Category Archives: Prostate cancer therapy

Delaying metastatic disease – ASCO GU18


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Previously, we have discussed the conundrum of the rising PSA and when to start therapy. I also opined that for some men with a very slowly rising PSA, it might be best to just forget about it and enjoy life, comparing it to watching a clock, an opinion that understandably garnered negative comments from some. Of course the nuances surrounding PSA kinetics and their meaning are myriad. However, one graphic that helps understand this better is shown here.

Screen Shot 2018-02-12 at 2.49.27 PM

Smith, JCO 2013

This figure illustrates the fact that individuals with relatively long doubling times (>8-10 months) have a much lower risk of developing metastases or dying from prostate cancer than those with shorter doubling times. In a classic study published almost 2 decades ago, Pound et. al. followed a large number of patients who had rising PSAs following prostatectomy at Johns Hopkins. On average, men with rising PSA’s  who received no additional treatment, did not develop metastases for ~8 years. “In survival analysis, time to biochemical progression (P<.001), [i.e. the time from prostatectomy until PSA rise was detected] Gleason score (P<.001), and PSA doubling time (P<.001) were predictive of the probability and time to the development of metastatic disease.”

With these findings as a background, two studies were presented at the ASCO GU18 meeting, both involving use of improved analogues of bicalutamide (Casodex): enzalutamide (Xtandi) or apalutamide (Erleada). These drugs block the androgen receptor, thus preventing stimulation of prostate cancer growth, but are more potent than bicalutamide. Patients with rising PSA’s in spite of having low levels of testosterone from surgical (orchiectomy) or medical (GnRH agonists/antatgonists) castration, short doubling times (<10 months), but no metastases were treated either with apalutamide/placebo (SPARTAN trial) or enzalutamide/placebo (PROSPER trial). The trials were both remarkably positive in delaying the time to development of metastatic disease.

Screen Shot 2018-02-19 at 8.44.28 AM

SPARTAN TRIAL (Apalutamide)

Screen Shot 2018-02-12 at 2.42.37 PM

PROSPER TRIAL (Enzalutamide)

These are remarkable findings and great news for patients with the most aggressive forms of prostate cancer. However, there are (as usual) numerous questions raised by the trials, as was nicely discussed by Dr. Kantoff after the data were presented. These included a more careful analysis of the side effects and clinical benefits. Obviously patients are psychologically better off when they don’t have a rising PSA or metastases, but neither study reached statistical significance when it came to improved survival (both are trending in this direction). What are the side effects of being on such drugs for longer periods of time? In the enzalutamide study, there were more deaths from “other causes” – not pca within 3 months of progression. Why? In the apalutamide study there were more falls and fractures compared to placebo. Why? To these, I would add the issue of “pay me now or pay me later” – how much time/quality of life do you really lose by waiting until the first metastasis shows up, never mind the extraordinary costs (to patients, insurers, medicare, etc.) of remaining on these drugs for years. Further, neither study compared the outcome to using bicalutamide, the generic and much cheaper alternative anti-androgen, instead of placebo. And what about using the newer scans? All of the patients have metastatic disease, we just can’t see it until there are enough cells in one spot to turn a scan (e.g. fluciclovine or PSMA PET) positive. We can possibly gain advantages in staying off ADT of any sort in some patients by radiating oligometastatic disease. Nevertheless, these studies are great progress and landmarks in the fight against prostate cancer. Apalutamide became the first drug to be approved by the FDA for use in this setting with a “snap approval“. And I need to disclose that I am a paid advisor to J&J, although I have no personal stock in their company, and did not treat patients on either trial.

