Cancer – reasons for hope in the near future

[Trell]

I wouldn't know. I think it's a question of cooking temperature.

It is cooking temperature combined with time at that temperature, with lower temperature can be compensated with longer cooking times to kill common germs and parasites.

 

[Swerd]

It is cooking temperature combined with time at that temperature, with lower temperature can be compensated with longer cooking times to kill common germs and parasites.

It's always both time and temperature.

 

[Swerd]

Really hope everything continues to go well for you.

Thanks .

The other issue is that the FDA in general doesn't really have enough budget/resources to investigate everything they need to. Just look at the Oxy epidemic. The whole thing was how quickly the drug passed through the FDA. They even bragged about it. People were told it was safe, FDA had passed it so they believed it. They were wrong.

Agreed. In the past 20 years, since the Clinton administration, the FDA's budget has been seriously cut. No more fat is left, and enough muscle was cut so that bones show.

The long sad story behind the Oxy epidemic is very complex, just from the medicine & science point of view. It was made much worse when politics became involved. Big Pharma spent Big Money buying the loyalty – ahem, lobbying for support – of senators and congressmen. That worked for far too long.

I'm sure the above doesn't (hopefully) apply to food, but I think they've got their work cut out for them with how much there is out there for them to test. So many manufacturers and so many methods to how they produce things I feel it would be almost impossible.

Buried in those two graphs I posted of cancer death rates from 1930 to 2015 is an interesting phenomenon, probably related to food. Before 1945-50, stomach or gastric cancer used to be the number one killer of all cancer types. Over the years, deaths by stomach cancer dropped, to a low level today. At the same time, deaths by colorectal cancer increased. This was true for men and women, but it's easier to see in the graph for men. What caused that? Science doesn't know exactly what, but it has to be food or drink.

The general population in the USA is genetically mainly of European origin. But the pattern of gastric cancer vs. colorectal cancer in Europe varies. In more modernized Western European countries, the pattern resembles that of the US. In the less economically developed European countries, gastric cancer rates remain high and colorectal cancer rates are lower.

In Japan, things are different. Japan is certainly an economically developed country, but it's rates of gastric cancer remain high and colorectal cancer are low, like that of the USA prior to 1945. Among Japanese-Americans, the rates of these two types of cancer are no different than Americans of European descent. This is a generalization, but most Japanese-Americans immigrants or their descendants tend to marry other Japanese descendants. As a result, they remain genetically no different from the general population of Japan today. So what is different? Their diet.

So, we still don't know what may cause gastric or colorectal cancer. But we can be pretty certain that food has something to do with it.

Then there's the "supplements" that aren't approved by the FDA at all. Who knows what's in that stuff?

The so-called "food supplements" were potential pharmaceuticals that never could pass the FDA's much more rigorous test process for drugs. The FDA gets to define what types of products may qualify as food supplements, but they don't otherwise regulate them. The Federal Trade Commission (FTC) has jurisdiction over that. And they do regularly crack down on them for false advertising claims.

 

[panteragstk]

The so-called "food supplements" were potential pharmaceuticals that never could pass the FDA's much more rigorous test process for drugs. The FDA gets to define what types of products may qualify as food supplements, but they don't otherwise regulate them. The Federal Trade Commission (FTC) has jurisdiction over that. And they do regularly crack down on them for false advertising claims.

That is true. Pretty sure Dr. Oz got in trouble for promoting the false claims of some of those products.

Yep. He got sued.

 

[Pogre]

Nitrites are essential in processed meats to prevent bacterial growth. Far more people would suffer if the nitrites were left out.

Only if they ate spoiled food!

Nah, I get what you're saying. If we weren't able to preserve meat and prevent spoilage folks would starve. I don't disagree with you. The message I get is go ahead and have your bacon. Just don't have it for breakfast, lunch and dinner every day.

 

[Dan]

Happy to be of service big brother. Given the family history, I'm sure my time will come and yes I check my PSA annually.

First off to the non medical types cancer is not a single disease. Rather it is a collection of over a hundred unique diseases with more being found. They each have individual characteristics and require different therapies, so it is likely that some will find cures and some will not. They can't all be lumped together. However the new advances in immunotherapy targeting certain genes in the tumor is the most exciting thing I've seen in cancer treatment in over 30 years of medicine. Folks facing fast death sentences previously are now long term survivors.

