Last week, I had the pleasure of giving a talk on cancer at the University of Iowa Carver College of Medicine Mini-Medical School, a series of presentations provided to the lay public to introduce them to a topic in medicine. Every time I give a talk to a lay audience, I think back to a wonderful woman I had as a patient when I was doing my oncology training in the 1980s. She was a retired English teacher who took pleasure in gently ribbing me about the words I selected when I spoke with her (once a teacher, always a teacher). I recall one time when I suggested we consider putting her “on trial.” Her response – “Put me on trial? What a strange phrase. I certainly wish getting cancer was against the law! Why do you want to put me on trial?” That lead to an animated conversation about not only that phrase, but how doctors use expressions when talking to each other that are interpreted differently by patients. While I don’t recall which additional specific phrases we discussed back then, that conversation had a long lasting effect on me, and the phrases I use when I speak to patients, families and the public.
It has been a while since I submitted a blog entry, and one of my New Year’s resolutions is that I will get back to posting entries more regularly. I thought I would start with a summary of the past year in the field of cancer in general and the Holden Comprehensive Cancer Center in particular.
Many years ago, while I was doing my research training, I was told by a nationally admired, very senior cancer researcher that cancer therapy with monoclonal antibodies was a “failed hypothesis” and that I would throw my career away if I insisted on working in that field.
Thinking back, this was some of the most helpful advice I ever received – not because I followed his advice (indeed, I did not), but because his advice taught me that even the smartest , most experienced, greatly admired role model can be wrong. It taught me to recognize I will not be as smart as I think I am.
On multiple occasions over the subsequent 25 years, I have listened to colleagues and trainees express a desire to press on despite initial negative results. I have been tempted to say “nice idea, but don’t waste your time since the results so far demonstrate the idea is a failed hypothesis.” However my early experience taught me to be very cautious about such a knee jerk response.
Here are some examples…
When it was first suggested to combine antibody therapy with chemotherapy, I thought it was a crazy idea. We need the immune system to help antibodies work and chemotherapy is known to suppress the immune system. Nevertheless, I agreed to move ahead with such studies. , . Iowa was part of the first studies to look at this approach which we now know can work well in many cancers and are now part of standard therapy.
Many research groups, including my own, have been intrigued by the potential of retargeting killer T lymphocytes, a white blood cell, to kill cancer cells. Initial clinical studies exploring this approach were negative. Now, after 20 years of research, studies based on this concept are finally showing promise including use of bifunctional antibodies and of T cells genetically modified to attack the cancer cells (so-called Chimeric Antigen Receptors or CARs).
Finally, wouldn’t it be fantastic if we could design a virus that would attack cancer cells but not normal cells? As with the other examples outlined above, initial trials exploring such “oncolytic viruses” were discouraging. On the other hand, these studies taught us much about the biology of both cancer and viruses. Investigators persisted, and there is now growing evidence that such treatment may be effective.
Persistence can pay off. Research hypotheses can also fail and not be worth pursuing. How do we know if a failure represents a temporary detour or a true dead end? First, we look at the science on which the proposed approach to treatment is based. Sometimes, the science lags behind the ability to conceive of a practical application, and the science needs to advance before a concept can be applied effectively to cancer treatment. We also look carefully at the results of the unsuccessful clinical studies . While the primary therapeutic end point of such clinical trials may not have been met, there are often hints in the correlative science that speak to how the treatment can be modified and improved. Following these hints can help move the treatment forward.
So, when a young researcher tells me she has decided not to pursue an intriguing idea because a senior advisor said it has been studied already and has already proven to be a failed hypothesis, I advise her to think again. On the other hand, maybe she should not listen to me either, since I know I am not as smart as I think I am.
This spring, we once again had heavy rains in Iowa with rivers and reservoirs approaching capacity, umbrellas in our hands and buckets on the floor to catch water from leaky roofs. The climate certainly seems to be changing, and there is new urgency in developing a master plan to respond to this new reality. Fortunately, this year’s flooding caused less damage than in prior years in part because communities and organizations have started to work together to manage the increased water flow.
The climate for cancer research is also changing dramatically, and this is having a major impact on how we conduct clinical cancer research. We now know that cancers are driven by genetic changes, and cancers that look the same under the microscope can have very different genetic drivers. There is growing evidence that patients benefit from treatments that are tailored to each patient based on the genetic makeup of their cancer. This major leap forward in our understanding of the biology of cancer is taking place at a time when financial support for cancer research is shrinking. Researchers are overflowing with ideas and desperately want to move their research discoveries downstream to where they can help more patients. This requires doing clinical cancer research in new ways, and is where umbrellas and buckets come in.
In an “umbrella trial,” patients with a given type of cancer are assigned a specific treatment arm based on the molecular makeup of their cancer. Umbrella trials have many different arms under the umbrella of a single trial. Patients are assigned to an arm on the trial based on the molecular makeup of their cancer. Umbrella trials allow us to test a variety of targeted drugs at the same time in the patients who are most likely to benefit, i.e. those with cancers that have the specific molecular abnormality targeted by the drug. However, such studies are not easy – their modular structure is quite complex and can lead to various arms being moved in and out of the study as new drugs become available and results from testing of other drugs become clear.