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Filed under General Prostate Cancer Issues, Oligometastatic prostate cancer, Prostate cancer therapy, Uncategorized

Of Prostates and Teslas


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If you thought this might be an article about how your urologist shops for his/her newest fancy car, you are mistaken (sadly…). Nikola Tesla was a fascinating inventor and ultimately “mad scientist” at the turn of the last century. Every time you plug your cuisinart into the wall to chop something up, you are the beneficiary of his contributions to the alternating current coming to your kitchen and the motor driving the chopper. My favorite story (because of the local connection) was his laboratory in Colorado Springs, where he attempted to develop a method of transmitting power without wires. By creating YUUUGE electromagnetic fields, he could make lots of electrical things happen at considerable distances, including knocking out the power station for the city. Here’s a quote from the Wikipedia article:

He produced artificial lightning, with discharges consisting of millions of volts and up to 135 feet (41 m) long.[11] Thunder from the released energy was heard 15 miles (24 km) away in Cripple Creek, Colorado. People walking along the street observed sparks jumping between their feet and the ground. Sparks sprang from water line taps when touched. Light bulbs within 100 feet (30 m) of the lab glowed even when turned off. Horses in a livery stable bolted from their stalls after receiving shocks through their metal shoes. Butterflies were electrified, swirling in circles with blue halos of St. Elmo’s fire around their wings.[12]

Of course, for purposes of this blog, the key thing is that the strength of magnetic fields was named after him. When you get an MRI of your prostate, brain, or anything else, you are put into a machine with a superconducting magnet that produces 1.5 or 3 “T” of strength. At the risk of being completely wrong and oversimplifying, what happens in the MRI machine is that a strong magnetic field temporarily lines up the hydrogen atoms in the water that is 70% of “you”, and when these atoms “relax” they give off radio signals that can be converted to images. Details and images are here. Early on, my colleagues and I were fascinated by the possibility of using MR to investigate the prostate gland and published an article (completely ignored – cited only 3 times, so must not have been that important…) showing changes in MR that occurred after testosterone administration to castrated rats.

Now there are complex MRI protocols to image the prostate using techniques I don’t fully understand (multiparametric imaging) that give us remarkable pictures of the prostate gland. Here is one:

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Prostate gland with red arrow indicating a suspicious lesion that could be biopsied or followed closely.

As with any radiologic imaging technique, the skill of the radiologist as well as the equipment being used determine the accuracy of the MRI to diagnose a cancer.

While most of us learned how to “read X-rays” in medical school, it is beyond most clinicians to read MRI’s of the prostate. Fortunately, the radiologists have developed a system that helps us think about “how abnormal” some area of the gland is, called PI-RADS.  This can be very useful in thinking about what area to concentrate on when biopsying a patient, or in trying to determine whether surgery or radiation therapy should be altered if there is concern that the cancer is outside of the gland. An interesting question that is still controversial is whether the MRI could replace repetitive biopsies in a man who has chosen active surveillance. Particularly when combined with molecular techniques (see my previous blog here) to characterize biopsies, it may be that Tesla will be helping to do more than get you from one place to another or run your electric shaver. (Rock on, Elon Musk) To me, that is a pretty interesting outcome from knocking out all of the lights in Colorado Springs!

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PCa Immunotherapy (for people in a hurry)


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I just finished reading Niel deGrasse Tyson’s book on astrophysics that was pretty understandable. Although I am no immunology expert, and certainly not at the academic achievement level of Dr. Tyson, I have made monoclonal antibodies in my lab and participated in several prostate cancer immunotherapy trials, so I’ll give this a try. My inspiration comes from a truly excellent and comprehensive review on the topic by Laccetti and Subudhi that appeared in Current Opinion in Urology. I will follow their outline with my own “layman’s view” and comments.

Provenge (Sipuleucel-T) was the first immunotherapy ever approved for treating Pca, and has been available since 2010. To be eligible, you have to have failed standard androgen deprivation therapy (though not necessarily the newer agents) and have metastases that can be detected on bone or CT scans. While the treatment works, has been shown to slow the rate of PSA increase and prolong survival, it is complex to administer. You need to donate your own immune cells for “activation” in a treatment facility, following which you receive them back as a transfusion. The process is repeated 3 times and costs in the range of $100K. Many of us wish it was even more effective given the costs and inconvenience, and of course all patients want to see their PSA go down with ANY treatment, which doesn’t happen often with this treatment. Efforts to improve the efficacy have included earlier use when patients are still hormone sensitive and combining SipT with ipilimumab, an antibody that enhances immune responses.

