Revealing the presence of cancer cells turned invisible by TKI - 1266459

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bernie3
Revealing the presence of cancer cells turned invisible by TKI - 1266459

Dear CancerGRACE team

I attended the Acquired Resistance seminar in Boston. It was very informative and it took me a full month to absorb all the information provided. I have now a question to ask about dormant cancer cells in NED patients.

Once the EGFR patient has become NED, it is difficult to know whether the body is free of cancer or whether there are still cancer cells alive (inhibited and therefore invisible on the scan, and yet alive). If we knew the real situation, we could make adjustments in our treatment (I have a few ideas for myself, which I cannot detail here because of the 2000 character limit).

But first, we need to assess the objective situation. I was thinking of doing the following:
-- stop the inhibitors for five days (and let the body wash them out);
-- perform a PET-CT;
-- restart the drug immediately thereafter.
It seems to me that the scans would then provide a real picture of the remaining cancer, showing both active and dormant cells.

There is an important assumption here, which is the fact that tumours can go from NED to visible on scans within 5 days. It certainly depends on the individual patient's cancer (I guess some tumours can be harder to wake up than others). Pharmaceutical companies provide half-life values for the drugs. The half-life of Tarceva is 36 hours. I would imagine that after five days, at least a certain proportion of cancer cells would start consuming glucose and become visible on the scan. Maybe the image would not be perfect; maybe SUV values would be underestimated; but at least we would get some basic understanding of the objective situation.

In order to deal with a potential flare, I was thinking of doing intermediary blood tests during the period; if the CEA marker starts sky rocketing, I would restart the inhibitors straightaway.

My question is, does this make any sense?

Bernie

JimC
Hi Bernie,

Hi Bernie,

Welcome to GRACE.

I can appreciate what you're trying to achieve with your plan, but there are a few matters to be addressed. First, the term "NED" (No Evidence of Disease) is applied when a patient's scans do not show any remaining tumors. Neither CT nor PET can show individual cancer cells, only conglomerations of such cells variously referred to as nodules, masses, lesions or tumors. It is these conglomerations which appear on scans. As cancer cells circulate through the bloodstream, they eventually form tumors, but this is not a process that is likely to occur over a short period such as five days. In addition, though five days might be long enough that Tarceva would no longer be present in the body, its effect on cancer cells may remain, at least with respect to the cells which remain sensitive to it.

In any event, an EGFR TKI does not make cancer cells invisible, it kills them. When the treatment is fully successful (a "complete response"), tumors become invisible because they have ceased to exist or become too small to detect on scans. If we knew that the drug has killed every cancer cell in the body (currently not possible), then a patient could be referred to as "cured". Unfortunately, in most cases neither chemo nor targeted therapy kills all cancer cells, and with targeted therapies eventually those cells become resistant to the treatment and once again begin to form tumors visible on scans.

Finally, in lung cancer though CEA values can tend to rise with progression for some patients, they are not a reliable measure in most cases and therefore many oncologists do not even track them. The two best methods of detecting progression remain imaging results and change in symptoms.

Research into methods for detecting circulating tumor cells continue, but unfortunately nothing reliable has yet emerged that can be used in practice.

JimC
Forum moderator

<p>I began visiting GRACE in July, 2008 when my wife Liz was diagnosed with lung cancer, and became a forum moderator in January, 2010. My beloved wife of 30 years passed away Nov. 4, 2011 after battling stage IV lung cancer for 3 years and 4 months</p>

bernie3
Dear Jim

Dear Jim

Thank you very much for your answer.

I would prefer to keep the CEA discussion aside at this point because this is not the central point.

Reverting to the question of invisible cells, I'm afraid I don't agree with your explanation. Luckily Tarceva does kill some cancer cells; but it also inhibits other cancer cells without killing them. Tarceva can block the activity of infected cells, making them invisible on PET scans. But sadly the infected cells are still present. If we stop taking Tarceva, then the disease comes back very fast (this is the flare effect). Growing from too small to be visible on a scan to several cubic centimetres would take years. But lighting up because the inhibition has stopped can happen within a few days to a few weeks. Experience demonstrates that if a NED patient stops taking Tarceva, cancer usually comes back in a matter of days or weeks, not years.

I had a few lymph nodes resected eight months ago (when we removed my primary tumour which was resistant to Tarceva). According to the histopathologist, the cancer cells from the lymph nodes looked very much alive under the microscope despite being invisible on the PET scan (which demonstrates that they were inhibited but not killed by Tarceva). First I was a bit doubtful, so I asked a second lab and received the same answer.

Most NED patients have dormant cancer cells in their body (I am talking about full grown tumours, not isolated cells). I believe our course of action could be adapted if we knew how much dormant cells we have, and where they are located. But as you rightly pointed out, the difficulty with my proposal is that the effect of Tarceva could remain even after a five-day wash-out period. My hypothesis is that this is partially true, but that at least some dormant cells would have waken up during the five days. This is why I believe we could get a low contrast image of the remaining tumours. But I don't have any evidence to support my hypothesis.

