Change in plans - looks like neuroendocrine

[TonyS58]

From my last post, I had an allergic reaction 15 minutes into my first dose of Docetaxel - part of a clinical trial combining Docetaxel and Xofigo (Radium-223). Two weeks later, I had a second reaction despite additional precautions (oral decadron 3 days prior, IV Benadryl and Decadron immediately prior to chemo, half flow-rate of chemo), and this time, in only 5 minutes. I was told that if they restarted the chemo, I would stop breathing (anaphylaxis). My adverse reaction disqualified me from continuing the clinical trial, but I would be able to start the second drug, Radium-223, as its own monotherapy. It took three weeks to coordinate, obtain insurance approvals, and order the drug, but I received my first injection three weeks ago. It's been five and a half years since I was diagnosed with prostate cancer, and I can honestly say this was the first time I felt that a treatment made me sick. I had constant nausea, chronic fatigue, bone pain, and a general malaise to the point where I just didn't want to move. On top of that, I developed a chronic cough which was just enough to make me crazy. This all lasted about 12 days, then cleared to the point where I actually felt good. Even that was short-lived when after four days, I experienced #10 pain with numbness running from my right buttock down to my foot. Ibuprofen didn't touch it. A double dose of Aleve helped me sleep through the night, but it took a double dose of oxycodone, then one every 4 hours to cut the pain so I wasn't in tears, squirming out of my recliner with pain. My oncology team responded quickly and suggested a high dose of oral decadron followed by a regular dose twice a day. Within hours, I was able to stop the oxycodone and woke up in the morning, pain and numbness free - the miracles of steroids.

My nurse navigator was able to secure a "stat" MRI for me at 0530 Thursday morning, and it appears that even with the chemo and Radium-223 treatments, my prostate cancer has progressed further in the sacrum, impinging on the nerve bundle that runs down the right leg. With an additional clue that my PSA has barely increased, this isn't behavior that would be expected with traditional prostate cancer, so my oncologist believes that the cancer has de-differentiated to a neuro-endocrine subtype. Neuro-endocrine cancer requires a completely different set of drugs than prostate cancer, so he is recommending that I start on a combination of chemotherapies (carboplatin and etoposide) as soon as possible.

Reviewing the literature, especially Dr. Beltran's paper from 2016) and TA's summary on treatment-induced neuroendocrine prostate cancer, from the same year, it appears the indicators are all there. Fortunately, my mets are confined to bone and have not jumped to soft tissue or organs, so I feel I have a fighting chance (maybe unrealistically). There was a 2018 Japanese paper that refered to adding Doxorubicin to the mix, but not much detail beyond that, so when i mentioned it to my oncologist, he suggested that "the only and best consideration right now would be to add an anti-PDL-1 inhibitor based on the new standard for lung neuroendocrine".

I am concerned at the lack of recent literature and if anyone can point me in the right direction, I would appreciate it.

Keep up the good fight.

Thanks for the support.

[Hidden]

keep up the good fight, brother.

I'm trying to understand senescence and it seems that your cancer has finally done a work around. so is it the starting and stopping Lupron that causes it, the 18 months to begin with that causes it, or the failure to maintain it the entire time that causes it. or none of the above. realizing that no one knows, just wonder what has been speculated.

[TonyS58 in reply to Hidden]

Those are the big questions. In my opinion, #1 is using the ADT vacation as a diagnostic tool, ie: "let's see what happens". For aggressive cancer, this is foolish. On the other hand, there is #2, speculation that long-term ADT creates an environment where neuroendocrine cancer can establish itself. Now, there are lots of APC patients who have been on Lupron for 10-20 years without an emergent, aggressive, small-cell cancer developing. That brings us to #3 and the recent proliferation of novel antiandrogen therapies: Abiriterone; Enzalutimide; Apalutimide, etc... This is an open question. The literature barely touches on it, and there I have found nothing more recent than 2019.

Regardless, it touches on the lack of diagnostic tools and tests, the danger of relying on PSA as a diagnostic tool, and the need for constant vigilance and driving the oncology community to respond quickly with pain control and diagnostic imaging when there are physical changes. This also means being willing to drop the current treatment plan and move aggressively to plan B without delay.