I am involved in the colon cancer screening world a bit. Sat on an FDA committee and do some CT colonography (virtual colonoscopy). If you look at the colorectal cancer curves from Swerd you will see a decline in death rates topped only by lung (from decreased smoking). This is almost solely due to screening from colonoscopy. Sorry but stool occult blood testing works pretty poorly. Not only are early cancers found with the scope, many more are PREVENTED by removing the polyp before it goes bad. The scope works. My virtual scope works about as well. So far nothing else comes close but the other tests are all cheaper.

All screening costs tests have the obvious benefit but also carry risks. One is cost, colonoscopy ain't cheap. Virtual has had trouble gaining traction because the government thinks it can't be afforded too although it is cheaper than the scope. The cost of treating advanced colon cancer is much more so many studies have shown it is a no brainer but the government is still foolish and unable to agree on anything. As a comparison mammography costs about 50-100 thousand dollars for every life saved all coming from our pockets one way or another.

The other is problem is the incidental findings. I find a lot since my CT scan included the whole abdomen and pelvis. Some are great. I found a kidney cancer in the first one I ever read. Colonoscopy would never have seen that. But we carry lots of little unimportant things around as we age that if docs go crazy trying to evaluate them the cost goes way up and the harms including unnecessary biopsies and surgeries go up too. Screening is a double edged sword. So it needs to be applied judiciously.

 

[Swerd]

It's been about half a year since I was diagnosed with low-grade prostate cancer (PC, I like to use abbreviations, but only if I define them). At the time, I decided on active surveillance for the PC, rather than surgery or any other active treatment. It fit the general recommendations that there has probably been too much unnecessary treatment of the low-grade type of PC.

In the past, I’ve also revealed some other details of my own health matters to you in the past, cataract surgery, inflamed eyes requiring chronic strong medication.

Since then, the equation has changed for me. I'm telling it now because I strongly believe it's a good example of how we can benefit from a team of MDs who communicate with each other. In my case, there are now 4 MDs: my internist (a woman who must be about 25 years younger than me) she has taken over as my general manager, an ophthalmologist in Baltimore (at the Wilmer Eye Institute of Johns Hopkins U.) who specializes in auto-immune eye inflammation, a urologist (at Georgetown U. Hospital), a now a rheumatologist (private practice). My internist recommended both the urologist and the rheumatologist because she knows and trusts them. I now think very highly of her.

A different ongoing medical problem has reappeared. My inflamed eye has flared badly. My cornea is threatened, a serious problem, and I must take high-dose prednisone, 60 mg/day, until that is controlled. So far, I’ve been on it for >2 weeks. It is likely that my previous maintenance dose of prednisone 7.5 mg/day plus methotrexate 25 mg/week is no longer effective. A new higher dose, or new combination of drugs must be determined. Since 2017, it’s been my goal to get off prednisone and take a more effective anti-inflammatory drug, such as the anti-tumor necrosis factor alpha (anti-TNF) agent known as Humira, that has much fewer unwanted side effects than prednisone.

At the insistence of my internal medicine doctor, I saw a rheumatologist – just last Monday. He can definitely diagnose me with ankylosing spondylitis (AS), a form of rheumatoid arthritis. In AS, patients are rheumatoid factor negative (a simple blood test), as I am. In many other types of rheumatoid arthritis, patient blood tests are positive for rheumatoid factor. My X-rays show only mild signs of AS in my pelvic bones and lower back. The most severe cases of AS suffer from fusing of shoulder joints, pelvic bones, and/or vertebra in the lower back. As many as 30% of AS patients have eye inflammation with no other symptoms at all. This diagnosis would explain my longer than 10-year history of on again/off again eye inflammation.

The good news is that Humira is approved by the FDA to treat AS. It’s an injected antibody that is the best available way to suppress a variety of auto-immune diseases. In January 2017, my Baltimore eye doctor who treats my red eye, tried to get me on Humira. My diagnosis at the time was idiopathic auto-immune scleritis, where the word idiopathic is Greek for "we don't know what the hell that is". The word sclera refers to a thin tissue layer in the eye, and scleritis is a sore owie of that tissue. The Humira manufacturer (those miserable SOBs) refused to cover what was an “off-label” use. Now, with the AS diagnosis, there should be no question that Medicare will cover it. I still expect to have a fight with them, so we’ll see.

