IN SUPPORT OF RIGHT TO TRY LEGISLATION
In a great editorial piece in the Wall Street Journal on 27 November , Darcy Olsen author of " The Right to Try", out this month from Harper/ Collins, makes the case for support of right to try legislation now passed by 24 states. This legislation simply says that terminally ill patients have a right to try a promising new drug, even if it is not approved by the FDA , as long as it has passed basic safety tests. I liked the editorial  because we had a working version of right to try in operation, approved by the FDA and the Pharmeceutical industry and  operated by the NCI all the way back in 1976. It was called the Group C program. It was a rough slug fest to get it operational, as the FDA never liked it. But the NCI director has the use of the bully pulpit to defend its programs and cancer patients and I used it.  The FDA never liked being out it bright sunshine so they approved it as part of a master plan submitted by NCI for cancer drug development. But it was never codified by the FDA so they took the first opportunity to drop it in  1987 shortly before my departure as NCI Director  in favor of the treatment IND program . The latter was developed to cover drugs for AIDS patients and has never worked for cancer patients who have been denied free access to promising cancer drugs by the FDA ever since. This is all described in detail in my book "The Death of Cancer ", written with Elizabeth DeVita -Raeburn, in a chapter called " The Francis Kelsey syndrome" also out this month from Ferrar Strauss Giroux.
In the Group C program all cancer drugs in development and supported in any way by the NCI were put into three groups A, B and C. A and B were for drugs in early testing called  phase I and II trials. If a drug showed promise in a minimum of two trials in groups A and B the NCI could move it into group C. Once in group C a drug was available for cancer patients who were not in a clinical trial for compassionate use. The determination of the potential benefit for  cancer patients was made by the patient's doctor at the bedside. He or she only had to be registered at the FDA which required filling out a one page form 1573 only once. The only paper requirements was that the physician needed to report any adverse event to the NCI which in turn reported them to the FDA. Notice that all the important decisions were made by active cancer doctors. The decision to go into group C by NCI doctors; the decision to use the drug, by the patient's Oncologist. The FDA claims, as Olsen points out, that patients can still access drugs through their compassionate use program which is pure and utter nonsense because the paper burden on a doctor is oppressive and unworkable. And there are other notable difference between the present compassionate use program and NCI's group C program. The determination of whether a drug should be made available at all is made by the FDA not the NCI and the determination of whether the drug should be used in an individual patient is made by an FDA bureaucrat thousands of miles away not the patient's doctor who is actually at the bedside. And another factor was added to the authority of the FDA. They had to determine that giving out the drug would not be harmful to NCI's clinical trials program. There is no other way to determine this except to  ask the person running the trials in question who invariably protect their turf by saying it would be. This is a straw man used to suppress access to drugs by cancer patients by organizations that should know better including the NCI . I ran the Clincal trials program in the period from 1976 until 1987 and there was no evidence  that making drugs available to patients, many of whom weren't  even candidates for clinical trials, had any negative effect on NCIs trials. The Pharmeceutical industry by the way liked the program and willingly supplied drugs to NCI at no cost . They felt it was good exposure for their programs.
The right to try legislation differs in some ways from the group C program. In right to try a drug has to have completed phase I testing for safety. This is not unreasonable but in some circumstances drugs already show great promise in Phase I trials. The most recent example is the agent brentuximab vedotin , the hottest new treatment for advanced Hodgkin's disease , which was already producing complete remissions in heavily pretreated patients in its phase I trial which was published in the prestigious New England journal of Medicine. The oldest example is the drug vincristine which is part of almost all curative programs for childhood leukemia which was clearly active in the earliest of clinical trials. And drug companies are able to recover the cost of drugs in right to try legislation.
Two more points.  The FDA is panicking over loss of control as a consequence of right to try legislation and is promising to speed up their compassionate use program which is really a tacit admission of the failure of he program . Nothing promising has been forthcoming and none is likely.
 The final point is that the NCI which  should be on the bully pulpit urging passage of the legislation has been silent. So have organizations who purport to be the voice of cancer patients like ASCO ( The American Society of Clincal Oncology ) and even the AACR ( American Association for Cancer Research) and the American Cancer Society all in defense of the integrity of clinical trials based on zero evidence. We need an NCI director who will rise to the occasion and  take the lead again and speak up for cancer patients everywhere.