[pjoshea13 in reply to TonyS58]

In 2004, I had PSA persistence after prostate removal (& then after salvage radiation.) There were few options at that time. With Lupron mostly failing within 18-24 months, it looked as though I was on the fast track to the graveyard. So I said no to Lupron, although I did expect it to be in my future.

The odds of Lupron being effective for 10 years or more are very slim. One day, someone will study long-term responders & figure out their secret. Maybe some need not be on ADT? Perhaps protected by something else?

In 2004, there were already studies on how ADT affects the androgen receptor [AR]. AR in the biopsy sample is generally 'wild type', i.e. not mutated. After ADT has become 'refractory' (they call it CRPC now), AR is generally still in play.

The following is from 1995 & typical of the time:

"Our findings suggest that hormone-refractory prostate cancers are genetically very complex and show intratumor genetic heterogeneity. Increased copy number of chromosome X and the amplification of the androgen receptor (AR) gene may confer proliferative advantage during androgen deprivation and thus contribute to the development of recurrence."

pubmed.ncbi.nlm.nih.gov/749...

When we are diagnosed, we may already have some abnormal cells that have no survival advantage as long as normal testosterone [T] levels are present. One or more types might well have survival advantage during ADT. Alternatively, since classic ADT does not eliminate adrenal hormones, adaptations might develop to make cells viable in a low-T setting. So it's not surprising that cells that were originally thought of as being androgen-independent were mostly still dependent on the AR-axis.

{Also in 1995, Docetaxel [Taxotere] was approved. & that became Plan B for ADT refractory guys. lol - was anyone even working on a Plan B?}

The discovery of AR still being in the game led to Abiraterone (& Enzalutamide).

With Abiraterone [Zytiga], the adrenal hormones are also targeted. There must have been some disappointment among researchers that Abi did not add years to CRPC survival.

By efficiently targeting the AR-axis, we now select for cells that do not even have AR (neuroendocrine differentiation), or have splice variants where the AR doesn't even need androgen.

Again, no Plan B. Some years ago, Johann de Bono, who was involved in the development of Abi & Enza, fretted about the lack of a protocol following drug resistance.

Some here favor aggressive treatments, but they ultimately accelerate progression.

As with classic ADT, we hear of men who have been on Abi or Enza for years - but that's not the norm.

My approach has been to slow things down & also to not provoke adaptation.

The first step to slowing things down is to tackle inflammation.

The next is to inhibit metastasis. Primarily by targeting altered coagulation.

& so on.

-Patrick

[Hidden in reply to pjoshea13]

"With Abiraterone [Zytiga], the adrenal hormones are also targeted. There must have been some disappointment among researchers that Abi did not add years to CRPC survival."

wonder why not. it doesn't make sense to me that if you get rid of all the testosterone, vs. say almost all of it, that there wouldn't be some benefit.

apparently my being looked at by a urologist that favored longer courses of ADT and an RO that was ok with a shorter course created some friction or discussion internally since the RO is now saying the longer course is recommended. I have an appointment to discuss it soon and take another shot and have a lot of questions. Unfortunately, I don't have a lot to go on other than "I read it on a forum"

[pjoshea13 in reply to Hidden]

With classic ADT, selecton is mainly for cells that have adapted to low androgen levels.

With a better mousetrap (Abi), we see more selction for cells that do not depend on the AR axis. Hence, more neuroendocrine cells.

The focus has long been on the AR-axis. Not much attention to resistance pathways.

[Tall_Allen]

I think the first step is an IHC panel on some biopsy tissue. The IHC panel should ideally include the following antibody stains: chromogranin A, neuron-specific enolase (NSE), synaptophysin, DLL-3, CD56, PD-L1, and somatostatin. You may not be able to get all those stains locally. I agree that a PD-L1 inhibitor may help. If it expresses DLL-3, there' are a couple of clinical trials; one in the US, the other is Australia and Belgium.

prostatecancer.news/2016/12...

[TonyS58 in reply to Tall_Allen]

The problem is that I don't have any soft tissue mets... just some edema near one of my affected vertebrae. The recent liquid biopsy that I had gave no clues.

