Contributions of Physics To Advancing Cancer Research Have Been Profound

Human cancer (fibrosarcoma) cell studied at Johns Hopkins University Physical Sciences -Oncology Center for identifying metastatic agents.


It was two years after I received my first cancer treatment (at UCSF) using its high dose rate afterloader, see account here:

The Longest Day...And Then Some...

That I learned how advanced physics was contributing to the study of cancer and improving our understanding, mainly via PS- OC (Physical Science - Oncology  Centers) at different universities. Their origin goes back to 2009 when a dozen PS-)Cs were created by the National Cancer Institute. Their purpose was to team physical scientists with biologists and oncologists to seek a new understanding of cancer development.  This in turn could lead to new and improved treatments as well as diagnostics.  In the words of Paul Davies - a cosmologist who is the lead investigator at Arizona State University's PS-OC: (PT, Nov., 2014, p. 23)

"Cancer research is far too much money chasing far too few ideas. We need to think our way to a solution, not spend our way to a solution."

Davies then goes on to observe that both experimental and theoretical physics are useful in understanding and modeling metastasis.  At ASU one such synergistic project requires cancer cells to transition from static to slippery and motile, then squeeze through the tissue around the rumor and secrete membrane -dissolving chemicals to get into the bloodstream.

Once that occurs then other organs can be colonized and full metastasis is underway.  For example, in prostate cancer - which I have dealt with for 7 years now (latest PSA held steady at 4.8 from 6 months earlier) -   once the cancer cells get into the bloodstream they often migrate to the bones and especially the spine, where they become "mets". e.g.


PET  scan of patient with advanced prostate cancer showing extent of bone metastasis (dark spots) congregated in the spine and even brain.  These are actual prostate cancer cells that have migrated from that gland to these other, distal locations.

For the advanced prostate cancer patient the only way known to get a further lease on life is via hormone therapies. such as ADT (androgen deprivation therapy) which slows tumor growth by cutting off the cancer's primary fuel: testosterone.  Since the side effects can be horrific, i.e. constant brain fog and cognitive incapacity - memory loss, depression, gynecomastia, weight gain, diabetes, cardiac issues etc. it's regarded as a desperation, last resort option by many.   Given all of this it is easy to comprehend why figuring out the metastatic process is important in cancer treatments, diagnostics.

At ASU one project that's received attention concerns the use of atomic force microscopy to measure the degree to which cancer cells (like the fibrosarcoma cell shown at top) soften as the disease progresses. The approach entails obtaining the Young's modulus of the cancerous cells being investigated.

The Young's modulus is a dimensionless quantity in the elastic mechanics of solids defined as the tensile stress divided by the tensile strain, e.g.

Y  =  (F/A) /  (D L/  L _o )

The tensile stress then (numerator) is the ratio of the external force acting F, to the area A.  The tensile strain is the ratio of the change in length D L (the quantity Y is usually applied to wires) to the original length ( L _o ).  In terms of the ASU experiments, the researchers - to get Y-  prodded the cancerous cells with the tip of the atomic force microscope. According to lead investigator Davies:

"That change in Young's modulus is critical to the whole metastatic process, the squeezing through gaps."

The takeaway? Limit the cancer cells ability to stretch themselves and "squeeze" (e.g. keep D L  a minimum) and it might be possible to control metastasis.  As Davies adds:

"What has become abundantly clear the last few years is that the physical mircoenvironment can play a critical role in cell behavior. Just pressure forces or even shear stresses can affect gene expression."

Given all this, we certainly should expect much more cancer research funding to find its way to the physicists working at PS-OCs and now playing an equally important role to oncologists in extending our comprehension of cancer metastasis.

Latest Medical Finding: Hormone Treatments Put Prostate Cancer Patients At Higher Risk Of Alzheimer's Disease

PET-scan showing extent of bone metastases in a prostate cancer patient. Each dark area represents actual prostate cancer cells, i.e. in the spine, pelvis, neck etc.  Such evidence would definitely indicate the need to begin ADT or other hormone therapy.

As I noted in my June 3rd post, as a prostate cancer survivor unsure of how many years he has left, or what the disease is doing now (though the last PSA test did how the velocity slowing  from 0.21 ng/ml / mo. to 0.12 ng/ml/ mo.) I am trying to take an open minded approach combined with a realistic one.  Basically this means (and my wife and primary care doc agree) postponing any hormone treatments until I become symptomatic.   This decision actually was based on advice from leading Hopkins urologist Patrick Walsh, in his book Dr. Patrick Walsh’s Guide To Surviving Prostate Cancer’.


Therein he wrote (p. 338):

"If you have metastases to bone, bone pain, or a large mass of cancer that is obstructing your kidneys or bladder, you need to start ADT right now.    In this situation it's the right course of action - one that can make a huge difference in your quality of life and can protect your body from the ravages of cancer.