Getting to the meat of the issue.

I must say I don't blame the public for being annoyed at the announcement  that eating red meat or bacon can increase your risk of getting cancer. Some articles even say you can put these foods in the same category as tobacco. And some medical sites on Facebook are having a field day scaring the public with the new information.
These data come from epidemiological studies that are notoriously difficult to carry out because they rely on people's memory of what they ate or drank years ago. And while some studies do show an association between these foods and cancer it is with one cancer, colon cancer, not all cancers. And to lump  bacon and red meat in with tobacco is misleading and in fact ludicrous and perhaps harmful. If you make a bar graph of different lifestyle factors plotted against the risk of getting cancer the smoking bar would not only be the highest bar it would go through the the roof while the rest would stay on your table !
 If you smoke and eat a lot of red meat and bacon quit smoking and your risk of getting a whole bunch of cancer will decrease dramatically. If instead you stop eating red meat and bacon but keep  smoking you will see very little decrease in your risk of dying of cancer.
This is called the relative risk. While from a public health perspective it is useful to encourage people to eat a healthy diet the advice needs to be put in perspective. People enjoy eating. And if you expect them to respond to advice you need to temper the advice to take enjoyment and relative risk into account.
Here's another  example of why you need to temper your advice. In the early 1980s I was at an international cancer congress in Seattle Washington when an article was published in the New England Journal of Medicine, a prestigious medical journal, by Brian McMann and equally prestigious epidemiologist, showing that drinking a lot of coffee increased the risk of getting pancreas cancer.  The press ran with it and a real panic set in. I was director of the National Cancer Institute then and the Reagan White House called me and asked me what my position was. I said I thought the conclusion was flawed. They asked if I would hold a press conference and say so. It so happens I was asked to go on a morning TV show and talk about it. I walked out on the set with a mug of coffee in my hand. That made the point. No subsequent study ever confirmed the association of coffee with pancreas cancer.  I used to joke with my staff that any  study reporting an association of a lifestyle factor and cancer should be kept in a vault until a second study on the same subject became available to confirm or deny it. That won't happen of course but instead those of us in the medical profession who need to interpret these kinds of results for the public should proceed with more caution.

The FDA Feigns Activism

On March 6^th I picked up the most recent edition of “The Cancer Letter,” a trade newsletter read by many oncologists, and saw a picture of Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research, beaming out at me.  

Pazdur’s smiling face was accompanied by the announcement that, on March 4^th, the FDA had rapidly approved Bristol Myers Squib's drug, Opdivo (nivolumab), citing “a dramatic increase in survival in second-line squamous non-small cell lung cancer.”   

“The Cancer Letter” characterized the approval as activism by the FDA, saying that it was an example of the “extraordinary activist stance” the FDA can take when it sees an advantage in overall survival. They went so far as to say that the FDA, had “sprung into action” when they received the clinical trial data, moving toward approval before the results of the study were even clear to the sponsoring drug company.  

It would have been amusing if it wasn’t so sad.

PD-I inhibitors are a new breed of therapy that inhibit cancer cells’ ability to evade its host’s immune system. Every lung cancer specialist in the country has known that PD-1 inhibitors such as Opdivo are the most important advance in the treatment of advanced non-small cell lung cancer to come along in 40 years. For the last two years, in fact, most oncologists have been seeing data on the effectiveness of these drugs presented at national meetings and widely discussed among investigators.

Some might say defend the FDA by saying that the food and drug laws require that the FDA determine that a new drug is both safe and effective before it is approved for general use. True, in a general sense. But in this case, we know that the two PD-1 inhibitors now in advanced clinical testing, Opdivo (nivolumab) and Keytruda (pembrolizumab) are safe. In fact, the FDA said so itself when they approved both drugs for patients with advanced melanoma. (Though, as usual, they tied doctors’ hands—allowing them to be used only in patients who had failed other therapies and listing all the prior treatments the patients had to have failed before their doctors were allowed to use them).

