posted by oldcookie48
My husband is 77 yr old. He was diagnosed 2013 w/GBM 4. Full Resection & Radiation. Took TMZ for 12 mos, then CCNU for 6 mos. Optune for 15 mos/stopped due to skin issues-skin cancer. Recurrence in 2018. Full resection/radiation. Now on 10th round of TMZ. Taking Ben Wms' Supplement cocktail since 2013. Only RX: Valproic Acid (never had seizures), Celebrex, Bactrim. Only issues are cognitive, motivation, fatigue. He is MGMT meth. Seattle NO says go to 12 mos (that 2 left). UCSF NO suggesting he stop TMZ due to fatigue since no validation it helps past 6 mos. Blood runs are good.
Stephen, do you think we should finish the last two rds to make 12 or stop at 10?? NO's leaving it up to us. Any other recommendations based on his gene testing below? I have been ill so difficult for me to focus very well. My husband can't focus at all so leaving it up to me.
Appreciate your thoughts. Thank you kindly.
INTERPRETATION:
Tumor-only sequencing of this recurrent glioblastoma demonstrates a hotspot mutation in the promoter region of the TERT gene, focal deep deletion of the CDKN2A and CDKN2B tumor suppressor genes on chromosome 9p21, focal amplification of the MDM4 oncogene on chromosome 1q32, focal amplification of the PDGFRA oncogene on chromosome 4q12, a nonsense mutation in the PTEN tumor suppressor gene with loss of the remaining wildtype allele, a frameshift mutation in the BCOR tumor suppressor gene, and focal amplification of the EGFR oncogene on chromosome 7p11. This EGFR amplification is accompanied by a missense mutation that localizes within the extracellular ligand-binding domain and has been recurrently found in glioblastomas, often in conjunction with gene amplification as seen in this tumor [refs. 1-2]. This EGFR mutation is present on a majority of the amplified EGFR alleles given its allele frequency of 74%. Extracellular domain mutations in EGFR have been shown to correlate with resistance to type I EGFR inhibitors such as erlotinib but sensitivity to type II EGFR inhibitors [ref. 3].
The quantity of somatic mutations and mutational signature of this recurrent tumor is not suggestive of the hypermutation that is known to occur in a subset of gliomas following treatment with alkylating agents such as temozolomide [ref. 4].
Chromosomal copy number changes in the tumor include gain of 7 and losses of distal 2p, interstitial 3q, 8p, 9p, 10, portions of 11q, 13q, distal 14q, and distal
Only 11 of the 1,068 microsatellites assessed in the tumor (<2%) demonstrate instability, consistent with a microsatellite stable tumor.
Together, the genetic profile is consistent with the diagnosis of recurrent glioblastoma, IDH-wildtype, WHO grade IV. The cytogenetic alterations (trisomy 7, monosomy 10) and genetic alterations (CDKN2A deletion, TERT promoter and PTEN mutations, amplifications of EGFR, PDGFRA, and MDM4) are some of the most common seen in IDH-wildtype glioblastomas arising within the cerebral hemispheres in adults [ref. 1]. Additionally, this glioblastoma demonstrates a truncating mutation in BCOR, which encodes a transcriptional co-repressor protein that is commonly inactivated in pediatric high-grade gliomas but is not known to be a recurrently mutated or deleted gene in adult IDH-wildtype glioblastoma [refs. 5-6].
Genetic features of a diffuse lower-grade glioma (e.g. chromosomes 1p/19q co-deletion or mutations involving IDH1, IDH2, TP53, ATRX, CIC, and FUBP1) are not identified.
This might be throwing you a curveball, but in terms of treating the tumor (not in terms of quality of life or side effects), my opinon is that a round of lomustine (CCNU) might do more good than another 2 rounds of TMZ.
ReplyDeleteThough lomustine and TMZ are both aklylating agents, they have different mechanisms. He's had TMZ-12, CCNU-6, and TMZ-10. Just continuing to use TMZ over and over is like asking the tumor to develop a resistance to it. In the case of MGMT-methylated GBM this resistance often will take the form of mismatch repair deficiency, rendering those cells completely resistant to TMZ. I actually don't think its a bad idea to alternate between TMZ and lomustine frequently, although there is no clinical trial data to back this up.
The main question I would have are: are his blood counts in good enough shape to contemplate a round of lomustine, and would it be worth it in terms of quality of life (how severe is his fatigue)? It's very possible (likely) both UW and UCSF doctors would not agree with a doing round of lomustine (as opposed to no more chemo in the one case, or two more rounds of TMZ in the other). But would be interesting to bring it up and see what they say.
WILL DO STEPHEN. THANK YOU! His blood counts have done amazingly well during these 10 TMZ mos. What you said made total sense. When he took the CCNU 2014, it did knock him down very quickly. I honestly never thought his blood runs would improve, but in time they did. At his age, I hate to knock him down again but we have to consider the alternative as well. Also, thanks for moving my post. I am not very good at this anymore. Appreciate your time Stephen. Best to you!
ReplyDeleteThe fact he has tolerated 10 cycles of TMZ that well, but CCNU knocked him down quickly when he tried it is a strike against my idea of doing a round of CCNU.
DeleteDosing of CCNU can also be adjusted. My friend did 4 cycles of CCNU (at 90 mg/m2) combined with Avastin before her platelets went too low. She did one or two cycles at 75 mg/m2 CCNU when her platelets went back up. Standard CCNU dose is 100 mg/m2.
If he had a complete resection and there is no residual tumor, many doctors would also advise saving the big guns (like CCNU) for later, or in other words save his bone marrow in decent condition for when you actually do need chemotherapy to fight an actively growing tumor. This argument makes sense as well. Do you really want to knock his bone marrow down when the tumor is under control? So my own opinion is wavering because I didn't consider whether he had active tumor or not currently, I was just assuming he did.
Thank you dear Stephen for your additional comments. Don's MRI's have been good since his recurrence w/ full resection Jan 2018, so maybe we will forego the 11th & 12th round of TMZ for the reasons you mentioned earlier and likewise save the CCNU for the big guns! Due to his age, I like the idea of a lower dose of CCNU as well.
ReplyDeleteCurious when you mentioned: alternate between TMZ and lomustine frequently......did you mean monthly or couple months on one, then switch to other?
Based on his gene interpretation, is there anything you feel we should add to his prescriptions? He's taking all the standard cocktail supplements. He has never taken chloroquine.
Also, where on your Astrocytoma site can we make a donation? Don't know how you do all that you do Stephen but you are amazing!
Thank you.