PCV regiment and P-gp inhibitors

Inspired by Ben Williams who used Verapamil on BCNU and later on PCV regiment I was planning to use P-glycoprotein (P-gp) inhibitor like Verapamil during PCV chemotherapy.

Problem is that I can't find any research characterizing alkylating agents such as Carmustine, Procarbazine or Lomustine as P-gp substrates. Am I missing something?

Thank you.

PCV vs Temodar in IDH1 mutated unmethylated astrocytoma

There must be a lot of people who have already dealt with this issue but I didn't see any discussions on it.

I'm 47 years old with a recurrent grade 2 Astrocytoma previously treated with surgeries. Just over 12 years ago it was also treated with radiation, but not with chemotherapy. It's IDH1 mutated, unmethylated and 1p/19q are intact. I'm deciding between radiation followed by PCV or radiation with Temodar and adjuvant Temodar.

The results of RTOG 9802 make PCV appear to be a reasonable option, but RTOG 0424  Temodar results are just as good. My doctor's say Temodar will be as effective as PCV and more tolerable. The advantages of PCV are: the RTOG 9802 survival plot for IDH1 mutations looks good, it's a multi-agent treatment, the methylation status isn't a factor, and there seems to be less risk of hypermutation.

Has anyone with similar tumor characteristics chosen PCV over Temodar, if so what influenced your decision and how did it work out?

Hi,

I'm updating this discussion for anyone in the future who might be interested.

I've had the 3 opinions below.

UCSF:

They didn't give me any new information about hypermutation. Results of trials will be released in 3 or 4 years.

They confirmed my diagnosis and recommended SOC with 6 cycles. They said there was no information more cycles or a different dose schedule provided any benefit. I wasn't eligible for the Everolimus or the other 2 trials for low-grade tumors.

UCLA:

This is where the recurrence was initially diagnosed.

They recommended SOC. With the following expected response rates for patients similar to me

50% without radiation.

75% response rate with radiation.

I didn't get a definition of response, but I think it means either shrinkage or cessation of growth.

Said there's no data to indicate the ketogenic diet helps, but it won't hurt

UCSD:

Confirmed diagnosis.

Said preliminary study results indicate Temodar works about as well as PCV.

10 or 15 % experience hypermutation.

12 cycles recommended.

Most tumors cease growing and about 15% of patients see a reduction in tumor size.

MGMT is less important in low-grade tumors than high-grade tumors.

IDH1 mutated tumors are more chemosensitive.

Treatment: I decided to go with proton radiation + Temodar. I can always change my mind after radiation if new information indicates switching chemo is best. I'm also taking various supplements and started the ketogenic diet.

I had my first proton and Temodar yesterday and woke up surprised by how much it affected me. Symptoms included: fatigue, headache, and I threw up after only 3 sips of coffee. An extra Ondanestron cleared up the nausea after about 1/2 hour.

Temozolomide vs PCV for recurrence

My husband's glioblastoma has recurred.  He is having surgery for the second time (first time was August 2015).  His NO is considering either a second course of TMZ or PCV. Any views on which may be better please?  He is methylated and IDH1 positive.
thanks
Anne Marie

Hypermutation Risks of Temodar

Hi all,
I've found great value in this blog and am posting for the first time.

I was diagnosed in march 2016 with grade 2 oligo.  Its a somewhat larger tumor, about 7x6x5cm and unlike most oligo's is not in the frontal lobe, but is left parietal and overlapping motor, sensory and speech areas and nearing midline crossover.  Because of all that it was considered a high risk surgery zone and so I have so far only had a biopsy and have been doing chemo.   I'm IDH1 mt, mgmt meth, 1p19q codel, ATRX normal, p53 normal.

So the broad plan was chemo then RT.  The hope was to shrink the tumor to be able to reduce the RT zone. So far 6 rounds of Temodar but I have now switched over and done 1 round of CCNU after having learned more about hypermutation risks with TMZ.