A number of [somewhat] more traditional vaccines are in trials. In a phase II trial, Prostvac, utilized a pox virus approach to deliver PSA (as the antigen) along with co-stimulatory molecules to help the immune system recognize and kill PSA producing cells. Although the phase II data looked very promising, the phase III trial was closed in September when the data did not support continuing to treat patients. Given this disappointment, it is not surprising that the immunologists/clinicians pursuing the goal of a successful prostate cancer vaccine would turn to the “checkpoint therapies” as a possible way to induce the body to fight prostate cancer.

Perhaps the best known of these approaches (due in part to intense advertising on the evening news channels) are nivolumab (Opdivo™) and pembrolizumab (Keytruda). The general idea here is that the immune system would potentially constantly be fighting our own body parts if there wasn’t a way to turn it off. Examples include diabetes (immune system attacks the insulin secreting cells of the pancreas) or rheumatoid arthritis (immune system attacks your joints). The checkpoint system, known as PD-1 (programmed cell death protein 1) is a shutdown system whereby the attacking T-cells are turned off by the PD-l1 ligand, a protein that can also be secreted (unfortunately) by the cancer cells. Thus the cancer cells can turn off our own immune system which is trying to attack and kill the cancer. The checkpoint antibodies effectively throw a monkey wrench into this system, allowing the immune cells to do their thing (and of course, as you would predict, the side effects can include attack of other “self” organs like the lung or colon or pituitary gland). This approach has shown real promise in melanoma, lung cancer, head and neck cancer, bladder cancer, and in some patients with colorectal cancer. Another checkpoint player is ipilimumab, which was first approved for melanoma and also releases “blunted” T-cells to go on the attack. Unfortunately, none of these checkpoint inhibitors have been promising by themselves in early tests in advanced prostate cancer, but there is optimism that by combining them with some of the vaccines in trial, or, perhaps by timing their use with androgen deprivation or radiation therapy when lots of pca cells are dying we will see improved responses. There are 19 actively recruiting studies at clinicaltrials.gov with the terms “vaccine, prostate cancer, recruiting”.  As with many of the challenges in prostate cancer, the best time to use an immune approach is likely early on, when the disease burden is low (for example, a Gleason 9 patient with NO evident metastases). These trials are challenging because such patients are fortunately uncommon, and because these men also can live for many years with current treatments, making the evaluation of a new treatment modality difficult.

2017 was a year when we lost one of the most inspiring teacher/researchers in prostate cancer, Dr. Donald Coffey. The good news is that his legacy lives on in the large number of researchers who continue to push the frontiers of prostate cancer diagnosis and treatment. We owe him a great debt of gratitude for his tireless efforts to advance this field of medicine. I predict it won’t be long until we have the kinds of exciting pca immunotherapies that have made such a remarkable difference in melanoma and other cancers.

 

 

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23 & You – Genetic tests for pca


The genetics of prostate cancer are daunting, but there are now a range of tests available that could be used at almost every stage of the disease IF you can deal with the answers you are likely to receive. Generally these tests are the product of science that goes something like this: A complete molecular picture is taken of all the mutations or all the genes expressed in a series of prostate cancer patients diagnosed years ago. For these patients “all you need to do” is go back to the paraffin blocks that were saved for each patient, extract the DNA/RNA and quantify gene expression and any mutations that can be detected. A decade ago, the technology for doing this was daunting, but now it is relatively easy. Once you have the gene expression profile, you can ask a computer to look for gene expressions that correlate with a certain outcome. For example, you take 500 patients from one center for whom the outcome is known…50 patients are dead, 32 from prostate cancer…70 patients developed metastases by 5 years…these 315 patients are alive and well with no evidence of recurrence…etc. Let’s say there are 50 genes that show changes in expression or mutation. Do we need all 50 to forecast what happened to the patients in that group? No. A computer algorithm can keep testing combinations and permutations of genes and reduce the 50 to a smaller number. We can either let the computer pick the final genes, or we could start with genes we think are related to tumor progression and then do the reduction. In the end, we have a small number of genes with characteristics that accurately separate the patients into “good” and “bad” groups and everything in between. We now take our gene panel, reduced to something like a computer chip and apply the test to 500 patients at another institution blinded from what actually happened to those patients. If our algorithm works, we should be able to accurately predict what happened to those patients in the next 5 or 10 years. If it works, our testing system has been validated, and we can begin offering the test to newly diagnosed patients at some stage of illness. For example, a Gleason 3+4=7 patient might fall into a group where surgery produced a 90% chance of being cured at 10 years, or a 40% chance depending on the gene expression. BUT…and this is key…what to do about the result is still a complex decision for both patient and physician. If you are a Gleason 3+3=6 patient and with no treatment at all you have an 85% chance of “cure” at ten years, is that good enough? What if it is a 95% chance? Will that make you more comfortable choosing no treatment, or do you want to be cured at any cost (impotence, incontinence, other side effects of radiation or surgery)?

