Stage IV: a totally different disease

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O Stoma Mia
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Stage IV: a totally different disease

Postby O Stoma Mia » Tue Sep 14, 2021 1:49 am

I'm re-posting this earlier post of GrouseMan because it contains an excellent overview of the profound difference between Stage IV disease and Stage I, Stage II and Stage III disease. Stage IV disease is really a different disease and requires a different, customized approach.
GrouseMan wrote:Well said Catstaff! I would go on to say that almost always the mix of mutations in a Met is different than it was in a primary. That's why its important to get biopsies of Mets if possible to help direct chemotherapy or Immunotherapies. Your primary could have been removed and gene tested, but that doesn't mean your Met's have the same set of mutations in its genes it could have a subset or new set of mutated genes. This is one of the main reasons we have such a difficult time treating advanced solid tumor cancers of any kind. A particular Met might be composed of many different mutated cancer cells even. A biopsy and tests on different parts of the met might yield different results. Outer parts of the tumor with a good blood supply might have one set where deep inside where it might not be as well vascularized could have another set.

This is why a lot of oncologists don't put a lot of faith in Genetic testing up front. Usually they have only the primary to test and its not a reliable indication of what the Met might be like. They stick pretty much with tried and true (ie Clinical trials) methods that appear to work for however long for a particular type of cancer. Everyone's Colon cancer is unique to that individual. They are as unique as each of us are to one another.

In preclinical testing of cancer chemotherapies and immunotherapies we use a lot of mouse models. They are at best crude approximations of a patient. They are often referred to as Xenographes. We might find a drug that works phenomenally in these models but only moderately well once in the clinic. I was involved in the discovery and development of one such drug. It was actually the first drug that our tumor biologists had ever seen where the mouse was cured and lived out its life to old age. That had never been seen in these Xenograph tests before. What is done is a tumor of a certain size is implanted in usually am immune compromised mouse species. These tumors are standard tumor types (ATCC Colon Types are Colo205, HCT-2998, HCT-116, HCT-15, HT29, KM12, and SW-620 all of human origin). The tumor is grown to a certain size for several days. Then treatment begins in the treated leg and usually drug vehicle is used on the control. Sort of matched pairs you might say. The size of the tumors are observed over several weeks and you end up with two curves, one showing growth in the controls verses the treated leg. Mind you this is done with many sets of mice at different doses and schedules to find the optimal one. In the tests of this particular drug - the optimal set of dose and schedule the test mice survived and tumors completely disappeared at least in terms of being able to find or locate them including biopsy! At that point dosing was stopped and they waited for the tumors to start to grow back. In the case of standard treatment methods using standard approved chemo drugs these tumors always came back. In the case of this particular drug treatment they never did. The treated mice lived out their natural lifespan. We thought we had a winner!

So what am I getting at. Well We went into human trials and this drug although useful and it had gotten approval, it didn't work nearly as well as we had hoped in people. The tumors in people mutated to become resistant to the drug over time. It was a much more complex situation than the mouse models suggested. Since then Anti-Cancer drug developers have learned a great deal more. And we constantly apply whats learned. We go after the mutated gene itself now rather than the one than the normal gene that controlled the proliferation of the tumor to begin with. So we now have 3rd generations of these drugs that do a better targeted job, but in people the tumor still finds a way to resist in some folks.

Unlike Bacterial, Viral and other diseases in cancer even for a particular cancer type we are attempting to treat thousands of really different tumors unique to each person.

GrouseMan (Former Anti-cancer drug discovery chemist).


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Re: Stage IV: a totally different disease

Postby GrouseMan » Thu Sep 16, 2021 9:28 am

Well - Thanks for the boost in ratings :D - I wish this were not the case. Some of the folks here are coming thru Stage IV colon cancer better these days than when my wife was diagnosed in 2013. I remember back in those days on the forum we lost a lot of dear folks that had been diagnosed with late stage colon cancer. There were fewer success stories back then and I lost my wife to it nearly 4 years to the day of diagnosis. But now we are starting to see people that are making it longer and managed to stave it off well enough and qualify for newer treatment options not available then, and extend that life out further to the point where they may end up being cured! Stage IV is a long game. You do what you can to really slow it down and try to further prevent spread so that later perhaps you qualify for something new, that might knock it further down etc. My wife initially responded pretty well. The met on her spleen completely disappeared in scans. Liver Mets all calcified (Oncologist said probably dead). But what we didn't know was that she had tumors hard to image in her Peri cavity. Very hard to treat. That's what eventually got her.