Humira is very expensive (anywhere from $3,500 to $5,000 per month street price), and large companies including Medicare, supplemental drug insurance, and Big Pharma manufacturers such as AbbVie, the maker of Humira, tend to look after themselves first. You probably have seen the frequent TV advertising for Humira. AbbVie uses it's obscenely high revenue to pay for those ads. They also pay a premium to lobby Congress to extend their patent protection well past the normal 16-year expiration. It's been about 20 years so far for Humira.

Thursday I went to see my urologist at Georgetown U. Hospital. The twice monthly Humira injections will, if approved, go on for a very long time, perhaps a lifetime. I asked my urologist if the potent immune suppression from Humira poses a risk for patients with low-grade untreated PC. He said a clear answer is not known. He doubts if it is a risk, but he cannot rule it out.

I am eager to get away from prednisone and start on Humira as soon as possible. As a result, I will get prostate surgery and eliminate the PC. I’m less eager about the surgery and it’s possible after effects, especially incontinence, but I definitely want to deal the PC first before taking Humira.

Surgery is scheduled for Monday, April 13, at Georgetown University Hospital in Washington, DC. If all goes as planned, I should be home by Tuesday April 14.

Trying to sleep at night while on high-dose prednisone is at best an adventure, or at worst, a roller coaster ride from hell. Since deciding on surgery, I’ve actually slept 6 uninterrupted hours for the last 4 nights! As Yogi Berra was famous for saying, “99% of the time things are half mental”. Maybe I’ve relaxed because I’ve finally made up my mind to take decisive steps.

Thanks for reading. Please remember, I'm feeling ecstatic at the possibility of eliminating my PC, and dealing with the nagging problem I've had with my red inflamed eyes. If all that happens as I now imagine, I will be one lucky camper.

 

[Beave]

How long have you been on the 7.5mg of pred? If it has been more than a few weeks, you'll need to taper very slowly. If it has been months or years, you'll need to taper super slowly.

Did you ever try steroid eye drops before going onto the oral prednisone?

As for the Humira, your insurance will probably push you in one direction or another, but Remicade might be worth trying before Humira (being an infusion, it takes up more of your time, but it probably has better pharmacokinetics/pharmocodynamics than the injectable anti-TNFs like Humira).

You might also want to (or be told to) stay on the methotrexate to reduce odds of developing antibodies to the anti-TNF medication.

Good luck!

 

[Dan]

Several good lessons to be learned I think. One is that a good team is necessary when things get complex with multiple diseases. Docs need to communicate well with each other to coordinate care and this is the job of a good internist. I'm glad yours is doing a good job. This is where medicine becomes less science and more art since the multiple competing variables inherent in a complex multicellular organism introduce variables that would be avoided in a lab experiment. I'm glad you're in a big city with academic medical centers. In the rural west medical care is very limited and not going in the right direction.

I'm always happy to help and lend an ear or advice as well as grease the wheels my brother. I have had one episode of uveitis now so I may be heading down our shared genetic pathway eventually. As always I benefit from your experience and advice too.

 

[Swerd]

Thanks for your good wishes Beave. You obviously have some experience with drugs like these yourself. I appreciate your concern.

How long have you been on the 7.5mg of pred? If it has been more than a few weeks, you'll need to taper very slowly. If it has been months or years, you'll need to taper super slowly.

I've been taking 7.5 mg/day prednisone plus 25 mg/week methotrexate since the spring (April?) of 2017. I'm well aware of the short & long term consequences of prednisone exposure. My inflammation eye doc in Baltimore treats patients with the same medications as those who have rheumatoid arthritis. He and others in his group are highly experienced in treating patients with these meds. The problem is that if I stop prednisone plus methotrexate, I'd loose my cornea and possibly my eyesight. So the obvious choice is to live with that damn prednisone.

Did you ever try steroid eye drops before going onto the oral prednisone?

Yes, prednisilone acetate 1%. Within a few minutes after putting in my eyes, all eyedrops drain from the eye socket by the tear ducts, into the back of the mouth. These drops do work, but they also did a number on several of my teeth. It causes calcium loss, resulting in 3 crowns.