As none of these tests has been proven in a prospective study – that is, using the tests to do something like even more aggressive therapy in a group of high risk patients, we are still in the early stages of understanding how and when to use them. Fortunately, my colleague, Dave Crawford and some colleagues have put together an excellent website to help patients/doctors understand the tests. http://www.pcmarkers.com has a list of most of the available tests and you can see what results might look like before you and your physician decide to send one off. This is a rapidly evolving field however, and not every test that is being commercialized is listed, and at big centers, there are always new tests being developed.

Finally, as with all of medicine, the payment systems/insurance coverage is crazily complex. Only today, I received an email with the “news” that a cardiologist/congressman, Rep. Buchson has introduced a bill called the “Prostate Cancer Misdiagnosis Elimination Act of 2017” that uses DNA profiling to make sure the tissue being tested is yours. You could theoretically apply this test to ANY cancer biopsy of course, so why prostate cancer? Then there is the motivation…call me cynical, but I suspected that the good congressman, meddling in medicine, might have a local connection, and sure enough, the company that markets the test is from his home state, Indiana. Not to say it isn’t important to know that tissue being tested comes from the correct patient or that the test isn’t a nice application of the kind of technology that identified OJ’s blood, just that we live in interesting times where medical technology is rapidly consuming more and more of our tax/insurance/personal dollars. Personalized medicine will depend totally on this type of technology and can be incredibly expensive. Whether it saves money or consumes it may depend on how many “worthless” (for that patient…and is a treatment with only a 5% chance of working really worthless??…not if you are in the 5% group) treatments are avoided and at what cost. I don’t have the answers. Hopefully this blog at least helps you begin to understand the current molecular diagnostic landscape.

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A statin a day??


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I remember when the statins first came out in the late 1980’s. I had a mildly elevated cholesterol that didn’t respond much to the dietary changes (admittedly few) I was willing to make, so taking a statin seemed like a great step forward. But… were they safe? Of course the same could be asked of aspirin, bike riding, eating meat, or skiing. It’s really about risk/benefit in the end. In the years that followed, I ended up taking statins with the permission of my doctor and they work far better than dietary manipulation for my cholesterol and I combine their use with exercise for all of the other benefits (read here). I previously posted about statin use here, but there are new data all the time worth keeping up with.

In a recent JCO article, a large group (31,790) of Danish men were evaluated for prostate cancer specific and overall mortality depending on their use of statins. Even though there was a higher mortality from prostate cancer than is usually seen in such studies (23% – potentially because there is lower use of screening in Denmark), the prostate cancer specific death rate and overall death rate was 15-20% lower in the men who took statins after diagnosis. This was regardless of their treatment (surgery, radiation, hormones). Since I mentioned aspirin, other studies have suggested that men with high Gleason scores (≥8) may benefit from aspirin use as well. Statins have also been shown to inhibit a long list of other cancer causes of death that you can read about in Wikipedia, so the benefits to prostate cancer patients, who often die of other cancers or cardiovascular disease is not limited to their concerns about prostate cancer itself.

