If we can put a man on the moon…

In September 1962, President John F. Kennedy said, “We choose to go to the moon in this decade and do the other things, not because they are easy, but because they are hard.” In December 1971, Richard Nixon said we are “totally committed to provide the funds that are necessary, whatever is necessary, for the conquest of cancer.”

To state the obvious, we have succeeded in going to the moon, but not in conquering cancer. Indeed, just about everyone involved in cancer care or cancer research has been asked the following question, “If we can put a man on the moon, why can’t we cure cancer?”

We have learned a lot since the 1970s about the difference between these two challenges. It turns out that cancer research is not rocket science – it’s much more complicated than that.

Going to the moon – There is only one moon, and by studying it, we know how big it is, where it is, and can predict precisely where it will be at any time in the future.

Curing cancer – Every patient is different and every cancer is different. Each behaves in a unique manner. Cancer is not predictable.

 

Going to the moon – The principles of physics apply, which are consistent and measurable.

Curing cancer – The principles of biology apply, which involve great complexity and are very difficult to describe accurately in mathematical terms.

 

Going to the moon – We made amazing progress in a short period of time.

Curing cancer – Progress has been slower than predicted because cancer is much more complex than we ever imagined.

 

Going to the moon – Each space flight provided the public with clear evidence of progress towards the stated goal on the new and exciting media of the day (live TV). The public remained engaged.

Curing cancer – Progress is complicated to explain to the public and cannot be effectively illustrated in a video clip or explained in a short sound bite. Many in the public do not recognize we are making progress.

 

Going to the moon – We landed men on the moon 7 times and declared victory.

Curing cancer – Even millions of successes are not enough.

However, there are some similarities between going to the moon and conquering cancer.

For both, there is a direct link between societal commitment and progress.

For both, we are in a race. The space race was with the Russians. With cancer, we are racing against time for ourselves, our children, and our grandchildren.

In looking forward at how we can reduce the burden of cancer, I will paraphrase both Kennedy and Nixon. We need to do research and apply those research advances to the prevention, early detection, and treatment of cancer not because it is easy, but because it is hard, and we need to revitalize our commitment to providing the funds that are necessary, whatever is necessary, for the conquest of cancer.

Only that way will we be able to say at some point in the years ahead that, through commitment and persistence, “we put a man on the moon and, although it took a bit longer, we conquered cancer as well.”

Not as smart as I think I am.

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.

Climate change in clinical research – mastering buckets and umbrellas

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.

Exhausted but rejuvenated

We all need to recharge our batteries now and then, although we don’t all like to do it the same way. My wife’s preferred method is to put her feet up on lounge chair and read a good book. For me, something a bit more physical is a preferred choice.   There is nothing quite like going for a jog after a stressful day at work in the cancer center to help me clear my head.

My preference for unwinding on vacation includes being physically active. Indeed, I am doing so this week. For the past eight years I have spent the end of July with a group of friends riding on RAGBRAI. For those of you who are not familiar with this Iowa standard, RAGBRAI is the “Register’s Annual Great Bicycle Ride Across Iowa.”   It is one of the largest recreational bicycle rides in the world. On RAGBRAI, more than 10,000 bicyclists spend a week riding from the west edge of Iowa to the east, with each year taking a different route. RAGBRAI is a rolling folk festival with riders in costumes and the small towns bringing out the town band and selling sports drinks and other high energy foods to bicyclists as they take a break during the ride. You may have heard there is also a beer garden here and there along the way (and no, I am not among the “wilder” RAGBRAI crowd frequenting the beer gardens while riding a bicycle). What I love about a day on RAGBRAI is that it is incredibly different from a day in the cancer center. No discussion of cancer; no deadlines or meetings; everyone is carefree and relaxed. The biggest decision I have to make in the morning is whether I should stop for a breakfast of pancakes or ride two more miles for the French toast. The afternoon dilemma – apple versus cherry pie.

Now, as usual, I thought about turning my time on RAGBRAI into cancer metaphor. How we can help the immune system recover and rejuvenate in order to fight cancer? The relationship between mental and physical well being? Nah … They are both good ideas for future blogs, but not today. After all, I am on vacation …

So, back to the ride. Tuesday’s was the longest ride of the week and included a RAGBRAI tradition called the “century loop” which, for those of us who took this detour, resulted in a ride of about 105 miles.   It was fantastic. I was physically exhausted but mentally rejuvenated.

