My husband is a 47-year old International Airline pilot who was in perfect health prior to his diagnosis in April. After two surgical resections and 6 weeks of RT/TMZ, he is now taking daily TMZ on a metronomic schedule.
| 3/31/18 | Presented with acute aphasia and vision loss, medevacked to Palmetto Richland hospital (Columbia, SC) tumor was discovered in left temporal lobe |
| MRI (missing report details) | |
| 4/2/2018 | TRANSPORTED TO MUSC, CHARLESTON, SC |
| 4/4/2018 | SUBTOTAL RESECTION OF LEFT TEMPORAL MASS performed at MUSC, Charleston, SC |
| 4/5/2018 | MRI BRAIN W/WO CONTRAST |
Status post subtotal resection of left temporal mass with residual enhancing
tumor along the medial margins of the resection cavity measuring approximately
2.4 x 3.3 cm. Additional enhancing satellite nodule along the posterior
inferior aspect of the resection cavity compatible with residual tumor.
Similar mass effect and partial effacement of the left lateral ventricle with 5
mm rightward midline shift. | |
| 4/6/2018 | NEUROPATHOLOGY REPORT - DIAGNOSIS: GLIOBLASTOMA MULTIFORME WHO GRADE IV |
(PARTIAL COMMENTS FROM REPORT DATED 4/6/2018)
Date Collected: 4/4/2018 15:05
Diagnosis
A. BRAIN, LABELED AS "TUMOR", RESECTION:
· GLIOBLASTOMA MULTIFORME, WHO GRADE IV
· IMMUNOHISTOCHEMICAL STAINS:
o IDH-1: NEGATIVE
o GFAP: POSITIVE
o SYNAPTOPHYSIN: NEGATIVE
o KI-67: PROLIFERATIVE INDEX OF 10 %
B. BRAIN, LABELED AS "TUMOR", RESECTION:
· GLIOBLASTOMA MULTIFORME, WHO GRADE IV | |
| 4/19/2018 | MRI FUNCTIONAL BRAIN |
| 4/20/2018 | MRI BRAIN LAB WITH CONTRAST |
| 4/20/2018 | Surgical Resection performed by Dr. Allan Friedman, Duke |
| Loss of right peripheral vision in both eyes post surgery | |
| 4/21/2018 | MRI BRAIN W/WO CONTRAST |
| FINDINGS: Postoperative changes of left temporal craniotomy with subjacent resection cavity within the left temporal lobe demonstrated. Surrounding increased signal on T2 weighted imaging is unchanged. There are blood products along the margins of the resection cavity. There are small areas of superimposed contrast enhancement along the posterior margin (series 12 image 90),medial margin (series 12 image 95), inferior margin (series 12 image 81), and superior margin (series 12 image 101). The areas of residual contrast enhancement are largely improved from intraoperative MRI. Trace extra-axial fluid and dural thickening at the craniotomy site. There are expected postoperative ischemic changes surrounding the margins of the resection cavity. Status post left temporal mass resection with foci of contrast enhancing tumor along the margins of the resection cavity. | |
| 5/17/2018 | Day 1 of 6 week Radiation/ Temozolomide therapy (MUSC, Charleston, SC) |
| 6/4/2018 | SEIZURE (occured 2 days after gradually stepping down Dexamethasone to 0mg/day) |
| - MRI & CT scan performed | |
| “Postsurgical changes of subtotal resection of left temporal mass with increased size of the resection cavity and likely increased local mass effect with entrapment of the temporal horn of the left lateral ventricle and slightly increased medialization of the left uncus. The component along the resection cavity demonstrating elevated CBV has decreased in size from prior studies. Overall, these findings are suggestive of evolving post-treatment related changes with persistent residual tumor.Stable 5 mm rightward midline shift.” | |
| - Increased dose of Keppra to 1g 2x day | |
| - Increased Dexamethasone to 6mg 2 x day (to gradually step back down) | |
| 6/8/2018 | MGMT GENE METHYLATION ASSAY - “GENE METHYLATION NOT DETECTED” |
| 6/8/2018 | PATHOLOGY - GENERAL/OTHER - “ NEGATIVE FOR IDH1 R132H MUTATION” |
| 6/27/2018 | Completed 6 weeks of Radiation/ Temozolomide treatment |
| 7/11/2018 | SEIZURE (occured 2 days after gradually stepping off dexamethasone) |
| - MRI & CT scan | |
| “ADDENDUM: Similar appearance of a linear area of incomplete filling in the posterior superior sagittal sinus. This has been present on multiple prior studies, including the patient's original outpatient imaging and may reflect an underlying dural reflection or potentially chronic sequela of remote partial filling defect. No occlusion of the sinus flow is seen. IMPRESSION: Posttreatment changes from subtotal resection of left temporal mass with persistent residual tumor and slightly decreased size of the resection cavity.Slightly increased vasogenic edema predominantly along the left insular region. Stable 5 mm rightward midline shift and early left uncal herniation. No acute infarction.” | |
