Tumor Progression

It has finally happened to me - the dreaded news of cancer progression.  After 4+ years on Sandostatin LAR and debulking surgery my remaining tumors have started to grow and progress.  The good news is there are no new visible tumors. Things were stable until this March when my MRI showed tumor progression in my liver and one of my lymph nodes.  We increased my dose of Sandostatin LAR from 20 mg to 30 mg in March, hoping that might slow down any further progression.  My doctor wants to do another MRI in July to see if the tumors are still progressing.  In July, if the tumors are stable we’ll just continue with the 30 mg Sandostatin LAR. Since there are no approved drugs for mid-gut NET patients that have progressed on Sandostatin LAR, My doctor mentioned some clinical trials that I might be well suited for that are going on at Dana Farber as follows:

1)  Immunotherapy Phase 1B trial of MK-3475 in patients with advanced solid tumors

2)  Angiogenesis inhibitors (new form of chemotherapy) – there are a few choices for me in this category

The immunotherapy trial originally sounded interesting.  MK-3475 is the immunotherapy drug that has been used in advanced melanoma patients that has put some of them into remission.  It works by targeting a protein called PD-L1 that allows the cancer cells to live and multiply without disturbance from the immune system.  MK-3475 is a drug that blocks the PD-L1 protein so that your own immune system can attack the tumor.  Basically, if my tumor tested positive for PD-L1 then I would be eligible to try this clinical trial to see if the drug would work for my NETs. 

Unfortunately, my tumor test was not positive and from what I understand, none of the NET tumor samples tested positive.  I guess it means that this particular pathway to immunotherapy does not work for NETs and from what I’ve heard, most other gastrointestinal cancers.  So if the tumors progress further, it’s on to angiogenesis inhibitors for me.

Angiogenesis inhibitors have dissimilar side effects from most conventional chemotherapy medications because they work very differently. Rather than killing healthy cells along with cancer cells, as many chemotherapy drugs do, angiogenesis inhibitors only prevent new blood vessels from forming. 

At this point, there are no FDA approved angiogenesis inhibitors for mid-gut NETS.  For pancreatic NETs, Sunitinib (Sutent) and Everolmus (Afinitor) are approved.  The clinical trials that my doctor presented to me are for two drugs as follows:

1)  Cabozantinib:  This is a phase 2 trial of a drug that is approved for thyroid cancer. 

2)  Aflibercept:  This is also a phase 2 trial of a drug that is approved for colorectal cancer.  

Both these drugs, like all cancer drugs, have multiple side effects associated with them.  All things being equal (and I don’t know if they are), I’d take the Cabozantinib because it is available in pill form rather than infusion.  Neither of these clinical trials is randomized, meaning that there is no placebo arm so if I do one of them, I will definitely be getting the real drug.

My issue with angiogenesis inhibitors is that they seem to work better for pancreatic NETs than for mid-gut NETs.  My feeling is based on some articles I have read and the fact that they are only FDA approved for pancreatic NETs.  My doctor generally agrees with me but believes that the inhibitors may still work for mid-guts, just not as well as they do for pancreatic NETs.  

She also suggested taking Afinitor on an off label basis, meaning that it is not approved for my specific condition.  If I took Afinitor, at least I would not be subject to the rigorous rules of a clinical trial.  Novartis released information last week about a phase III trial called Radiant-4 that showed that Afinitor met the trial goals for gastrointestinal and lung NETs. This study might be enough for the FDA to approve Afinitor for other NET types than pancreatic.

I asked her if we should consider peptide receptor radionuclide therapy (PRRT). She said that this could be a possibility at a later stage.  She also doesn't think any liver specific treatment makes sense at this point since I have low liver involvement and tumors outside my liver. At this point my tumor load is light and I don’t have too much carcinoid syndrome. The angiogenesis inhibitors make sense to see if that helps slow progression. 