More specifically, after the long ride, I spent time sitting under a tree with my feet up.   Maybe my wife was on to something after all.

 

 

Isn’t that nice!

We have all heard about “Iowa nice.” Iowans tend to work hard and do an outstanding job, but are modest and do not seek recognition or brag. Well … I will try to retain my “Iowa nice” but will cross the line slightly when it comes to modesty.

An annual rite of passage for academic medical centers is the release of national rankings such as the US News and World Report listing of “Best Hospitals.” Leaders of medical centers acknowledge that the formulas used to calculate these ratings are quite arbitrary and don’t directly measure the quality of the care we deliver.   For example, reputation score plays a major role in the rankings, changes slowly over time and can be influenced by creative approaches to marketing.

Nevertheless, despite these limitations, we look carefully to see how our ratings change from year to year, and think about how we can improve them.

This year, the University of Iowa Holden Comprehensive Cancer Center was ranked No. 27 nationally among cancer hospitals. We had the highest possible scores in survival, number of high-risk Medicare patients, advanced technologies and patient services as well as recognition for being an NCI-designated cancer center and a Nurse Magnet hospital.   This ranking is particularly notable given that the majority of top-ranked cancer hospitals are in major metropolitan areas.   Indeed, we are the only cancer center ranked in the top 50 in a town as small as Iowa City.

It is gratifying to see the hard work, excellence, team spirit and dedication of our faculty, nurses, and staff get recognized at the national level even if by an imperfect mechanism such as the US News rankings.

Not bad for a hospital in the middle of the corn fields!

As we say in Iowa – “Isn’t that nice!”

So it goes …

In Slaughterhouse-Five, the masterpiece by Kurt Vonnegut (from our own Iowa Writer’s Workshop), the protagonist Billy Pilgrim used the phrase, “So it goes,” repeatedly when considering various traumas including the incredible horrors of war.  Much has been written about what Billy, and hence Mr. Vonnegut, really meant by this phrase.   I will not weigh in on this debate, but instead reflect on what this phrase means to me. Continue reading

Standard protocol—individualized

I will always remember this spring as a time of weddings.  First (and foremost!), my daughter’s wedding in Iowa City in late May followed by weddings in June of a cousin in Florida and a nephew in Maryland. I also came upon a number of weddings during my recent visit to Romania, including a wedding procession marching down the main street in a tiny Transylvania town and weddings taking place in the Orthodox and Catholic churches of the beautifully preserved and restored fortress town of Alba Iulia. Continue reading

Yogi Berra and Molecular Oncology

I can think of nothing better than Yogi Berra quotes to organize a brief discussion of how molecular oncology is impacting cancer medicine.

“It’s tough to make predictions, especially about the future.”

When I was growing up in New York, if you had asked me which was more likely – for me to spend my career as a cancer center director in Iowa, or to own a flying car, I most definitely would have predicted the flying car. So much for predicting the future. Continue reading

Culture shock

I am on the road this week.

First, I took a trip to West Palm Beach for a family wedding. On arrival at the airport, and at the wedding, it was apparent there are some small stylistic differences between southern Florida and the Midwest. However, the similarities far exceeded the differences and it would be a stretch to say there is a big cultural difference between the two.

Then, yesterday, I got on a plane and flew over the Atlantic to represent the Association of American Cancer Institutes at a meeting of the Organization of European Cancer Institutes in Cluj-Napoca, Romania. In fact, I am sending this blog from Cluj where I arrived a few hours ago. I spent this afternoon walking around the town to help me deal with jet lag before the meeting starts tonight.   In less than 24 hours, I went from tanned Florida retirees to a dynamic eastern European country where I don’t know the language. Now, that is culture shock! Continue reading

Succeeding together over winning

All of us have thought at one point or another about what we would have done professionally if we had the opportunity to start over and take a path totally different from the one we actually pursued.   For many years when asked this question, I answered that I would have enjoyed being an architect. Designing buildings would have allowed me to use both the scientific and the creative aspects of my brain. I also like the tangible and long-lasting aspects of building something – attributes that also apply to my current career in academic medicine. Continue reading