I've dug thru what published data there is and its all clear as mud.  On the one hand the 2014 Science paper (Johnson et al from the Costello UCSF lab) that seems to have really launched this topic found very clear and scary linkages showing hypermutation and upgrading at recurrance to GBM in about half of the patients treated with TMZ vs none with only RT, on the other hand it was a very small data set, had mixed genetics, was clearly a selected dataset and not randomized, and only looked at TMZ alone or RT alone, not the more common RT+TMZ.  The few other studies I have found add some implications that mutations in TP53 and mismatch repair genes  increase the risk, though some data also shows TMZ driving mutations of TP53 and MSHx which then creates the path to hypermutation.

In simplified terms if chemo mutates the cancer to a point where the 'self check' mechanisms during cell division stop working then the next time the cell gets hit with chemo it will go ahead and replicate in spite of the genetic damage from chemo and create new set of mutations.

To further complicate the picture most of the historical data looking at different chemo options is comparing PCV to TMZ, but procarbazine is a monoalkylating agent that is quite similar to TMZ.  So I've gotten some input from Doc's that CCNU alone may be less mutagenic because it is a bi-alkylating agent and will more effectively stop DNA replication thru double strand breaks.

So Steven or others who are into the science side of cancer, do you have any thoughts on how to unravel all this?  Recommendations on other approaches to consider, or ways to enhance effectiveness of chemo for low grade cases?

Thanks,
Bryan

SW edited this post to include the image below, from a presentation at the 2016 SNO conference in Phoenix Arizona:

Help in moving forward with 20 year old son diagnosed with Grade 2 Astroscytoma

Thank you Stephen for the invite, and thank you to this community for all information gathered here, and Astrocytoma Options, regarding my sons recent diagnosis of a Grade 2 Astrocytoma.

This is all very overwhelming, in processing a lot of information, in a short period of time, while making decisions regarding treatments and such.

My son Brett, had a bad seizure on Christmas eve morning while playing football with his friends. Fast forward, he had surgery the following Friday, December 30th. His tumor was located on his right frontal lobe(cerebral), apparently just over 4 centimeters.

Post-op MRI report stated a full resection, however the Neurologist who preformed surgery said that he feels as though a piece, possible the rim of the tumor remained. When discussed with the tumor board, the over all consensus of the group, agree with him. Being that is it a slower grower tumor, that are allowing his body to heal, and have scheduled his next MRI next week, to further review.

We met with his Neuro Oncologist yesterday to go over his pathology report. Which is where I am seeking advice. Trying to stay positive through all of this, I felt like a UFC fighter kicked my in my stomach when I learned that his tumor is IDH1 negative, 1p/19q not co-deleted(none detected), his TP53 mutation: Present, 60 percent of nuclei stain positively by immunohistochemistry.

We have an appointment at UPenn Thursday afternoon for a second opinion. Do you have any recommended questions, regarding anything? I am starting to feel lost. From what I have read(very carefully), prognosis is quite favorable with IDH1 mutated, co-deletion in tact.

She offered us a treatment of radiation w/ Tremodar, or radiation 5x's a week followed by a restrictive diet chemotherapy, Matulane, Lomustine, Oncovin. She does not lean one way or the other. The choice is ours, however, she stated that statistics back up the second suggestion. I read that combination chemo and radio are best.

Please forgive me for throwing this all out there, I'm writing in my car while picking up my 12 and 14 year old from school. Absolutely and advice would be much appreciated!!

Sincerely,

Marlena

Off label drugs for astrocytoma grade 3

We are looking for repurposed drugs for a family member and since most of the research has been done for GBM that is grade 4 tumor I wonder if there is anything to take into account while treating a grade 3 tumor. I once read somewhere, but can't remember where and how reliable this source was, to be careful with cytotoxic drugs for lower stage cancer as they may cause the tumor to develop to a higher grade. Could you let me know what are your opinions on this? What type of drugs would you chose or have you chosen for lower grade tumors? Thank you.

Long term analysis of NOA-04 for anaplastic (grade 3) gliomas published today

This was a randomized phase 3 trial testing radiation therapy (followed by chemotherapy with PCV or TMZ at recurrence) versus chemotherapy (followed by radiation therapy at recurrence). Half the chemotherapy patients were randomized to PCV and the other half to temozolomide.