In an editorial accompanying the JCO article by Mucci and Kantoff, there is a thoughtful review of whether statins should be recommended for all men with prostate cancer. The article also discusses how they might work to slow down prostate cancer, so be sure to read it for the excellent summary. They conclude that the evidence is still not there, although certainly the large number of studies and meta-analyses they provide make a strong case. My question would be “what is the risk?”, and it seems to be minimal. Statins are cheap and widely available. They provide risk-lowering effects on cholesterol/heart disease, and the only side effect that is a problem in general is the muscle pain that occurs in some patients, which almost always goes away when you stop the drug. I can’t disagree with the thought that a prospective randomized trial in a subgroup of prostate cancer patients is desirable, but in the absence of such a trial to invite patients’ participation, I personally encourage patients to take statins unless their primary care physician disagrees. For that matter, I would almost encourage their presence in the water supply like fluorides given all their other benefits (just kidding, but they really do have a long list of benefits and very favorable risk profile in my view).

An apple a day is a good idea. Statins should maybe join that, and keep exercising!

 

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Rising PSA – When to start therapy


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One of the most frequent situations I encounter in my small “prostate cancer only” practice is a man who has had treatment (usually surgery or radiation) several years ago and now has a rising PSA. He feels absolutely fine, may be exercising daily, and his PSA is often so low that a routine scan won’t show anything. What to do?

The options in this situation are changing. Treating oligometastatic disease (few metastases) is somewhat of a new frontier in this situation. In the “old days” when I wrote about this subject, we reviewed the non-randomized data that suggested no advantage to starting ADT earlier. More recently, the idea of treating some men with radiation or surgery directed at the mets if they have only a few has become more popular. Added to this is the increased sensitivity of the newer PET scans (choline, acetate, PSMA targeted) that may reveal metastases even with PSA values less than 1.0. While it is hoped that some men could be cured by this approach, it is also possible that one could delay the implementation of ADT and its side effects. There are multiple ongoing clinical trials looking at this issue. With such rapidly changing technology, it will be difficult to come up with a “right choice” in every situation. What may have been considered “non-metastatic rising PSA” last year could become “oligometastatic” simply by the implementation of the new scans.

Beyond this is the issue of treatment-related side effects. In an article this week in Lancet Oncology, the side effects of treating men with asymptomatic, non-curable prostate cancer (TOAD and TROG studies) was reported. This study is one of the few randomized studies in this setting. The men were about 70 years old with rising PSA’s, most having been previously treated. They were randomized 1:1 to starting ADT immediately or waiting until at least 2 years later unless “symptoms or metastases developed or PSA doubling times decreased to 6 months or less”. Earlier, the investigators published the survival data in this study, indicating some advantage to starting earlier, as shown in this graph. Screen Shot 2017-09-12 at 9.14.48 PM

However, keep in mind that the men who were in the immediate ADT arm also experienced the ADT side effects sooner according to the new report. The most important areas of symptoms were the hot flashes and decreases in sexual activity (reported only in the men who were sexually active) which were significantly worse with the immediate treatment, as might be expected. In a “global quality of life” measurement there was also worse quality of life, although it was not significant (the score number was 72.39 for delayed therapy vs. 70.83 for the immediate group). Further, the type of ADT used varied, and included both intermittent and continuous therapy (usually intermittent therapy has at least some improvement in quality of life). Finally, none of the men in these studies received the newer (and vastly more expensive -but probably more effective) ADT agents, abiraterone or enzalutamide which have been shown to improve survival when used “up front” in the metastatic setting.

Thus, a rising PSA is obviously a reason for concern, but choosing a management strategy is quite complicated at the present time. The best news to come out of this study is that prostate cancer is a slow disease. “Overall, 18 (6%) men died from prostate cancer, 12 (8%) in the delayed treatment arm and six (4%) in the immediate arm…” This is not to say that as time goes on there will not be more prostate cancer deaths, and there was earlier metastatic progression in the delayed group, but it is equally important to realize that at age 70 there will be significant competing causes of mortality. Something will get us eventually, so the key is to not let prostate cancer (or the PSA) dominate our thinking. What other things can you work on? Stop smoking. Exercise. Improve your diet. And most of all, enjoy each day as a gift and live it to the fullest regardless of how you decide to deal with a rising PSA.

