgery and then surgery to get "leftover" in 2012. He was found to be IDH1+. Because of the infiltrative nature of tumor on path, he then entered into a clinical trial on the cognitive effects of proton therapy, which he completed 11/12. No chemo was given. (No apparent cognitive effects in his case either...did very well in college and is/was in med. school.) On routine MRI 12/17, he was found to have a 6-7 mm area of enhancement in the middle of his resection cavity (tumor never enhanced before). Advice was to watch for 2-3 months, but we moved up the surgery. Note that his tumor grew about 1 mm in each dimension in 6 weeks. He had a very generous GTR 2/15 and has had a pretty easy recovery--no apparent deficits.
Unfortunately, the path showed GBM IDH1+ unmethylated. They also looked at his tumor from 2012 and it was also unmethylated. Foundation One is not back yet. We have been looking at different options and consulted physicians from several different areas. Many have been very generous with their time and there is no consensus. Opinions below...
(he didn't qualify for TOCA due to small tumor size and no prev. treatment)
--Local neuro-onc: olaparib + Temodar + more proton. Wasn't really certain of dosing. (PARADIGM2 could provide that)
--Tumor board at Mass. General....some said NO treatment, some said Temodar. Told to wait on radiation as scans might be too difficult to interpret
--Physician who is expert on IDH1....feels that IDH1+ GBM shouldn't be considered as really a GBM. Rec. no radiation and PC(noV) since it has been shown to work.
--Physician at another institution who is involved with IDH1 studies...PCV. He said to delay radiation because of "better things coming" and it will probably take radiation + chemo to really eradicate tumor
--Second Opinion from well-regarded cancer institute....PCV has not been shown to work. Use Temodar and radiation, though consider immunotherapy.
--UCLA...IDH1+ more indolent, possibly PARP + Temodar...perhaps immunotherapy depending on mutation burden. Not good luck with olaparib, though don't know about mutant status of those patients. Told that IDH1+ SHOULD be methylated and that test not very accurate.
So....he just missed a slot on the BGB-290(pamiparib) + Temodar (but without radiation) trial...expansion cohort likely opening in 4 weeks. Evidently fairly well tolerated. He strongly wants to return to school in August, which seems somewhat unrealistic, but not impossible. Waiting 4 weeks for treatment doesn't seem like a great idea, unless one accepts the idea that this is a more indolent tumor.
Would really appreciate advice in this matter! Thanks, Marcia
(And thank you so much, Stephen!)
PC(V) and TMZ probably all have roughly equal chance of working, as they (procarbazine, lomustine, and TMZ) are all alkylating agents repaired by MGMT. This is assuming vincristine isn't providing much benefit. A major argument in favor of adding a PARP inhibitor is that it could render a drug like TMZ effective even in the presence of MGMT (ie for MGMT unmethylated tumors). I didn't realize that tissue from 2 different surgeries both gave unmethylated results for MGMT. Of course adding PARP inhibitor to chemotherapy will probably increase the side-effect burden in terms of myelosuppression, but it might be worth a try to see how well he tolerates it. It's a tough decision given the 4 week wait for BGB-290 + TMZ trial.
ReplyDeleteOn the topic of re-irradiation treatment, I suggest you discuss with his Neuro-Oncologist the clinical benefits vs the risk of neuro-cognitive impairment. While radiation therapy has improved with technology advancements, I am unaware of any prospective randomized trials of re-irradiation. My understanding is delayed neurological deficits is a significant risk with re-irradiation.
ReplyDeletehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712688/
In case of lack of hypermutation, one can do active specific vaccination to induce an immune response, and then modulate further with checkpoint inhibitors (which is called here immunotherapy but is in fact only modulation if an immune response against the tumor is already there).
ReplyDeleteIvosidenib (Agios mutant-IDH1 inhibitor) could be FDA approved as early as August 21 of this year, for AML. I would like to see combinations of this drug with vaccine/immunotherapy for IDH1-mutant gliomas, as preclinical studies shows that the 2-hydroxyglutarate metabolite produced by these tumors play a large role in their immunosuppression.
Deletehttp://investor.agios.com/news-releases/news-release-details/fda-accepts-new-drug-application-and-grants-priority-review-0