All the best,

JimC
Dr. West has said this about

Dr. West has said this about the "Tarceva flare":

"I would say that the rebound progression or “flare” reaction is something that is possible but pretty uncommon, well under the 20-25% range reported in one paper from Memorial Sloan Kettering, and more like a 5% possibility." - http://cancergrace.org/topic/risks-to-stopping-tarceva-to-change-treatme...

In the same thread, Dr. Creelan agreed:

"I agree with Dr West – the so-called rebound progression or ‘flare’ after stopping Tarceva may actually be rather unusual...Bottom line: I don’t think the reported flare phenomenon warrants the degree of anxiety that is often observed in patient forums."

JimC
Forum moderator

<p>I began visiting GRACE in July, 2008 when my wife Liz was diagnosed with lung cancer, and became a forum moderator in January, 2010. My beloved wife of 30 years passed away Nov. 4, 2011 after battling stage IV lung cancer for 3 years and 4 months</p>

bernie3
Hi again Jim

Hi again Jim

I must acknowledge that the notion of cancer coming back very fast is not a precise notion. But whether it comes back almost instantly (as a flare), or in a matter of weeks does not change the fact that this cannot be the consequence of natural progression; this can only be explained by the waking up of dormant cells.

If a NED patients stops Tarceva,-
-- do we agree that a several cubic centimetre tumours can often be observed after a few weeks only?
-- do we agree that this cannot be explained by the natural progression of tiny tumours too small to be visible on the earlier scans (as these tiny tumours would take several years to reach a size of several cubic centimetres; except in rare cases of super-fast growing cancers)?
-- as a consequence, do we agree that NED patients have dormant cancer cells (again, I am talking about full grown tumours, not isolated cells)?

Thank you very much for your opinion.

Bernie

JimC
Hi Bernie,

Hi Bernie,

The part of your theory with which I would have the most trouble is the idea of a NED patient having tumors which don't appear on scans. If the tumor is present but the cancer cells are "dormant", they may not light up on a PET scan, but the tumor will appear on a CT. Many NED patients have absolutely nothing show up on their CT.

JimC
Forum moderator

<p>I began visiting GRACE in July, 2008 when my wife Liz was diagnosed with lung cancer, and became a forum moderator in January, 2010. My beloved wife of 30 years passed away Nov. 4, 2011 after battling stage IV lung cancer for 3 years and 4 months</p>

catdander
Hi Bernie, I think I've seen

Hi Bernie, I think I've seen your name and avatar around before though this may be your first thread? Welcome thanks for this good discussion. It's the kind of thread that can lead to a lot learning for a lot of people.

First of all I want to thank Jim for being here. Jim, you have an excellent way of describing things, such as what the present line of thought and understanding of lung cancer and management is. I on the other hand ramble to get to a point...

I've asked Dr. Sequist to comment though it may be a day or 2 coming she seems to be ooo. Either Dr. Sequist or colleagues debate about the rate at which flare is seen. We all agree it happens enough to watch carefully those who've had a good run on a TKI. An average growth pattern is probably more like many weeks or months but not usually years in nsclc.

The idea of dormancy has been described more like the cancer and anticancer agent working at a steady growth/kill rate so the tumor doesn't grow or shrink but isn’t dormant in the real sense of the word either. It's not thought to be just sitting around doing nothing. However that wouldn’t explain no FDG take up, perhaps, like my husband there is scar tissue where the cancer mass was. It would be helpful to hear a good explanation of why dormancy sounds like a good explanation of why a mass was growing, stopped, then started again.
Insurance may not pay for the imaging but if you're willing and able a succession of PETs or CTs could be taken as you've described to catch a flare or a better understanding of your cancer’s biology.

Janine

catdander
I just did a search on Grace

I just did a search on Grace for dormant.

I found this,

"The problem is that it’s really not possible on initial scans to tell the difference on scans between completely dead cancer with just residual scar tissue and a very tiny, microscopic amount of viable cancer in an area of just dead scar tissue. The former never changes over time, but the latter becomes metabolically active and eventually grows.
-Dr. West"
http://cancergrace.org/topic/progression-in-dead-tumors/#post-1246081

bernie3
Hi again Jim

Hi again Jim

This is interesting.
It is true that I did not have a CT contrast scan before they resected my lymph nodes. For some reason, my oncologist has a preference for PET scans. I am certain the lymph nodes were invisible on the PET, and yet the tumours were alive. But as you say, they might have been visible on the CT scan.

So your point is, once a patient is NED on the PET, he should seek confirmation with a CT contrast scan. Because cancer and lung tissues have different natures, the fully inhibited tumours would show on the CT scan even if they don't light up on the PET. Obviously this seems much easier than what I propose.

============

Janine and Jim

It will be interesting to read if Dr. Sequist has additional information to share on this matter.