But what if you have no cancer in your bones  and no sign that anything is wrong except a rising PSA level after surgery or radiation - or the presence of cancer in your lymph nodes- and you feel fine?   Many doctors would advise you to start hormonal therapy as soon as possible.  Others - and I'm in this group - believe that in most cases there is no evidence that starting hormonal therapy immediately, as opposed to later, will prolong life.

Hormonal therapy does two things: it stops cells from making PSA, and it shrinks the hormone sensitive cell population.  Thus, a man's PSA falls and it takes longer for his bone scan to become positive for metastases.  But it doesn't stop the clock. The hormone insensitive cells keep right on growing silently."

The last sentence makes an important point, and as Dr. Dr. Walsh goes on to elaborate:

“A drug or hormone therapy that targets only one kind of cell won’t have any effect against another variety so the one size fits all approach doesn’t work here. Plus some of these cells have learned to be resistant and to grow in the absence of male hormones…so the drop in PSA may be misleading. These are called androgen independent or androgen sensitive cells.” 

 Adding:

“When male hormones are shut off, the PSA making process may indeed stop, but this doesn’t mean the cancer cells are dead or have stopped growing.”

Now, a study out of the University of Pennsylvania’s Perelman School of Medicine supports this recommendation by Dr. Walsh.  The study, in JAMA Network Open, included 154,089 men whose average age was 74 and who had diagnoses of prostate cancer. Of these, 62,330 received ADT  and the rest did not. The study found a link between drugs commonly used for hormone therapy and an increased risk of developing dementia.as well as Alzheimer's disease.

The study adjusted for socioeconomic status, age, race, severity of prostate cancer and other factors.

The lead author, Ravishankar Jayadevappa, an associate professor at the University of Pennsylvania Perelman School of Medicine, said that for advanced cancer, ADT. can be a lifesaving treatment and should not be avoided because of any increased risk for dementia. But, he said, “Patients with localized cancer should be looking at the risks of dementia, and possibly avoiding A.D.T.”

I totally concur with that but with the additional proviso: that patients with NO  evident symptoms should also be looking at the risks, and not just from cognitive disability.  With diabetes running in my family, and having seen its ravages, I can't simply adopt a therapy to fight a cancer while not recognizing the other - perhaps greater- threat.   (Currently, through the use of diet I am keeping the a1c and blood glucose under relative control, but it's still rated as "pre-diabetic")

Back to the UPenn study:  In an average follow-up of eight years, the scientists found that compared with men who had no hormone therapy, one to four doses of ADT was associated with a 19 percent increased risk for both Alzheimer’s disease and other forms of dementia, and the risk increased with the number of doses. At five to eight doses the increased risk was 28 percent for Alzheimer’s and 24 percent for other dementias.  Since most advanced prostate cancer patients are given doses every 6 months, and this could go on easily for 5 or more years, that threshold is easily crossed.

Further, the  University of Pennsylvania researchers found that 22-percent of prostate cancer patients who received ADT were later diagnosed with dementia compared to 16-percent who did not receive ADT. As well, 13-percent of ADT recipients developed Alzheimer’s disease compared to 9-percent who did not receive the hormone therapy.

Though this hormone-blocking therapy - first discovered in the 1940s -  has been proven highly effective for slowing prostate cancer, it comes with a number of risk factors including:  increased risk of depression, strokes, diabetes, cardiovascular disease, bone density loss (with attendant fractures)  and progressive cognitive decline.

The UPenn study was cited by at least one member of the prostate cancer survivor's group to which I belong, as he wrote:

"This study has convinced me that I'd rather die from prostate cancer than take ADT overly long and get dementia or Alzheimer's!"

An extreme statement but I agree with him, after seeing the ravages of Alzheimer's and dementia on three close family members (Krimhilde, my sister-in-law, the most recent).  So, as I told my primary doc I plan to postpone beginning ADT until I become symptomatic, and then plan to cut it off after  6- 12 months by which time the most PCa grievous symptoms should subside and before profound cognitive incapacity arises.

This news is definitely a wake up call for prostate cancer patients, many of whom are pushed into hormone therapies much too early - and often as an accompaniment of other treatments, i.e. radiation.

See also:

https://www.youtube.com/watch?v=KtIfsvQh2qI

And:

https://www.pcf.org/c/adt-what-you-really-need-to-know/

No, You Don't Have To Accept Further Treatment For Prostate Cancer

MRI scan (not mine) with possible hot spots, lesions.

As noted in earlier posts, if prostate cancer returned I'd have to reconsider getting any kind of "retreatments" or salvage treatments, see e.g.

http://brane-space.blogspot.com/2014/01/rising-psa-after-radiation-therapy-dont.html

Well, that time is now upon me as I finally received the MRI scan report (still no scan images themselves) but the results were definitely not encouraging. Adopting the PI-RADs MRI imaging scale the report noted 4 lesions ranging in size from 7 mm to 12 mm (almost a half inch across) with a PI-RADS score of category 4.