In this new update, patients are divided into three molecular groups:  CIMP negative, CIMP positive 1p/19q codeleted, and CIMP positive 1p/19q non-codeleleted.  CIMP positivity in this study is essentially another way of saying "IDH-mutant" as IDH mutation virtually always leads to the CpG Island Methylator Phenotype (CIMP).   The latter two subgroups correspond to molecular oligodendroglioma and molecular astrocytoma, respectively.

One of the more important findings in this study is that PCV was superior to TMZ in the molecular oligodendroglioma subgroup.  (This image shows progression-free survival, but the same trend was evident in time-to-treatment failure analysis and overall survival).

On the other hand, PCV and TMZ were more or less equivalent in efficacy for the molecular astrocytoma group (CIMP+ non-codel).

These findings support the use of the PCV regimen for molecular oligodendrogliomas, however it's still an open question whether the addition of vincristine (V) to procarbazine (P) and CCNU (C) adds any benefit.  Some retrospective evidence suggests that PC chemotherapy (without vincristine) is comparable in efficacy to PCV.

This study was published in the November 2016 edition of Neuro-Oncology, and the figures above are taken from the Supplementary figures.

http://neuro-oncology.oxfordjournals.org/content/18/11/1529.abstract?etoc

MRI revealed new tumor growth despite being on TMZ. Please help! Need some advice on what to do!

 My husband is 33 y.o. and has been battling a reoccurrence since july. His tumor is oligoastrocytoma grade 4 (as of 5 years ago with first tumor biopsy). He has been taking 450-455mg of TMZ since august on the 5/23 schedule. His tumor was huge and has been shrinking since we strated TMZ, metformin, Celebrex (on and off) and a bunch of supplements. However today's MRI Revealed a new tumor growth that is being resistant to TMZ (decembers MRI did not have new spot).

Doctor suggested adding Avastin to the current TMZ dose and schedule of 5/23, or doing Avastin with CCNU, or going to Dana Farber in Boston for clinical trials. We feel a little lost! My husband read a while back that Avastin had a lot of bad side effects, so he is affraid of that (quality of life and at the end not work either), and he is affraid that once he start avastin he is not longer qualified for a lot of clinical trials. So Doctor suggested to try a clinical trial first and then go to avastin if it doesnt work.

What are your opinions? I don't know much about clinical trials and don't even know what questions I should be asking. Do you guys have any suggestions on that and questions I need to ask?

How many of you are taking Avastin? How well are you tolerating it? Can Avastin put cancer into remission?  What other drugs should we use with avastin to synergize its effect on cancer?

Do you recommend clinical trials or just going with avastin and other off label meds?

I really appreciate if you give me some info or advice! Thank you very much for your time!

Help on Accutane/PCV interaction

Hi All,
This is my first post so far, thanks to all for the knowledge shared especially to Stephen for the time he spends on this.

My wife was diagnosed 2 months ago with a GBM (mutated IDH1 / no MGNT) , It evolved from 2 full resection (201203-AAG3 / 201504-AAG3). Due to the internal capsule in compromised, there is a high risk of hemiplegia, so NO decided to apply PCV protocol in order to produce some regression that may help the work of the NS in a future surgery, decreasing the chance of collateral damage. Her tumour growth was fast in the last 3 months, but after the first PCV it has been stabilized. At that time we found Ben Williams story, Astrocytoma Options web, so we decided to follow cocktail aproach to create sinergy. She is now in the 2nd PCV cycle and we added Tamoxifen, Verapamil, Celebrex, Metformin and a bunch of suplements like Curcumine, Boswellia, Resveratrol, Fish Oil and a couple more. So now we want to add Accutane but we want to be aware of any possible interactions with PCV and avoid them.

PCV Protocol:

• Day 1 - Lomustine.
• Day 8 till 21 Procarbazine.
• Day 8 and 29 Vincristine.
• 2 weeks off.

Any advice on when she should take Accutane?

Thanks in advance.
Francisco.