If you allow me to keep playing the devil's advocate, I wish to ask one more question:
If a NED patients (as per CT scan) stops Tarceva, can he grow a large tumour (say several cubic centimetres) in three months? I understand that this could happen if the patient is NED solely on the PET scan. If I correctly interpret Jim's point, this could never happen to a patient NED both on PET and CT (except in very rare cases of super-fast growing cancers). Am I mistaken?

Thank you very much

Bernie

catdander
Yes, anyone with nsclc can

Yes, anyone with nsclc can grow a tumor to that size in a matter of a month.

Most PET scanners also provide a CT scan. If you're getting sizing with FDG uptake the sizing such as cm is from a CT (though probably at a lower resolution than a stand alone CT. Also neither PET or CT or any other device or test can pick up nsclc on a cellular level with any consistency. Most FDG uptake begins measuring after a nsclc tumor is at least 1cm. CTs can pick up just a mm or so these days, even at a cancer mass of just a mm the amount of cells is in the /100s of thousands I think/.

I won't speak for Jim but I'm sure that's not what he meant. One of my husband's PET/CT scans showed a new mass after 3 months of 3 cm. It was considered fairly quick for his history though absolutely not out of the question.

A quick search on our site will give you tons of info on scanning.
Keep up the learning process. I hope it last for years!

Janine

catdander
I found it. Dr. Weiss says

I found it. Dr. Weiss says at the beginning of the 2nd pp to my favorite intro, "Cancer cells are microscopic. The tip of a pen is the size of more than ten billion cells.", http://cancergrace.org/lung/2010/04/16/introduction-to-first-line-therap...

bernie3
Dear Janine

Dear Janine

Thank you for answering my messages. It is very important for patients to understand whether a NED assessment is for real or not.

But in all honesty I find it hard to believe that a cancer can grow from invisible on a CT scan (i.e, less than 2x2x2 mm = 0.008 cm3) to say 4 cm3 in 2 months time. That would mean a factor 500 i.e. 2^9 in 2 months. The doubling period would be one week only. All cancer cells must complete a mitosis every week again and again. I am sorry to say this so bluntly, if a patient has a doubling period of one week, he cannot survive for more than a few weeks after being diagnosed.

Assuming the radiologist did a proper job, the only plausible explanation -in my opinion- is that the said 4 cm3 lesion had a 2.5 cm3 size two months before but was somehow hidden. Could it be that Tarceva was actually hiding the lesion?

( I don't want to sound stubborn, but the sudden appearance of a large lesion contradicts the hypothesis that inhibited tumours are visible on a CT scan, despite being inhibited. )

Kind regards

Bernie

bernie3
Dear Janine and Jim

Dear Janine and Jim

Incidentally, I don't know whether you saw the presentation from Dr. Gregory Riely during the Boston seminar:
http://cancergrace.org/lung/2014/10/06/ar_forum_how_does_acquired_resist...
You may wish to watch the part starting at 00:15:30.
Dr Riely is showing tumours invisible on a PET scan which turn visible in a matter of days, as the TKI is stopped. I must say this made a tremendous impression on patients in the audience.

Kind regards

Bernie

catdander
Bernie, Don't worry about

Bernie, Don't worry about pushing the subject. You need to understand, I couldn't agree more. Though I won't clutter up the thread any more than I already have until we get input from a specialist or Jim to set out a better explanation to your questions.
:) Janine

Dr West
I can't readily explain the

I can't readily explain the significance of the flare reaction, but I can assure you that you would see lung nodules as present on a CT scan whether they were dormant or not. However, a doubling time of cancer cells in the range of days is possible for the most aggressive cancers, and it is in fact associated with a survival in the range of weeks if not treated effectively.

Bear in mind a few things about flare reactions. Dr. Riely made the point that this fraction of patients who had a flare reaction were hospitalized or died in short order, so it can be a very rapid process. However, to my knowledge, no other report has ever noted a frequency of flare reactions close to that high. In fact, the reason they wrote about it almost certainly was that they worked backward from a cluster of striking flare reactions and then wrote about it. Thousands and thousands of people with an EGFR mutation have stopped their EGFR TKIs without having a flare reaction -- all over the world, EGFR TKIs are discontinued temporarily or permanently without any other institution reporting a frequency of flare reactions of 20-25%. Finally, the reason the image of the flare reaction was shown by Dr. Rielywas because it was so dramatic, not because it was so representative of what happens in everyone.

As to stopping and starting EGFR TKIs, we simply have no experience with this. For the past 12-15 years since EGFR TKIs have been studied, they have almost always been continued without a break in the absence of significant progression of disease. While it's possible that pursuing an intermittent approach could be helpful, there is little enthusiasm for this, since it is widely understood that EGFR TKIs are only suppressing the disease and not eradicating it.

Good luck.