| - Increased Keppra to 1500mg 2 x day | |
| - Increased Dexamethasone back to 6mg 2 x day | |
| 7/13/2018 | FOOT DROP IN LEFT FOOT (possible stroke during seizure, MRI of spine schedules for end of month) |
| 7/27/2018 | MRI BRAIN W/WO Contrast |
| “Extensive irregular enhancement of the resection cavity extending to the ependymal surface of the left lateral ventricle, appearing slightly increased in size. Significant increase in relative CBV within areas of enhancement and nonenhancing T2 hyperintensity. There has however been interval reduction of overall mass effect and rightward midline shift.” | |
| 8/1/2018 | DAY 1 METRONOMIC TEMOZOLOMIDE (100MG/DAY) |
| STARTED DISULFIRAM 250MG/DAY + COPPER 2MG/DAY |
MEDICATIONS & SUPPLEMENTS:
NO Rxs:
- Keppra: 1500mg 2 x day (dose has increased 2 x after seizures)
- Dexamethasone: 6mg / day. (dose has varied due to seizures)
- Temozolomide: 100mg daily (metronomic schedule)
OFF LABEL RXs:
- Minocycline: 100mg 2 x day (May 17 - present)
- Metformin; 500mg 3x day (escalted to current dose starting May 17th)
- Chloroquine: 250 mg (May 17 - present)
- Disulfiram: 250mg / day (August 1 - present)
SUPPLEMENTS:
- Copper: 2mg (taken with Disulfiram)
- Milk thistle: 1000mg 2 x day
- Curcumin (Longvida): 1600mg / day
- Fish Oil: 1000mg / day
- Boswellia: 3g / day
- Turkey Tail (PSK): 3g/day
- Soy Isoflavones (Genistein, Daidzein, Glycitein) ?mg. 3 gelcaps/day
- Melatonin: 20mg at bedtime
- Vitamin D3: 10,000 IU/day
- Selenium: 200mcg / day
- Pterostilbene: 450mg / day
- Green Tea Extract: 750mg 3 x day
- CBD oil (Palmetto Harmony): 1ml 2 x day
QUESTIONS:
1. MEDICATIONS AND SUPPLEMENTS: Are there any others medications or supplements I should add to his cocktail at this point (currently
doing 100mg temozolomide, daily)
- Celebrex? I had this on my list, but I had trouble filling the Rx
- THC ? He is currently taking CBD oil, but wanted to refrain from the THC bc he is still an active Reservist in the US AF.
2. Dexamethasone - We have tried taking him off steroids twice, both times resulting in seizure. I have read that dexamethasone can inhibit the effectiveness of chemotherapy, but he obviously continues to struggle with swelling. Any thoughts?
3. UNDERSTANDING THE PATHOLOGY, BRAIN BIOMARKERS, ETC
- MGMT GENE METHYLATION ASSAY - “Gene Methylation NOT detected” = UNMETHYLATED
- NEUROPATHOLOGY REPORT:
- Date Collected: 4/4/2018 15:05DiagnosisA. BRAIN, LABELED AS "TUMOR", RESECTION:· GLIOBLASTOMA MULTIFORME, WHO GRADE IV· IMMUNOHISTOCHEMICAL STAINS:o IDH-1: NEGATIVEo GFAP: POSITIVEo SYNAPTOPHYSIN: NEGATIVEo KI-67: PROLIFERATIVE INDEX OF 10 %MICROARRAY COMMENT:1p/19q co-deletion - Not detected+7/-10 - DETECTEDCDKN2A/B homozygous deletion - DETECTEDEGFR amplification - Not detected
- BRAIN BIOMARKERS (IHC, FISH):
- IDH1: NEGATIVE, R132H IDH1 MUTATION WAS NOT DETECTED.
- EGFR does not exhibit amplification.
- EGFR RECEPTOR IHC ANALYSIS:Approximately 50% of the tumor cells exhibit 2+ staining of their cell membrane (score 2+), indicating that they DO express epidermal growth factor receptor.
- EGFR VIII IHC Analysis: none of the tumor cells exhibit staining for EGFR VIII (Score= 0)
- IDH1 IHC Analysis:IDH1 mutations result in a histidine at codon 132. An antibody specific for the IDH1-R132H mutation is NEGATIVE
- Brain IHC Analysis:
D2C7 IMMUNOHISTOCHEMISTRY ANALYSIS:
Approximately 70% of the tumor cells exhibit D2C7 detectable EGFR staining of their cell membrane (score 2+), indicating that they DO express at least some portion of the epidermal growth factor receptor protein.
POLIOVIRUS RECEPTOR (PVR) IMMUNHISTOCHEMTRY:
Approximately 90% of the tumor cells exhibit 2+ staining of their cell membrane (score 2+). The endothelial cells stains positively (3+) and serves as a internal control.
- TERT TARGETED MUTATION ANALYSIS: Positive.
TERT promoter mutation detected (C228T, c.-124C>T).
CAN SOMEONE PLEASE HELP ME UNDERSTAND THESE FINDINGS?
I understand the implications of his tumor being UNMETHYLATED, but I am struggling to understand the rest of it.
Also, I am waiting on the results from Foundation One, and hope those results prove useful.
I'll start with the most straightforward questions first.