As for the Humira, your insurance will probably push you in one direction or another, but Remicade might be worth trying before Humira (being an infusion, it takes up more of your time, but it probably has better pharmacokinetics/pharmocodynamics than the injectable anti-TNFs like Humira).

Remicade was developed from a mouse monoclonal antibody, and 'humanized' by recombinant DNA methods into a 'chimeric antibody'. It contains some mouse & some human sequences, and it is more likely to develop an immune response in the patient, making it ineffective. In contrast, Humira is a fully human antibody. Patient immune responses against it are rare. Both work with roughly similar PK/PD.

In the USA, Remicade is an expensive medication, costing about US $900 for a 100 mg dose. It is covered by almost every US medical insurance plan. Wikipedia says total costs can be as much as $19,000 a month in the USA. Remicade is supplied as a sterile, lyophilized (freeze-dried) powder, so it must be reconstituted in sterile saline and administered by slow IV infusion every 6 to 8 weeks by a health care professional, usually in a hospital or office setting. The first time a patient gets this agent may also require an overnight stay in a hospital to monitor for severe adverse reactions. For these reasons, it is usually covered under major medical insurance rather than prescription drug coverage.

Humira, supplied in a self-injecting pen similar to insulin or an epi-pen, can be injected by the patient at home. I believe it normally is given every 2 weeks. As I noted above, Humira is quite expensive, but maybe not as much as Remicade.

You might also want to (or be told to) stay on the methotrexate to reduce odds of developing antibodies to the anti-TNF medication.

Yes, combining methotrexate with an anti-TNF antibody is a possibility. Unlike prednisone, I've apparently had no trouble with methotrexate.

 

[Beave]

I haven't heard of anybody being told they need an overnight stay after their first Remicade injection. Where did you get that info?

As for the mouse protein component of infliximab vs the fully humanized adalimumab, I'm familiar with that too. I've also read countless times from various sources that that makes adalimumab less immunogenic. But have you seen data on that? Data I've seen shows that the difference in immunogenecity isn't nearly as big as that line of thinking would suggest.

As for the PK/PD, I base my comments on a presentation I attended by a PhD pharmacologist who doing research on this very topic at a nearby university. "Roughly similar" PK/PD is true but can be misleading - the small differences can be critically important for some people. For example, my brother only got partial response with the injectible anti-TNFs, but Remicade has given him a much fuller response.

 

[Out-Of-Phase]

Swerd, I wish you the best.

 

[Swerd]

I haven't heard of anybody being told they need an overnight stay after their first Remicade injection. Where did you get that info?

I was told that directly by my eye doctor at Johns Hopkins University, about 3 years ago. It was due to a rare systemic allergic reaction some patients had only on their first exposure. I suspect someone may have gone into anaphylactic shock. That can be fatal unless hospital support is readily available. Basically, they were not going to recommend Remicade over Humira.

As for the mouse protein component of infliximab vs the fully humanized adalimumab, I'm familiar with that too. I've also read countless times from various sources that that makes adalimumab less immunogenic. But have you seen data on that? Data I've seen shows that the difference in immunogenecity isn't nearly as big as that line of thinking would suggest.

I'd like to see publications that say a mouse-human chimeric is less immunogenic than a truly human antibody. I've always heard the opposite is the case. I have a PhD in biochemistry, and I've worked a career in cancer research and cancer drug development, including monoclonal antibodies.

Yes, there are probably some chimeric antibodies that have acceptable levels of immune reactions in patients, but most were dropped because they generated antibodies in patients that neutralized any activity they had. It can even be dangerous to inject a foreign protein, known to stimulate precipitating antibodies. It can lead to widespread antigen-antibody complex formation, leading to kidney failure in some patients. Once the method became available to make truly human antibodies that had no mouse sequence at all, the FDA generally insisted on it for future products.

As for the PK/PD, I base my comments on a presentation I attended by a PhD pharmacologist who doing research on this very topic at a nearby university. "Roughly similar" PK/PD is true but can be misleading - the small differences can be critically important for some people. For example, my brother only got partial response with the injectible anti-TNFs, but Remicade has given him a much fuller response.

Interesting, and certainly not impossible. But I personally doubt if differences in PK/PD behavior can be the only reason.