-Dr. West

+++++++++++++++++++++++++
Dr. Howard (Jack) West
Associate Clinical Professor
Medical Oncology
City of Hope Cancer Center
Duarte, CA

Founder & President
Global Resource for Advancing
Cancer Education

JimC
Hi Bernie,

Hi Bernie,

I thought and typed too slowly to reply before Dr. West, but here is what I wrote anyway:

Janine is correct - I am not saying that a tumor of the size you describe couldn't grow in a few weeks or months. Dr. West has often said that cancer can do anything, and after having read the histories of many GRACE members or their loved ones in the past 5+ years I've been active here on GRACE, I have seen many instances of new nodules or tumors appearing that quickly. I can't say that I know how this happens, but it does. I think Janine's description of the cancer cells beginning to grow at a faster rate than the treatment kills them is very apt.

Dr. West has written about doubling time of tumors here: http://cancergrace.org/lung/2007/11/12/lung-nodule-doubling-time/

JimC
Forum moderator

<p>I began visiting GRACE in July, 2008 when my wife Liz was diagnosed with lung cancer, and became a forum moderator in January, 2010. My beloved wife of 30 years passed away Nov. 4, 2011 after battling stage IV lung cancer for 3 years and 4 months</p>

bernie3
Thank you Dr West, Janine and

Thank you Dr West, Janine and Jim

So the good approach to detect dormant nodules is to look for them on a CT scan. They might be invisible on the PET scan due to their inactivity. However the tissue structure is sufficiently different from the lungs to make them visible on the CT scan. Large nodules lighting up at some point on a PET scan should normally be spotted in advance on a CT scan (except in rare cases of super-fast growing cancers).

The stunning flare images we saw in Boston are those of a statical outlier, used for didactic purposes, not for the sake of illustrating a common pattern amongst patient. No need to worry too much.

The practical conclusion is: when patients get a NED report following a PET scan, they should have it confirmed with a CT scan to reveal the possible presence of dormant nodules. This is now very clear. Thank you again.

Bernie

( It is tempting to ask why this is not universal practice; but I suspect I know the reason already: the cost. )

JimC
Hi Bernie,

Hi Bernie,

Actually, most thoracic oncologists use CT rather than PET (which are considerably more expensive than CTs) to assess the effect of treatment and for routine follow-up. As Dr. West has said:

"[A] CT scan is the standard of care (i.e., established mode of follow-up that is considered best practice), and I believe just about every faculty member here, who are all lung cancer experts, feel that PET scans are neither necessary nor appropriate for routine follow-up of advanced lung cancer and are greatly over-ordered by many oncologists. Like Dr. Pinder, I don't standardly get PET scans in this setting, and I would be inclined to challenge the oncologist offering an edict that a PET scan is clearly superior to a CT scan here to provide the evidence to support that position, because the lung cancer experts of the world haven't seen it yet.

Here's an FAQ post on this common question, also saying that CT scans are the standard of care and that PET scans, though perhaps the scan of choice in selected situations, tend to be significantly overused for follow-up of advanced lung cancer and other oncology settings:

http://cancergrace.org/cancer-101/2010/09/16/cancer-101-faq-assessment-r... "

The entire thread is illuminating, and it includes this from Dr. Pinder:

"I would say that a PET many times will not clarify progression when there are small variations on a CT scan. Follow up imaging is usually the very best way to figure out if someone is progressing. Research about how PET scans should be used to follow cancer is actually very far behind the marketing and utilization of PET scans. The radiologists I work with are doing research on how the SUVs on PETs can vary just by the time of day the PET is done in an individual patient. When patients are scanned on two consecutive days (much too short a time to actually see a cancer grow), there is enough variation that might be construed as progression.

[continued]

<p>I began visiting GRACE in July, 2008 when my wife Liz was diagnosed with lung cancer, and became a forum moderator in January, 2010. My beloved wife of 30 years passed away Nov. 4, 2011 after battling stage IV lung cancer for 3 years and 4 months</p>

JimC
"So I would say that changes

"So I would say that changes in the SUV of small or moderate magnitude are very difficult to interpret. However, I often see therapeutic changes being made in patients who have been followed by PET based on small changes in SUV with no actual growth in the lesion."

JimC
Forum moderator

<p>I began visiting GRACE in July, 2008 when my wife Liz was diagnosed with lung cancer, and became a forum moderator in January, 2010. My beloved wife of 30 years passed away Nov. 4, 2011 after battling stage IV lung cancer for 3 years and 4 months</p>

Dr West
Agree. Cost is an issue with

Agree. Cost is an issue with imaging surveillance, but it's PET that is very expensive, not CT, and PET scans have not been demonstrated to improve outcomes. ASCO, the American Society for Clinical Oncology, identified surveillance of treatment response by PET scans as one of their 5 most wasteful and unhelpful interventions in the practice of cancer care and officially discourages this practice.