According to the Radiopaedia site:

"PI-RADS (Prostate Imaging Reporting and Data System) refers to a structured reporting scheme for evaluating the prostate for prostate cancer. It is designed to be used in a pre-therapy patient.The original PI-RADS score was annotated, revised and published as the second version, PI-RADSv2  by a steering committee with the joint efforts of ACR, ESUR, and AdMeTech Foundation.

The score is assessed on prostate MRI. Images are obtained using a multi-parametric technique including T2 weighted images, a dynamic contrast study (DCE) and DWI. If DCE or DWI are insufficient for interpretation the newest guidelines recommend omitting them in the scoring. (DCE = dynamic contrast enhanced imaging, and DWI = diffusion weighted imaging.)
.
A score is given according to each variable. The scale is based on a score from 1 to 5 (which is given for each lesion), with 1 being most probably benign and 5 being highly suspicious of malignancy:

• PI-RADS 1: very low (clinically significant cancer is highly unlikely to be present)
• PI-RADS 2: low (clinically significant cancer is unlikely to be present)
• PI-RADS 3: intermediate (the presence of clinically significant cancer is equivocal)
• PI-RADS 4: high (clinically significant cancer is likely to be present)
• PI-RADS 5: very high (clinically significant cancer is highly likely to be present)"

-------------------

The primary benefit then is to standardize the acquisition of MRI images and reporting. On account of the behavior of water molecules in and around tumors,  density changes and so-called "restricted diffusions areas"  can be observed, and these are generally associated with possible malignancies. So, in effect, I have four "lesions" for which "clinically significant cancer" is likely to be present. That means all are probably malignant as inferred from confined "diffusion" regions with which they are associated.

This then has incepted the next step, recommended by my oncologist at UCSF (where I received the original treatment), e.g.

http://brane-space.blogspot.com/2012/09/thge-longest-dayand-then-some.html

That is, obtaining an MRI fusion guided biopsy, e.g.

https://health.clevelandclinic.org/2014/09/fusion-guided-biopsy-a-smarter-way-to-look-for-prostate-cancer/

 This will then limit the needle insertion (and extraction of tissue) to the four suspicious areas noted in the MRI as opposed to "shooting in the dark" with 12 random stabs in the standard needle biopsy. Fortunately, a phone call to the local Urological Associates has determined that they can do it - likely not too long after a mid-August appointment with the urologist. (This was after my primary doc twisted my arm to accept her specialist referral even after I complained I would accept no further treatment),

It was clear from talking with her that as an alpha female physician she was having no part in any "surrender" to cancer. At the very least then, I'd have to be referred to a specialist to whom I could raise my arguments.

And to me they are solid ones. As I told a Nurse Practitioner from UCSF who called me about getting the MRI biopsy, then suggested a further brachytherapy "re-treatment", I really did not want to endure a lot of horrific side effects. If I had five years left I didn't want to spend them in misery but with some degree of life quality so I preferred quality of life over quantity. She thanked me for my honesty but said I should still consider alternatives - even if some of the initial effects may not be so nice.

In one paper by UCSF oncologists the conclusion speaks of radio-recurrent  control of disease by two years after brachytherapy salvage, but with "Class III genito-urinary toxicity three years later". In other words, you will have the cancer under control but soon have to deal with likely urinary and fecal incontinence (meaning wearing large,  absorbent diapers) as well as possible rectal fistulas, plus impotence, penile shrinkage, possible urethral stricture  and need for intermittent "urethral dilation"  (i.e. they will occasionally have to insert a tube into your penis to clear out the "sloughing skin" or other blockage.)

Even the most 'nominal'  salvage treatment - ADT or androgen deprivation therapy'. - carries devastating side effects including: memory loss, impotence, increased cardiac and stroke risk, enhanced diabetes risk (metabolic syndrome), depression, hot flashes, breast enlargement,  and emotional  volatility.

Faced with such potential long term infirmities from the assorted treatments, say possibly lasting the final three of your last five years on Earth, any patient must have the right to say 'No!'  Thereby expressing his own voice and making it clear that adding more years just to live longer is not an option desired if that means years of aggravation, pain and humiliation at the end. This is an acknowledgement that the medical industrial complex will always have as its first priority "saving" you from whatever disease - never mind the  "cure" may be much worse. But this is actually why our medical costs are exploding because too many opt for life at any cost.
 

After those MRI biopsy results come back- in late August or mid-September-  I will then have to finally decide whether it is worth it to get any further "salvage treatment". My first inclination - on seeing all the side effects - has been to turn all down but that really nice nurse practitioner at UCSF, who phoned me three days ago, has me at least reconsidering brachytherapy retreatment. I am also considering another alternative called cyberknife.

Hopefully, the biopsy will show tumors with too low a grade (e.g. T1c) and Gleason score to worry about - making a decision to refuse treatment logical and justified. But we will see.

As one prostate cancer survivor site observes, every choice made has its own consequences and the state of cancer treatments (including prostate), is actually much more iffy and less successful than many specialists would have you believe. In the end, one must make the best choice he can and be prepared to live with it.