ReplyDelete3. Pathology
Most primary GBMs are negative for the IDH1 mutation, so this is nothing remarkable.
GFAP simply shows that the tumor is a glioma (a general term that includes glioblastoma)
Ki-67 staining shows the cells in active stages of the cell cycle (not resting). 10% is considered moderate for GBMs which often have Ki-67 from 15-25%.
1p/19q codeletion not being detected is unremarkable, as this alteration generally signifies a diagnosis of oligodendroglioma in conjunction with IDH1 mutation.
+7/-10q refers to gains of chromosome 7 and a loss of a copy of chromosome 10 in the GBM cells. This is unremarkable, as nearly all GBMs show these alterations.
CDKN2A/2B are cell cycle inhibiting genes (and so effectively tumor suppressor genes). Homozygous loss means the tumor cells have lost both copies of these genes. This is one of the most common genetic alterations in GBM.
The EGFR gene is commonly amplified (a gain of multiple copies of the gene) in GBMs. In your husband's case, amplification was not found, even though there was moderate degree of EGFR protein expression.
EGFRvIII is a deletion-mutation within the EGFR gene, commonly found in EGFR-amplified GBMs. This was also not detected in your husband's tumor.
TERT promoter mutation is found in the vast majority of GBMs, but this is not targetable with currently approved therapies.
I assume that the D2C7 and poliovirus receptor testing was done at Duke in order to evaluate suitability for two of their clinical trials:
https://clinicaltrials.gov/ct2/show/NCT02303678 (D2C7 trial)
https://clinicaltrials.gov/ct2/show/NCT02986178 (poliovirus trial)
If his tumor progresses on the metronomic TMZ, and you can get him into the poliovirus trial at Duke, this would be one of the best available options.
Have you looked into or discussed Optune yet (Tumor Treating Fields)?
Thank you so much for taking the time to respond, Stephen.
DeleteYour explanation of Mark's pathology is most helpful. I am hoping to get the results from Foundation One soon, and I am eager to see if there might be actionable therapies based on these results.
Yes, the DC27 and poliovirus testing was done at Duke. The poliovirus trial looks very promising, but my understanding is that my husband's tumor (or resection cavity) is currently too large to qualify.
"Patients must have a recurrent supratentorial WHO grade IV malignant glioma based on imaging studies with measurable disease (≥ 1 cm and ≤ 5.5 cm of contrast-enhancing tumor). Prior histopathology consistent with a World Health Organization (WHO) grade IV malignant glioma confirmed by the study pathologist."
Here are the comments from his last MRI "Left temporal craniotomy with a subtotal resection of a mass centered in the left temporal lobe. Persistent peripheral enhancement along the resection cavity which measures 5.6 X 4.0 cm (previously 5.9 X4.0 cm)....."
It seems like many of the most promising trials have limits on the tumor size. this is confusing and frustrating!
We have looked into Optune. I am reluctant to begin treatment because I am afraid it too will disqualify him from a good clinical trial.
I will discuss this again with our NO tomorrow.
2. Dexamethasone.
ReplyDeleteYou can try clicking on some of the labels on the right side of the blog, such as "cerebral_edema" for prior discussions on the subject.
Apart from possibly Avastin (bevacizumab) there isn't much that has the potency of glucocorticoids (like dexamethasone) for reducing cerebral edema, but there are several things that can reduce swelling and have "steroid-sparing" effects, allowing one to reduce the dose of steroids. These include Boswellia (I prefer the WokVel brand, for reasons outlined in prior discussions, click on the "boswellia" label); and angiotensin receptor blockers (ARBs) such as telmisartan.
https://www.ncbi.nlm.nih.gov/pubmed/26754004
Impact of Angiotensin-II receptor blockers on vasogenic edema in glioblastoma patients.
I have been giving him another brand of Boswellia (3.5 - 4g / day)
DeleteI just ordered the WokVel brand and will give him 3 pills/day when it arrives.
Thank you for the recommendation
Hi Stephen, can ARBs be given if blood pressure is already low/low end of normal? We are looking for options outside of Avastin to control swelling. Thank you:)
DeletePossibly, but you could run into problems. I would consult with a physician before attempting it.
DeleteGot it, will do, thanks!
Delete1. Medications and supplements.
ReplyDeleteThis is a much less straightforward question. Everybody is doing something different and nobody knows what is optimal for any individual.
Did you have a prescription for Celebrex, but couldn't get it filled? That would be surprising, as Celebrex is a very commonly used drug. Celebrex is another drug that could help with cerebral edema, at least if mouse studies are any indiciation.
https://www.ncbi.nlm.nih.gov/pubmed/12576462 (this study used rofecoxib, which is no longer on the market, and now celexocib/Celebrex is the more commonly used COX-2 inhibitor)
There is some evidence from a small clinical trial supporting the use of CBD+THC in combination with temozolomide.
https://btcocktails.blogspot.com/2017/07/sativex-thc-cbd-plus-temozolomide-for.html
and some supporting evidence from a mouse study was also just published (see my latest comment on the above post). I understand his hesitation though if it would affect his pilot status.