-Dr. West

+++++++++++++++++++++++++
Dr. Howard (Jack) West
Associate Clinical Professor
Medical Oncology
City of Hope Cancer Center
Duarte, CA

Founder & President
Global Resource for Advancing
Cancer Education

bernie3
Dear all

Dear all

I can now read GRACE posts in the light of my new knowledge about CT scans. But I am a bit puzzled about several comments, which seem to contradict what I understood earlier this week.

For instance:
http://cancergrace.org/topic/possible-progression-and-possible-options
[ ... ] It was a surprise for us that yesterday CT scans showed two new findings: a 3×1.5 cm thickness in the pleura and a new spot 1×1,5 cm in the liver. [ ... ]
Considering the longevity of the patient (mentioned in the rest of the thread), I believe we are not in the presence of a super-fast growing cancer.

This is not an isolated observation. Many patients have nothing visible in one lobe (as per CT scan) and are taken aback three months later with a tumour of several cubic centimetres in the same lobe. Again, I am not talking about patients with super-fast growing cancers.

How could something invisible on a CT scan reach a size of several cubic centimetres in three months?
Could it be that some tumours are not visible on a CT scan because the structure of tissues is not very different from the structure of lung tissues?

I am sorry to insist on this subject. I am not trying to be picky. But all our therapy planning is based on the scans. If the medical image is wrong, how could the choice of therapy be right?

Bernie

JimC
Hi Bernie,

Hi Bernie,

I think perhaps your conceptual problem stems from the idea that on one scan there are no cancer cells and on the next there is a tumor of significant size. In reality, there were plenty of cancer cells present in a certain location, but they can't be seen on a scan until they form a tumor and become metabolically active. Judging from the kind of example you describe, that process of tumor formation can occur very quickly, as opposed to the relatively slower growth process of most cancerous tumors. So you can't really apply the concept of doubling time to the process of tumor formation from individual cell to visible tumor (which results in astronomical doubling times, as you described in a previous post). The concept relates more accurately to the growth rate of established tumors.

JimC
Forum moderator

<p>I began visiting GRACE in July, 2008 when my wife Liz was diagnosed with lung cancer, and became a forum moderator in January, 2010. My beloved wife of 30 years passed away Nov. 4, 2011 after battling stage IV lung cancer for 3 years and 4 months</p>

cosmo72
Hi Bernie

Hi Bernie
It could be the CT Scanner used as some of the older ones do thicker slices ? hence depending on the position of the slice you could get quite different reports

where I have mine done its a Siemens AS Flash Low Dose 128 Slice CT
http://glenorchygazette.com.au/?p=300
previously it was only a 32 slice and higher dose of radiation

I always go to the same radiology clinic

I recently in Aug had a PET Scan and had a couple of areas of SUV take-up which they said was suspicious though no CT abnormality is evident as the CT scan that is done in conjuntion with PET is low res
so my Onc ordered a new CT in Oct to look in more detail at the areas that lit up on PET but nothing yet shows on CT in those two places yet though mental nodules have increased in size and numbers but still not big enough to biopsy the upper abdomen has some moderate peritoneal fat stranding and the impression of the formation of a confluent mass this did not light up on PET

as my CEA has now climbed to 679 been rising since Sep 2013 something is going on hence they are watching very carefully Realise not all Onc use CEA and some Poo Poo it but in my case it has been a usefull tool also possible many folk would get too much angst if they knew it was rising, and prefer to hear NED a term I have not heard used here in Australia Stable is used
but untill something is seen that is measureable and can be biopsied it is just a tool and treatment would not be changed based on CEA

I had a biopsy yesterday of a peritoneal confluent mass which is being sent to see if T790 M Mutation:0) as I have now been on Tarceva since june 2012 and possible am nearing resistance though I do think it is still working as I have been getting a rash again since May..... its complex
Lesley

craig
craig's picture
A couple of comments:

A couple of comments:

1. I respect Bernie's hypothetical, but recognize that it's a hypothesis and real life often disproves hypotheses. (E.g., the mean time for TKI flare in the original report was 8 days but the range was 3 days to 21. If you except a dramatic change on scans within 5 days you might be right, or maybe you'll be a person in whom the cancer load was so slight that it remains undetectable for 21 days or even longer?)

2. Although the original article on TKI Flare cited about a 25% chance of flare bad enough to warrant hospitalization (or death):
- http://clincancerres.aacrjournals.org/content/early/2011/08/19/1078-0432...
might seem higher odds than oncologists see in their practices, it isn't without some subsequent support although with lesser odds
- http://www.inspire.com/Scottb1963/journal/15th-world-conference-on-lung-...
(These notes from the 15th World Conference on Lung Cancer, Sidney, Australia, Oct 2013 anecdotally cited hearing 20% specified for both EGFR and ALK drugs.)
- http://www.ncbi.nlm.nih.gov/pubmed/23716023
(9% of 227 patients in China, median 7 days, range 3 to 18 days).

I'd imagine that since the measure "hospitalization (or death)" seems subjectively triggered, the actual % really requiring hospitalization in different populations and under different standards for triggering that could be quite different.