For those others still reading this, PK is pharmcokinetics. It studies how a drug's concentration in a patient's blood or plasma varies with time after injection or ingestion. How high does the concentration get? Is it high enough to achieve any therapeutic value? If so, how long does it stay there? How long does it take to clear out? Does clearance come via the kidney, liver, or both?

PD is pharmacodynamics. It studies the question of how specific a drug is towards it's intended target. Does the drug hit only that one target? Does the drug hit other unintended targets? Etc. These questions can vary widely depending on the drug and it's intended target.

I admit my biases on the subject of PK. I've seen many drugs come into testing with great promises of effectiveness based on early lab science studies. But they had disappointing activity in early clinical trials. The PK people always seemed to promise that if they could only try different doses or dose schedules in more clinical trials, they should be able to achieve better PK values in patients. But in my career, I only once saw that promise really come through. PK studies are necessary in drug development, but I personally think studies that dwell on it are a waste of effort.

 

[Beave]

I personally know multiple people on Remicade, and via forums I know *of* dozens more. Not a single one was told to expect an overnight stay at the hospital after their first infusion.

Maybe they consider it for certain high-risk patients with a prior history of anaphylaxis from other things? But it's certainly not standard treatment recommendations.

Also, most infusion centers have capabilities beyond the infusions, and/or they're located within a larger medical complex that often includes a hospital or ER.


As for this "I'd like to see publications that say a mouse-human chimeric is less immunogenic than a truly human antibody." That's not what I said. What I said was that the data I've seen shows that the fully humanized anti-TNFs are still immunogenic. Rates of immunogenicity for them may be lower than for infliximab, but only modestly lower, and certainly not to the point that they're negligible.

 

[Swerd]

I personally know multiple people on Remicade, and via forums I know *of* dozens more. Not a single one was told to expect an overnight stay at the hospital after their first infusion.

Maybe they consider it for certain high-risk patients with a prior history of anaphylaxis from other things? But it's certainly not standard treatment recommendations.

Also, most infusion centers have capabilities beyond the infusions, and/or they're located within a larger medical complex that often includes a hospital or ER.

As for this "I'd like to see publications that say a mouse-human chimeric is less immunogenic than a truly human antibody." That's not what I said. What I said was that the data I've seen shows that the fully humanized anti-TNFs are still immunogenic. Rates of immunogenicity for them may be lower than for infliximab, but only modestly lower, and certainly not to the point that they're negligible.

All of what you say is reasonable. I know plenty about anti-cancer drugs, but I'm a novice when it comes to rheumatoid arthritis and anti-inflammation drugs. So, I'm glad you spoke up. I do want to start some type of anti-TNF medication, but I'm not committed to only one. I'll certainly keep my eyes and ears open.

 

[Swerd]

I did a quick & dirty literature search on Google to see what come up. My search terms were: "Humira vs. Remicade immunogenicity".

The results I focused on were review papers, expert opinion papers, or meta-analyses (reviews of other reviews to see if there is any emerging trend). I didn't read any of them carefully yet, only to see if they might be worth reading. The whole topic is complex, so there are probably no simple conclusions.

This 2016 paper at first glance seemed to be the best read. It's nearly 5 years old, but that may not matter. It seems that overall, about as many as a third of patients form antibodies against Humira or Remicade. There are some difficulties with the assays needed to identify these immune responses, clouding the overall conclusion. I'm not surprised at that, this is known to be difficult. I'll read this one first, because I think it may be the best starting point.

I attached a PDF copy of this paper below.

This was published more recently, 2019. I found it somewhat harder to read. It may have been written by non-English speakers. Translations can sometimes make difficult reading.

Other papers that I found, but didn't seem to stand out. Again, some of them seem to be written by non-English speakers.

A 2018 meta-analysis. A wide analysis of many other publications and reviews. These types of papers always seem very boring when I try to read them.

This 2016 wants me to pay for a PDF copy. I don't think I will.

 

[Beave]

I don't know of any head-to-head data comparing efficacy or infliximab vs adalimumab, or comparing rates of antibody formation between the two (that's not to say that such things don't exist, just that I haven't seen them).

It wouldn't surprise me if infliximab did turn out to be *more* likely to lead to antibody formation compared to adalimumab (and the other anti-TNFs). But I do think that the early thinking when these were first coming out - namely that infliximab would be *substantially* more immunogenic due to its mouse protein component, or put another way, that adalimumab would be significantly less immunogenic - has not turned out to be all that true.

