Topic: Surgery not possible, but still hopeful for the future.
As I sit here today, I find myself more hopeful than I have been in a while about the future possibilites. I am sure it has a lot to do with the fact that my wife is in an ok spot for now (good response to chemo and finally feeling better after IMRT radiation). However, I think my rationale for hope is more than just her current situation. After thinking about it a bit, here is what I came up with:
Word of warning if you read this essay. I am not a doctor nor am I a medical researcher. The following are my views and could very well be biased, skewed, or flat out wrong. I did go from a point of virtually no hope to one of being cautiously hopeful. I believe that having hope is hugely important, so I wanted to write this up in case it helps someone else acquire hope.
My wife was diagnosed on April 1, 2013 with inoperable intrahepatic cholangiocarcinoma (ICC) -- one main 9cm lesion, two medium 4cm lesions and a constellation of smaller lesions all contained in the liver. While not in the field of medicine, I am a researcher by nature and profession, so of course I dove into the medical research with both feet. How depressing. Virtually every research article begins with this type of refrain: ICC is a rare disease with few treatment options and a poor prognosis. Most articles will also mention that surgery is the only curative option. Well, my wife is not a surgery candidate, and probably never will be. Even so, after helping my wife through treatment and continuing the research effort for the last 13 months, I am actually somewhat hopeful. I wanted to write up why I feel this way to help others that might be feeling hopeless.
Why am I hopeful? In a word, TIME.
In my opinion, the only way to beat this disease without surgery is to be around for the treatment breakthrough. Things that improve your odds fall into one of two buckets – they either increase the amount of time you survive, or speed up the process of finding a breakthrough. To me, both are happening.
Increased survival time – Good response to first line therapy
No way to sugarcoat this. One of the biggest needs right now from a patient perspective is a better first line therapy option. Cholangiocarcinoma is usually diagnosed at an advanced stage, and a lot depends on how the patient responds to the initial therapy. Unfortunately, for many patients, first line therapy does not work very well.
If you are not a surgery candidate, then, to me, a key goal for first line therapy is to buy time to get other options on the table. When viewed from this perspective, there has been some tangible progress. For example, suppose you assume you need to survive at least one year to enable other treatment options. As best as I can tell, it was in the early 2000s when gemcitabine therapy was shown to roughly double the one year survival odds compared to best supportive care. Later, in 2010, the landmark ABC 02 study was published and established Gem/Cis as the standard first line treatment. Compared to gemcitabine alone, this study reported that Gem/Cis roughly doubled the one year survival odds again. Other therapies, such as radioembolization and chemoembolization, are being explored as a first line option for locally advanced disease when surgery is not possible. However, I have not seen data on how these options perform in a first line setting.
Thankfully, my wife cleared that initial hurdle and had a good response to first line chemotherapy (Gem/Cis). The extra time provided by this response gives me hope because it both improves her shot at being around for a breakthrough, and also gives us more time to explore additional treatment options.
Increased survival time – New approaches, Clinical Trials and the 10%-15%
One thing you will notice if you look at survival curves for many clinical trials is that there is typically a small percentage, say 10%-15%, that have a pretty good outcome (e.g tumor shrinkage and substantial survival). What’s changing that gives me hope? I think about it this way: suppose there was only one option available, like traditional chemotherapy. If that is it, then you better hope that you are in the responsive 10-15%. Even if there are a lot of different clinical trials available, it may not help much if they all are just different approaches using the same basic mechanism (e.g. traditional chemo)
Things change dramatically if different trials attack the cancer in fundamentally different ways. Maybe your cancer doesn’t respond to traditional chemo, but perhaps your lymphocytes can be trained to attack your cancer (Trial NCT01174121). Or maybe your cancer would benefit from a MET inhibitor (Trial NCT 01285037). You might have a KRAS mutation or could benefit from an Anti-PDL1 agent (Trial NCT01375842). This list of options is growing. To me, this is hugely important. Perhaps you are not super responsive to one, but that doesn’t rule out you being response to a fundamentally different approach. If you could somehow try four different approaches each with a 15% chance of a good response, all of a sudden, your chances of getting a good response go up to almost 50/50! A huge improvement. Moreover, you could be responsive to more than one...even better.
I plan on keeping abreast of all the various clinical trial options. I am looking for trials that both rely on very different mechanisms and have minimal impact on quality of life. Quality of life is a very important consideration in general, but I also think good quality of life is critical to increase the number of treatments one can endure. The idea is if one approach stops working, another is available to quickly shift to. I think this strategy both helps her maximize her chances and helps others by participating in the clinical trial process.
Shorten the time to a break through – Overcoming rare cancer handicaps
First the bad news – compared to common cancers, rare cancers face two massive hurdles. First, drug companies often ignore rare cancers. Obviously, it is hard to make a “blockbuster” drug when total sales are capped in the thousands. Second, even with a new drug to test, the testing process is exponentially harder with rare cancers. Suppose you need a minimum of 200 patients to test your new drug. A breast cancer drug might fill that trial in a matter of weeks. For cholangiocarcinoma, it could literally take five or more YEARS to accrue that many patients. Many trials are cancelled or suspended due to lack of patient accrual. Needless to say, this environment leads to very slow progress.
Well that’s depressing…why is this hopeful? What is so hopeful is that cancers are more and more being grouped by their characteristics (e.g. genetic mutations and aberrant signaling pathways) and less by their place of origin (e.g. bile duct cells). For example, my wife has cholangiocarcinoma (small group), but her cancer may also have a KRAS, IDH1 or IDH2 mutation (big groups). So much of the scientific focus right now is on these mutations and pathways, that I think the odds of research over the next five years helping the typical cholangiocarcinoma patient is much higher than the previous five years. Going forward, I think it will be increasingly important to know what mutations characterize your cancer because this will help guide your treatment. While it is not particularly helpful right now, this is a good reason to try and get a next gen genetic test done on your tumor when possible.
The research process has made significant progress against many cancers, but rare cancers often are left behind. The focus on mutations and pathways that affect a large number of different cancers offers real hope that the next round of research will more broadly help rare and common cancers alike.
There is no denying that cholangiocarcinoma is a very bad cancer to have. Even so, there are reasons to be hopeful. The variety of treatment options available today provides new hope for extended survival. Moreover, the evolution of the clinical trial process gives real hope that new treatments will be far more likely to benefit rare cancers compared historical experience.
If you have other reasons why we should be hopeful, I would very much like to hear them.
All the best,