Although I have no hard data or personal or medical experience to support it, I'd speculate that a blooming of cancer often occurs in patients but without obvious/acute symptoms. After all, if cancer cells had been inhibited by their drug, it makes sense they'd become unleashed to proceed when that drug is removed. If most were all held back from cell division at a particular lifecycle stage, I'd further speculate that those might even proceed together in an initial wave of growth before settling into a more random pattern.

Best hopes,

Craig in PA

_________________________________
Stage 4 ROS1+ [mucinous BAC] adenocarcinoma NSCLC since 2011
Xalkori (crizotinib) 5 yrs
Alimta (pemetrexed) + carboplatin (mere months)
TPX-0005 (repotrectinib) TBD (1+ years as of Fall 2018)

craig
craig's picture
Further comments (broken out

Further comments (broken out due to 2000 char limit):

3. With no hard data either way, I shouldn't make an assumption of whether cancer cells blossom rapidly from undetectably few cells to CT-detectable tumors or just from a layer or group of cells that have been behaving themselves, looking like normal tissue. The former seems more consistent with example of patients whose cancer seems undetectable on CT, but on the other hand I can't help but wonder whether cancer cells which were not too badly multi-mutated were forced to behave like normal cells (via TKI inhibition) why couldn't those cells fall into line looking like regular tissue on NED CT scans (after apoptosis destroyed excess cells) and then regrow tumor shape/density after some number of days or weeks in at least some patients?

4. Speed of cancer growth from NED to detectable is probably very variable. Trying to unleash a flare effect should improve the odds of being able to detect a change sooner, but unless we have reserach data to prove otherwise, it also seems quite possible that in some patients the cancer might nonetheless not reach detectable levels for months.

5. FYI - An NED assessment is real -- it doesn't say there's no disease, just no evidence of it. Heck, 3 weeks before I was diagnosed with a 6cm tumor I had an x-ray report claim there was no tumor, just some ambiguous infiltrate. How does one go from no tumor to big tumor in 3 weeks? In the case, the x-ray was simply wrong.

6. Re: CT vs. PET: From personal experience, I'd wonder if I could alter my PET result just by eating foods which seem to increase my fluid-in-lung cancer symptom (foods which I usually avoid). FWIW, my last bill for CT scans was about $8,000 (before insurance discounts) -- not cheap! The only PET I had was for initial staging diagnosis (and it was wrong due to slow-metabolism cancer).

Best hopes,

Craig in PA

_________________________________
Stage 4 ROS1+ [mucinous BAC] adenocarcinoma NSCLC since 2011
Xalkori (crizotinib) 5 yrs
Alimta (pemetrexed) + carboplatin (mere months)
TPX-0005 (repotrectinib) TBD (1+ years as of Fall 2018)

Dr West
I can't explain everything,

I can't explain everything, but I recognize that there is no way to explain everything. Part of it is that much of the information you may predicate these world views on cancer behavior upon May be based on poor information. For instance, Craig's example of having nothing more than an ambiguous infiltrate on an x-Ray and then suddenly having a 6 cm cancer isn't because it came out of nowhere. It's because chest x-rays are horribly bad at showing almost anything reliable (a relatively great technology in 1914, but in 2014, not so much), and it took someone being insightful enough to make the diagnosis to have it called cancer.

About 90% of the people I see ultimately diagnosed with bronchioloalveolar carcinoma (BAC), a subtype of lung cancer that looks extremely like pneumonia in many cases, are diagnosed with and treated for pneumonia for weeks, months, or sometimes years before they're diagnosed with BAC. In most cases, their medical records still report that they had pneumonia for 4 months before they had lung cancer, but they didn't: their situation was misinterpreted. Very often, medical interpretations are wrong, and very often mistakes are just perpetuated in records.

All I actually mean to say is that I wouldn't base huge interpretations of the way cancer behaves on unusual cases and reports from patients who are relaying what they were told from a cancer doctor who may have never looked at the films directly and is relying on a report of a radiologist who may or may not be good at their job. There are MANY opportunities for inaccuracy in that chain of information.

One thing I often say here is a statement my mother told me growing up: "believe half of what you see and none of what you hear". I think it's a mistake to try to interpret the behavior of cancer from stories that may be full of errors. Besides that, the most common thing. I say here is that "cancer can do just about anything", so don't use outlier cases to interpret the world.

-Dr. West

+++++++++++++++++++++++++
Dr. Howard (Jack) West
Associate Clinical Professor
Medical Oncology
City of Hope Cancer Center
Duarte, CA

Founder & President
Global Resource for Advancing
Cancer Education

bernie3
Dear all

Dear all

Thank you very much for your detailed answers. Sadly I don't think patients can be satisfied with so many uncertainties. I certainly agree that some unexplained phenomena are only wrong perceptions from uninformed patients. But considering what is at stake, I think the investigation should not stop there.