I do have to disclose one bias in all of this: I personally hate Humira because of all the damn commercials they run. I don't recall seeing a single ad for Remicade in the 20 years it's been available.

 

[Irvrobinson]

I don't know of any head-to-head data comparing efficacy or infliximab vs adalimumab, or comparing rates of antibody formation between the two (that's not to say that such things don't exist, just that I haven't seen them).

It wouldn't surprise me if infliximab did turn out to be *more* likely to lead to antibody formation compared to adalimumab (and the other anti-TNFs). But I do think that the early thinking when these were first coming out - namely that infliximab would be *substantially* more immunogenic due to its mouse protein component, or put another way, that adalimumab would be significantly less immunogenic - has not turned out to be all that true.

I do have to disclose one bias in all of this: I personally hate Humira because of all the damn commercials they run. I don't recall seeing a single ad for Remicade in the 20 years it's been available.

Perhaps because this isn’t my field I’m easily impressed, but are you a medical or pharmacy professional, Beave?

 

[Swerd]

I don't know of any head-to-head data comparing efficacy or infliximab vs adalimumab, or comparing rates of antibody formation between the two (that's not to say that such things don't exist, just that I haven't seen them).

I'll keep looking for that. In the cancer world, the FDA usually asks for a head-to-head clinical trial to directly compare a newly approved drug vs. the previously approved drug.

It wouldn't surprise me if infliximab did turn out to be *more* likely to lead to antibody formation compared to adalimumab (and the other anti-TNFs). But I do think that the early thinking when these were first coming out - namely that infliximab would be *substantially* more immunogenic due to its mouse protein component, or put another way, that adalimumab would be significantly less immunogenic - has not turned out to be all that true.

The one factoid I've already learned is that antibodies against TNFα seem to be unusually capable of generating immune responses from treated patients. This seems to happen much more than with other monoclonal antibodies I've known about. I hadn't known that before.

I do have to disclose one bias in all of this: I personally hate Humira because of all the damn commercials they run. I don't recall seeing a single ad for Remicade in the 20 years it's been available.

I'm completely with you on this.

 

[Swerd]

I searched for head to head clinical trials of remicade vs. humira

This paper is another meta-analysis
Adalimumab versus infliximab for the treatment of moderate to severe ulcerative colitis in adult patients naïve to anti-TNF therapy: An indirect treatment comparison meta-analysis

However, it's introduction section did specifically say there has been no direct head-to-head trial of these two agents:

To date, the efficacy of adalimumab and infliximab for treating adults diagnosed with moderate to severe ulcerative colitis (UC) has been documented in a number of placebo-controlled randomized clinical trials (RCTs) and the efficacy of anti-TNFs in general (not distinguishing between adalimumab and infliximab) has been documented in a number of conventional pair wise meta-analysis. However, adalimumab and infliximab have never been compared head-to-head in a RCT, and thus, it is unclear whether one of the two treatments exhibits higher efficacy than the other. In the absence of head-to-head evidence, it is still possible to draw inferences about the relative efficacy of the two anti-TNFs through indirect treatment comparison meta-analysis, a technique that relies on evidence from RCTs that have compared either of the two active interventions to a common comparator (e.g., placebo) to establish relative effectiveness. The objective of the present study was to conduct an indirect treatment comparison meta-analysis of the efficacy of adalimumab and infliximab for the treatment of moderate to severe ulcerative colitis in adult patients with no prior anti-TNF experience.​

OK, now I can stop looking.

When I first found this paper I got all excited.
Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis

But then I reallized Vedlizumab (sold as Entyvio) binds to integrin α4β7, (also known as LPAM-1, lymphocyte Peyer's patch adhesion molecule 1, a dimer of Integrin alpha-4 and Integrin beta-7). It's found on Peyer's patches which are specific to the gut, not TNFα, which is a soluble cytokine found in blood, lymph and plasma. Never mind. Too bad – a paper in the New England Journal of Medicine on a clinical trial of 769 patients with ulcerative colitis is definitely of interest.

Just curious… why is your brother taking an anti-TNF agent? I've been diagnosed with Ankylosing spondylitis (AS). Would you tell me what his diagnosis is?