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3 Articles and a forth


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OK, I admit to a sleazy, seemingly misspelled word to attract attention. At least I didn’t tweet it at 3AM. So what about the “forth”? I’m using it to remind you to sally forth in your search for information about prostate cancer. I previously wrote a blog giving some practical instructions on how to find the latest research publications on prostate cancer that you can find here. Another possibility, if you want to be overwhelmed is to subscribe to the Prostate Cancer Daily, published by Uro Today. So far as I can tell it is open to all, presents the original abstracts, and links via PubMed to the article itself. I now realize that the prediction of patients knowing more than their doctors about a given condition is glaringly obvious, something I discussed when I first wrote about the Internet and Oncology two decades ago.

So, on to the 3 articles: Typically, the most important articles in medicine are published in high profile journals. The premier one for medical oncology is the Journal of Clinical Oncology, JCO. The editors recently published a “best of genitourinary cancer, 2017” edition in coordination with what we medical oncologists call “GU ASCO” (actually co-sponsored by ASCO, ASTRO, and SUO). I thought it would be of interest to briefly re-cap the 3 prostate articles chosen for that edition.

ARTICLE 1: Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial. This study compared the more potent anti-androgen, enzalutamide (Xtandi™) to the older drug, bicalutamide (Casodex™) in patients who had become resistant to initial hormonal therapy. About 2/3 of the men had positive scans, while in 1/3 the resistance was detected only by a rising PSA without a positive scan. As we might have expected from the way enzalutamide was developed, it was clearly superior, with progression free survival of 19 months for enzalutamide vs. 6 months for bicalutamide. In an ideal world, we would use enzalutamide instead of bicalutamide in almost all cases where an antiandrogen is indicated. However, the increased cost of this drug is dramatic, and there may be other options or confounding issues with interpretation of the study.

ARTICLE 2: Randomized Phase III Noninferiority Study Comparing Two Radiotherapy Fractionation Schedules in Patients With Low-Risk Prostate Cancer. This article reports on one of many studies looking at whether radiation therapy treatment times can be safely shortened by increasing the dose of radiation given with each treatment and giving fewer treatments (fractions). The underlying principles are that tumor cells cannot repair DNA damage from radiation as quickly as normal cells, so giving radiation in small fractions daily allows killing of the tumor while normal cells repair most of the damage. Giving all of the radiation at once would kill every cell (and the patient).  Experimentally, prostate cancer cells may be more susceptible to larger fractions, and this study demonstrated that a radiation therapy course could be safely shortened from 41 sessions to 28 sessions with similar “cure” rates at 5.8 years of followup. This is a general trend in radiation therapy for prostate cancer. Using newer radiation focusing technologies (IMRT, IGRT, Stereotactic radiosurgery, etc.) it is possible to treat prostate cancer with as few as 5 treatments, although the long term efficacy is still unknown, and the addition of androgen deprivation to radiation treatment at any dose also improves efficacy. How to combine these approaches, the optimal duration of ADT, and which patients should stay with the older methods is still uncertain.

ARTICLE 3: Improved Survival With Prostate Radiation in Addition to Androgen Deprivation Therapy for Men With Newly Diagnosed Metastatic Prostate Cancer. Proudly, many of the authors on this article are from the University of Colorado Cancer Center. The authors used the National Cancer Database to determine whether patients with metastatic prostate cancer, traditionally treated with hormone therapy (ADT) only (although more recently with hormone therapy plus chemotherapy) benefit from also radiatiScreen Shot 2015-10-30 at 11.02.16 AMng the prostate itself. The analogy would be burning down the barn after the horse has left (with apologies to my radiation therapy colleagues who never like to compare radiation
treatments to burning). The patients who had their prostates radiated
had a 5 year survival of 49% compared to 33% for those receiving ADT alone. Removing the prostate surgically also worked. The prostate may also be a site where metastatic cells from another location return, as illustrated in this picture and discussed here. The take home message is that the cancerous prostate may continue to “seed” cancer cells to the rest of the body, or be a home for circulating tumor cells and getting rid of it, even though not curative, may be a good idea (toxicities and costs aside).

Consider yourselves updated! (sort of…)

 

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