Going through the hurdles mentioned so far (and still considering the case of an apparently NED patient):
-- There are plenty of cancer cells present in the body, which cannot be seen on a scan until they aggregate and form tumours. This advocates in favor of monitoring blood markers and circulating tumor cells in parallel to the scans.
-- Older scanners provide thick-slice resolution. Patients should check the equipment used in their hospital; and if they are not satisfied, they should go to different imaging centers (easier said than done).
-- PET scans are less reliable because of their resolution. Patients should use CT scans instead.
-- Scan interpretation is tricky and despite all their experience, radiologists make mistakes. This suggests using PET scans in parallel because SUV images are somehow easier to interpret, and they provide enough redundancy to reduce the risk of human error. This advocates also in favor of asking for second readings.
-- CT scans cannot always be trusted because TKI can make cancer tissues behave and look “normal”. In all probability, PET scans would not provide better information, except if…
-- If we can stop momentarily the TKI and unleash the cancer cells, then we might be able to visualize on a PET scan the tumours invisible on a CT scan. This is an unverified hypothesis; and it might work, or not depending on how long the inhibition takes to wash out. A period of at least 10 days would be probably necessary to reveal a sufficient proportion of hidden cells.

Continued …

bernie3
Continued ...

Continued ...

If we envisage an ideal situation with no cost limitation, the following procedure should be necessary to confirm a NED report.
1. Make sure CT scanners have sufficient definition
2. Ask for a second reading
3. Do PET scans in parallel to confirm CT conclusions
4. Test blood markers and circulating tumour cells to confirm 1-2-3
5. If 1-2-3 are contradicted by 4, some tumours might be hiding somewhere in the body. In such a case, the patient should do a PET scan after a TKI wash-out to reveal the hidden lesions.

My main message is: patients need to know that there is a method to be reasonably certain that NED really means NED ; and if it does not, patients need to understand where the problem is. This is not only a question of psychological comfort; this is also a question of making the right medical decisions.

PS: I forgot to mention; I am not a native English speaker. I hope you can bear with me even when my syntax is approximate.

Dr West
Bernie,

Bernie,

Your English is very good, and you are clearly very thoughtful. I don't mean to minimize your concerns. However, your mentioning of the ideal world where cost is not an issue is not the world in which any of us live. I hope to be able to teleport there some day.

-Dr. West

+++++++++++++++++++++++++
Dr. Howard (Jack) West
Associate Clinical Professor
Medical Oncology
City of Hope Cancer Center
Duarte, CA

Founder & President
Global Resource for Advancing
Cancer Education

bernie3
Haha! … and I wish I could

Haha! … and I wish I could teleport myself to a place where metastatic cancer is curable :)
What I meant by ideal treatment is something that would be perfect for the purpose of assessing our medical condition. But ideal does not have to be unaffordable.

Of course I cannot speak for the US. Looking at costs in Europe and taking the case of the UK private sector, which we consider as expensive on this side of the pond:
CT scan = £ 1,100
PET scan = £ 1,250
Blood markers (CEA+CA12.5+CA19.9) = £ 420
Circulating tumour cells (Cyfra 21.1+telomerase+C-MYC+ERBB2) = € 550 (we do not have CTC tests in the UK; we need to send our blood to Germany, hence the price in euro)
Total annual prices for quarterly scans and monthly blood reports = £19,700 (i.e. $ 25,000).

Of course this is a lot of money, but we must consider that in Europe a significant portion of costs are paid by the state or private insurance. The remainder may be significant; but well below the annual price of most novel drugs (if we consider crizotinib for instance). So ideal does not mean unaffordable, in my opinion.

So dear Dr West, would you consider that the proposed diagnostic plan would be advisable to patients who can afford the cost.

Kind regards

Bernie

Dr West
I must confess that I don't

I must confess that I don't favor PET scans not because I can't get them for my patients or only because of the cost, but because I feel that the differences of what they detect are hard to interpret and lead to many bad clinical decisions when doctors and patients over-read the significance of small changes. You can see this with CT scans as well, but less commonly, and CT scans are far more established for following the clinical responses or progression of disease. By the same token, blood markers and CTCs are still of speculative value and haven't been demonstrated to improve survival in anyone with lung cancer. I don't order these tests, nor do most lung cancer experts, and not because we don't have access to the tests. We don't order them because they may add nothing but cost and confusion.

-Dr. West

+++++++++++++++++++++++++
Dr. Howard (Jack) West
Associate Clinical Professor
Medical Oncology
City of Hope Cancer Center
Duarte, CA

Founder & President
Global Resource for Advancing
Cancer Education

craig
craig's picture
I got the impression that the

I got the impression that the one use of PET scans that is common in the USA is for initial diagnosis because to help stage the disease that only seemed to appear early stage disease on initial CT scan and which show areas that should be subsequently followed more closely on CT scans.