So - Although peoples experiences here on the forum can inform - in no way are they the same as yours. Everyone needs to keep up their own fight! I try to inform on what I read on the preclinical side of things and perhaps clinical trial of new drug treatments, that I might read about.

Good Luck all.

DW 53 dx Jun 2013
CT mets Liver Spleen lung. IVb CEA~110
Jul 2013 Sig Resct
8/13 FolFox,Avastin 12Tx mild sfx, Ongoing 5-FU Avastin every 3 wks.
CEA: good marker
7/7/14 CT Can't see the spleen Mets.
8/16/15 CEA Up, CT new abdominal mets. Iri, 5-FU, Avastin every 2 wks.
1/16 Iri, Erbitux and likely Avastin (Trial) CEA going >.
1/17 CEA up again dropped from Trial, Mets growth 4-6 mm in abdomen
5/2/17 Failed second trial, Hospitalized 15 days 5/11. Home Hospice 5/26, at peace 6/4/2017

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Re: Stage IV: a totally different disease

Postby rp1954 » Sun Sep 19, 2021 4:45 am

For us, the "glue" to all mCRC treatments was to stop the metastatic process, particularly in the blood and lymph, and the hyperinflationary growth events (e.g. 2-6 mm LN to ca 2 cm LN, in under 2-3 weeks) with daily chemistry. Effective antimetastasis chemistry had many lower toxicity possibilities in generica that needed some customization or personal fit.

Various papers indicated that these antimetastasis requirements required lower doses than full scale assault dosing on the worst macro mets. If we knocked off some of the 1 - 10 mm stuff too, great. My expectation and requirement was to get surgery on the larger more resistant mets measured in cm and inches. However such surgery may require more effort than just snapping one's fingers to find that real surgical talent - experienced, ready, willing and able to do advanced surgery beyond "std". The phrase "world class" suggests one possibility, but perhaps there are more marketing claims than substance. Uninformed over conservatism is another problem.
watchful, active researcher and caregiver for stage IVb/c CC. surgeries 4/10 sigmoid etc & 5/11 para-aortic LN cluster; 8 yrs immuno-Chemo for mCRC; now no chemo
most of 2010 Life Extension recommendations and possibilities + more, some (much) higher, peaking ~2011-12, taper to almost nothing mid 2018, mostly IV C

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Re: Stage IV: a totally different disease

Postby Claudine » Sun Sep 19, 2021 10:18 am

But now we are starting to see people that are making it longer and managed to stave it off well enough and qualify for newer treatment options not available then, and extend that life out further to the point where they may end up being cured!

That is my dearest hope for my husband. Because he’s got a bone met, he can’t be cured - at least not with the current treatments. He’s also KRAS mutated. But he’s getting on 4 years with this damn disease and even though it has changed his life a lot (no more backpacking, skiing...), he’s still here and QoL is pretty great, considering.
Wife of Dx 04/18 (51 yo). MSS, KRAS G12A
No primary (involuted?)
Lytic tumor L4 vertebrae, EBRT 04/18, SBRT 02/19
Resect small intestine 05/18 (no cancer - Crohn's)
Failed adjuvant Xelox
Folfiri + Avastin 03/19 to 01/20
6.7 cm left adrenal mass 03/19, successful resection 02/20
CEA since 03/19: low 3.2, now 81.1
Scan 03/19: Multiple small lung nodules, now gone/calcified
PET 04/20 uptake by L4
L3-L4-L5 fusion surgery and partial corpectomy 05/20
Scan 09/17/2021: stable

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