In a “bucket trial” (also called a basket trial), cancers of different types are tested to see if they have a particular molecular abnormality. If they do, the patients with that abnormality are eligible to be treated with a new drug that targets that particular abnormality. The advantage of this approach is that it allows us to test new treatments across cancer types. On the other hand, we often have to test many patients to find the handful that have the abnormality targeted by the new treatment. This is inefficient for the research team that needs to explain the trial, get informed consent, and do the molecular testing on “a bucketful” of patients to find just a few who are eligible for the study. It can be incredibly frustrating for a patient who agrees to be tested, only to be told she is not eligible to be treated on the study because her cancer does not have the appropriate target.
Putting aspects of umbrella trials (exploring different treatments based on the molecular makeup of the cancer) and bucket trials (looking across different cancer types for response to a given targeted therapy) together can result in a “master protocol” such as the NCI MATCH trial that I discussed in a previous blog. In a master protocol, patients with a variety of cancers undergo molecular testing and are assigned a treatment arm based on the makeup of their tumor. Given the hundreds of possible genetic abnormalities that we now know can drive cancers, a truly comprehensive master protocol would have a very large number of arms and would be changing constantly. Each arm would only cover a small fraction of all the patients, yet a large fraction of patients would be eligible for at least one arm. Such a protocol would require unprecedented cooperation by cancer centers across the country if it is to be successful, yet would also accelerate progress.
Our current system for providing administrative and regulatory oversight of clinical trials was designed before umbrellas, buckets and master protocols were being considered. It was designed when most clinical trials involved testing a given treatment in a given cancer type at a single institution. Every clinical trial available at a given institution was only made available to patients after it was reviewed by an institutional committee responsible for assuring the trial was scientifically strong and another committee that assured protection of patient rights.
With the new trial designs, even the largest cancer centers will likely enroll only 1 or 2 patients onto many arms of a study. Putting each arm of each study through the scientific and ethics committees of each institution separately, as we have done for decades, would require a huge and duplicative administrative effort that, in this era of shrinking resources, would prevent such studies from being successful. What is needed is a new approach to administration, oversight and regulation of clinical cancer trials that is more efficient yet still assures safety and protection of patient rights. This requires reassessing the value of long standing policies, and working together more effectively, not only in conducting clinical cancer trials, but also in administering and overseeing them.
It is not an easy transition, but the cancer research community has started working within our own institutions, with each other, with the NCI and with other regulatory agencies to adjust to the new climate and enhance the efficiency of performing molecularly targeted, collaborative, modular clinical cancer trials such as umbrella trials, bucket trials and master protocols. Included in this effort is development of systems that allow for strong central review and oversight of clinical trials so the effort does not need to be duplicated independently at multiple individual institutions.
The climate is indeed changing, and we need to stay ahead of these changes if we are to guide the flood of new discoveries into improved care for our patients.
On a recent trip out of town, I had a bit of a disagreement with my rental car. I wanted to find NPR and listen to the news. First I tried the preset buttons on the radio, which led me to talk show hosts yelling at each other and golden oldies – not what I was looking for. I then tried scanning up and down the dial, where I found mostly Justin Bieber and Katy Perry (I would not have known who the “artists” were without the help of the hyper-kinetic DJ). I eventually gave up. Continue reading
I am not sure how to begin this blog so I will just come out and say it. Last week I shared with you Maddie’s inspirational story – she is an 8-year-old girl who has been struggling with leukemia more than half her life. Her parents had sought out a highly experimental immunotherapy. When I met her just a few weeks ago, it was clear the therapy was having a powerful effect on the leukemia and she was back to being a vibrant 8-year-old girl.
This week, I learned the sad news that Maddie’s leukemia has returned, and that she and her family are considering next steps. The cancer researcher in me is not surprised and sees this as further evidence we must proceed with research at all deliberate speed; my human side is devastated. Our thoughts and prayers go out to Maddie and her family at this difficult time.
Ironically, I learned this news on the same day that our federal government shut down. Indeed, the email telling me of Maddie’s relapse was sandwiched between two emails from colleagues at the National Cancer Institute (NCI) announcing they were being placed on furlough due to the shutdown. What does this mean? In addition to all of the issues you heard about in the news, it means the suspension of new NCI clinical cancer trials and review of new grant proposals. NCI employees are now legally forbidden from contacting cancer researcher collaborators across the country. There is no question in my mind that the progress of cancer research will be slowed.
Last week, I described how Maddie had matured beyond her years. She has a remarkable understanding of how her personal story impacts the bigger picture, yet still enjoys being a young girl. Sadly, she once again has to put those childhood pursuits aside to deal with an incredibly difficult challenge. Meanwhile, our congressional leaders continue to act like poorly-behaved children and focus on themselves, and not on the very real needs of those they serve.
There is an awful symmetry here, and it leads one to think about what would happen with respect to setting priorities if roles were reversed. If our congressional leaders were in Maddie’s shoes (or those of her parents), would that change their approach? I think it would. And how about the other way around? I am not one to quote Bible verses, but Isaiah 11:6 seems particularly poignant to me at this point in time: “and a little child shall lead them.”
If only it were so…