[Tall_Allen in reply to TonyS58]

Why is that a problem? Bone biopsies are often done.

[TonyS58 in reply to Tall_Allen]

Agreed. A bone biopsy from my sacrum in the area of latest radiographic progression should certainly be doable.

[TonyS58 in reply to Tall_Allen]

TA,

It's unfortunate that the information is so dated. Beltran is local to me, so I'll make an appointment with her and I'll share your biopsy recommendation with my MO.

Thanks

[Tall_Allen in reply to TonyS58]

Why do you think the info is dated?

[TonyS58 in reply to Tall_Allen]

Unless the date on the article hasn't been updated, it looks like 2016 information.

[Tall_Allen in reply to TonyS58]

I usually update my articles - it's easier than writing new articles with a lot of the same info. The data there is very current. I added a note on top that it is frequently updated.

[TonyS58 in reply to Tall_Allen]

Thanks. I didn't appreciate that it had been regularly updated. Thanks for doing that. In fact, thanks for everything you do for this community.

[Purple-Bike in reply to Tall_Allen]

TA, have the date of the update be the most visible date. "Frequently updated" is easily missed, I missed it too once before you told me.

[Tall_Allen in reply to Purple-Bike]

I can't control that feature.

[Purple-Bike in reply to Tall_Allen]

If it is possible to put "Frequently updated" immediately after the date of the original post, even better in capital letters, it would be good. Just a suggestion.

[Tall_Allen in reply to Purple-Bike]

It doesn't allow anything on that line. It's what I get when the site is free.

[Prostratehelp]

I also had bad reactions to docetacxel. First time was 2years ago. Started to have extreme pain across upper arms and across chest within 10 minutes of starting. Breathing became difficult. Gave me steroids to bring me around and it worked within 30 seconds. After a few weeks, They then tried giving me Xtandi. After 6 weeks on Xtandi I had extreme pain issues.

Two months ago, my MO at Florida Cancer Specialists sent me to see MO at Moffitt Cancer Center in Tamper FL. We discussed the issues(s) with both Docetaxcel and Xtandi. After calls with my regular MO and with MO from Moffitt they came up with a plan to give me the Docelaxcel again. They did the same prep with steroids and Benadryl and one other drug. Then they did “slow drip” of Docetaxcel. Was ok for 2 days and then extreme chest pains that resulted in admission to Hospital for 4 days.

They then decided to proceed with Xtandi. This time I got 17 days in before stopping it.. extreme bone pain through body. MO could not get the pain level down so they put me into a Hospice program for pain management. Been 2 weeks on only pain meds (no other meds) with medium success.

[Hotrod65]

Tony, im also a patient in Boston dealing with scNEPC differentiation...i did the 2 combo chemo, carboplatin and etoposide then Cisplatin and Docetaxol..limited response... MPC4 at diagnosis..Gleason 9 4+5, all cores positive for aggressive varients... PSA only 10.5..i already had NE and given 3-6 months..i went to Dr.Paul Mathew MD Genitourinary Oncologist with specialization in PC at Tufts Medical Cancer Center..he had faith and determination that he could pull the proverbial rabbit out of the hat!, Removed my diseased Prostate, sent it over to Foundation Medicine in Cambridge for Genomic Sequencing and data showed me as a candidate for 2 PDLI Checkpoint inhibitors and several clinical trials..we started Pembrilizimab as a sole agent with low dose Prednisone..fast forward, I'm now 7 yrs from that awful visit to clinic to hear I had little time left...I have had 50 infusions over past 5 years and completed treatment albeit 2 annual maintenance dosages and yearly Scans since Dec.2020..i have no quality of life issues and moving forward..I found one of the hidden Gems in Boston and a product of MD Anderson..Dr.Mathew is also Director of the Molecular Oncology Research Labs.and has taken my unique case on for further studies and papers he has published in several medical journals as well as ASCO in 2018..I'm a patient advocate for Foundation Medicine and the Cancer Research institute for the advancement of Immunotherapy, I have travelled for both and spoken on Genomics and immunotherapy, my background is in Biotechnology Medical Flow Immunocytometry for 32 yrs Retired...if I can help as the poster boy for NE...reach out...John.