If one assumed that in an ideal world with ideal treatments cure of previously stage-4 patients were possible, I'd imagine that the same use might make sense in a patient suspected to have reduced their disease down to possibly minimal locally-treatable locations (oligiometastatic). The flaw in that, of course, it that today's common treatments don't achieve that ideal in late-stage patients except for some very rare, lucky exceptions. . . . But maybe someday <play wistful music soundtracks or chimes here> . . .

Best hopes,

Craig
in PA

_________________________________
Stage 4 ROS1+ [mucinous BAC] adenocarcinoma NSCLC since 2011
Xalkori (crizotinib) 5 yrs
Alimta (pemetrexed) + carboplatin (mere months)
TPX-0005 (repotrectinib) TBD (1+ years as of Fall 2018)

bernie3
I understand that it is

I understand that it is widely considered that PET scans, blood markers and CTCs only bring complexity and confusion, so it is better to do without them. In some other experimental fields, it is said that measurement redundancy reduces the uncertainty. But I fully appreciate that applying Physics reasoning to the medical arena may have no clinical benefits.

Craig already knows what I have in mind (we spoke in Boston and repeatedly since then). As a patient and a scientist, I have a fairly elaborate strategy for myself. It is a three-phase plan.
1. from metastatic to oligo-metastatic
2. from oligo-metastatic to NED
3. from NED to chronic disease (or ideally to a cure)

I am applying the strategy to myself and already managed to get from metastatic to NED. As Craig hypotheses, maybe I have been lucky; but I don’t think this is true, as I had to face a challenging resistance after only six months on Tarceva.

NED is not good enough. Some of us hope to turn this deadly disease into a chronic disease. NED patients get a clear CT, then another clear CT, and yet another clear CT, and there is no valuable information to get from a straight series of clear CT scans. It is impossible to monitor the “NED to chronic disease” phase without more detailed information.

I actually have several options to choose from for my “NED to chronic disease” phase (I am currently implementing the first one). I would love to discuss them here. But I certainly don’t want to waste everyone’s time and honestly there is no way to discuss without referring to an “ideal world” monitoring.

Kindest regards

Bernie

Dr West
As I have said in this thread

As I have said in this thread and in many other places on the site, you can see just about anything happen with cancer. I would be very cautious about inferring global principles about the curability of metastatic lung cancer as a broad concept based on the behavior of a single case treated in a unique way.

You can become NED by resecting 10 metastatic lesions or potentially radiating 10 lesions. For some cancers that just happen to be indolent, you can even remain NED for a long time after that, but that doesn't mean that it's BECAUSE of the treatment that no other lesions have emerged and that the treatments have done anything more than using Adobe Photoshop to magically erase the lesions from the scans. Perhaps, but a single case acting in an unusual way is just called a day in the cancer clinic -- it doesn't upend decades of trials and management of hundreds of thousands of people with metastatic cncer.

I don't mean to imply that I or other oncologists know everything there is to know about how to best treat cancer -- in fact, I'm sure that's not the case. We may be treating cancer differently and, I hope, curing metastatic cancer in future years. If you remain NED, with no further cancer being detected or treated in the next 3-5 years, and then we see this in many other people treated the same way, ideally compared in a trial against other people with the same characteristics treated in a different way, I think it will be more appropriate to talk about potential cures. Until then, I think it's with remembering the variability in cancer behavior and not attributing too much cause and effect to the good outcomes of a single case. I'm happy you're doing so well, but we need to be appropriately skeptical about the generalizability of potentially very unusual situations.

-Dr. West

+++++++++++++++++++++++++
Dr. Howard (Jack) West
Associate Clinical Professor
Medical Oncology
City of Hope Cancer Center
Duarte, CA

Founder & President
Global Resource for Advancing
Cancer Education

JimC
I will just add two more

I will just add two more statements which Dr. West has repeated quite often.

First, the most important factor which affects how an individual patient fares is the biology of their cancer. Some patients have simpler, less aggressive forms which respond well to treatment (even if it takes a couple tries to find the proper treatment) while other patients have more complex, aggressive forms which don't respond well to any treatment. It may help to be a well-informed, active partner in your care, but if there are no treatments which are effective, the result is roughly the same.

Also, Dr. West has often stated that in trials and in the clinic, discovering progression a couple weeks or even a month or two earlier with more frequent scans does not generally lead to better outcomes. As long as a patient is followed closely enough so that he or she is healthy enough to resume treatment, the result will be the same, except in the case of especially aggressive cancers, in which case symptoms are often obvious even before a follow up scan has been performed.

As Dr. West said, I'm glad that your treatments have been effective, and I hope that they remain so for a very long time.

JimC
Forum moderator

<p>I began visiting GRACE in July, 2008 when my wife Liz was diagnosed with lung cancer, and became a forum moderator in January, 2010. My beloved wife of 30 years passed away Nov. 4, 2011 after battling stage IV lung cancer for 3 years and 4 months</p>

bernie3
OK I understand. Thank you

OK I understand. Thank you very much Dr West and Jim, for taking the time.