I went to a patient conference where Dr. O’Dorisio at the University of Iowa passed out a treatment chart that showed the different treatments available for NETs and their average time to progression (TTP).  If one looks at the treatment chart, the angiogenesis inhibitors have an average time to progression of 7 months.  That seems like a pretty short time to me but I know the TTP can be much longer for some patients.  My doctor thinks that there may be additional PRRT trials available in the US in the next year if necessary for my case.  It may make sense to partake in that treatment.  I could also go to Europe for PRRT where they are much farther along in the development of this therapy.  I have some time to think about this as I wait for my disease to progress.  Hopefully the progression will be slow.

The link to Dr. O’Dorisio’s chart is below:

norcalcarcinet.org/files?download=66:flowchart-for-treatment-of-nets-o-dorisio

Overkill

This week’s New Yorker magazine has another great article called “Overkill” by one of my favorite medical writers, Atul Gawande.  It’s about how new medical technologies and partnerships between doctors and health care systems have combined to produce excessive testing and scanning. These often render no value except to find abnormalities that do not need to be treated because they will never cause harm.  He goes into some potential solutions as well.  It is a comprehensive but enlightening article.  Enjoy!

Below are some excerpts as well as the link to the article. 

An avalanche of unnecessary medical care is harming patients physically and financially. What can we do about it?

Stuart Bradford in The New York Times

“Low value care is defined as one of twenty-six tests or treatments that scientific and professional organizations have consistently determined to have no benefit or to be outright harmful.  In just a single year, the researchers reported, twenty-five to forty-two per cent of Medicare patients received at least one of the twenty-six useless tests and treatments.”

“The virtuous patient is up against long odds, however. One major problem is what economists call information asymmetry. In 1963, Kenneth Arrow, who went on to win the Nobel Prize in Economics, demonstrated the severe disadvantages that buyers have when they know less about a good than the seller does. His prime example was health care. Doctors generally know more about the value of a given medical treatment than patients, who have little ability to determine the quality of the advice they are getting. Doctors, therefore, are in a powerful position. We can recommend care of little or no value because it enhances our incomes, because it’s our habit, or because we genuinely but incorrectly believe in it, and patients will tend to follow our recommendations.”

“Overtesting has also created a new, unanticipated problem: overdiagnosis. This isn’t misdiagnosis—the erroneous diagnosis of a disease. This is the correct diagnosis of a disease that is never going to bother you in your lifetime.”

“H. Gilbert Welch, a Dartmouth Medical School professor, is an expert on overdiagnosis, and in his excellent new book, “Less Medicine, More Health,” he explains the phenomenon this way: 'we’ve assumed, he says, that cancers are all like rabbits that you want to catch before they escape the barnyard pen. But some are more like birds—the most aggressive cancers have already taken flight before you can discover them, which is why some people still die from cancer, despite early detection. And lots are more like turtles. They aren’t going anywhere. Removing them won’t make any difference'.”

“We’ve learned these lessons the hard way. Over the past two decades, we’ve tripled the number of thyroid cancers we detect and remove in the United States, but we haven’t reduced the death rate at all. In South Korea, widespread ultrasound screening has led to a fifteen-fold increase in detection of small thyroid cancers. Thyroid cancer is now the No. 1 cancer diagnosed and treated in that country. But, as Welch points out, the death rate hasn’t dropped one iota there, either. (Meanwhile, the number of people with permanent complications from thyroid surgery has skyrocketed.) It’s all over-diagnosis. We’re just catching turtles.”

“Every cancer has a different ratio of rabbits, turtles, and birds, which makes the story enormously complicated. A recent review concludes that, depending on the organ involved, anywhere from fifteen to seventy-five per cent of cancers found are indolent tumors—turtles—that have stopped growing or are growing too slowly to be life-threatening.”

“We now have a vast and costly health-care industry devoted to finding and responding to turtles. Our ever more sensitive technologies turn up more and more abnormalities—cancers, clogged arteries, damaged-looking knees and backs—that aren’t actually causing problems and never will. And then we doctors try to fix them, even though the result is often more harm than good.”

http://www.newyorker.com/magazine/2015/05/11/overkill-atul-gawande