What are the odds that these drugs, which were deemed safe enough for some patients with advanced cancer, would have proven to be unsafe in patients with advanced lung cancer? The answer: between slim and none. In fact, the data show that they are even effective in patients with poor performance status, i.e. patients who are frail and bedridden, making them ideal for older and unstable lung cancer patients, especially those who have smoked.

But the real irony of the FDA seeing themselves as activists is the failure to approve the drugs for all subtypes of all non-small cell lung cancer, given that the data show them to be universally effective. Only 25% of advanced lung cancer patients have the squamous cell subtype for which the FDA has approved Opdivo. That means the majority of patients are excluded from this advance.

All lung cancer specialists already know the PD-1 inhibitors are far better than any existing drug doublet in use today. If they were approved for all lung cancers today the use of the myriad of doublets of far more toxic drugs would disappear overnight. In the meantime, many patients who might benefit from these drugs are getting old hat treatment. But when the family members and friends of physicians are diagnosed with lung cancer, these physicians find a way to get the new drugs to them using any loophole possible.

The FDA will eventually approve both drugs for all subtypes of advanced lung cancer and even as a first line treatment. They will have no choice. But they will do it in their own good time. Meanwhile, thousands of patients with lung cancer will die without the chance of getting access to these drugs to extend their useful lives. If the FDA really wants to be considered an activist, they should approve these drugs for all lung cancer patients now. 

-Vincent T. DeVita, MD

Worth a Read

Last week two articles related to cancer care caught my eye. Both were well written, and both spoke to problems in the delivery of cancer care in this country. The first, by Len Zwelling, speaks to the decline of dynamic and creative research at MD Anderson (but a problem typical of other institutions). (I found it so interesting that I'll forgive him for spelling my name wrong.)

The second was an Op-Ed by journalist Laurie Becklund called "As I Lay Dying," which appeared in the LA Times February 20th. Becklund, who was dying of stage IV breast cancer when she wrote it, takes on, among other things, the system of cancer care. She's right on a number of counts, but I was particularly struck by a paragraph about the FDA:

The medical establishment tells me I have “failed” a number of therapies. That's not right: The establishment and its therapies have failed me. The system we live in as metastatic breast cancer patients is simply not designed to deal with the cycle we are living and dying in. The estimated 40,000 women (and a few men) who die annually can't wait years for FDA-approved, “gold standard” clinical trials. We're dying now.

I wish more patients realized this and put pressure on the FDA to make drugs available for patients more quickly. Many, like Becklund, who died February 8th, don't have time to waste.  

The New Edition of Cancer: Principles & Practice of Oncology is here

The 10th edition of Cancer: Principles & Practice of Oncology is out. It's the only cancer textbook that is continuously updated online and searchable by a hand held device.

Helping Primary Care Doctors Manage Cancer Patients

In the long term, much of cancer care will be in the hands of primary care doctors. Given that reality, we realized we needed to do a concise, crisp and up to date version of Cancer: Principles and Practices of Oncology for primary care doctors. Our new book--Oncology in Primary Care--comes out May 1, 2015. Dr. Michal Rose of Yale joins us as an editor on this one. I'm biased of course, but I think it turned out well.

Research--The Moving Parts

In the process of going through transformation, the American Cancer Societyonvened a group called Research 3.0 that made recommendations to the ACS Board about how to transform its research programs in the next decade. It is worth looking at Research 3.0 to examine how it will affect two of the moving parts of research programs, the investigators who do the research and the grants or other instruments that support their research.

A good place to start is by defining what we mean by research. How does Clinical Research differ from Basic Research; what is Translational Research, and what do we mean by applied research and applied science? 

Louis Pasteur said there is no such thing as applied research, only research and the application of the results of research. The latter is applied science; the application of what we know to diseases. The failure to distinguish between research and applied science causes much confusion when trying to interpret science budgets and could potentially be a problem in interpreting the recommendations of Research 3.0. 

Research is really a methodology. All good research is characterized by the use of strong inference, a term coined and described in detail by John Platt in 1964 (1). It involves setting up alternative hypotheses, the designing of an experiment or experiments that will exclude one of the hypotheses, developing new hypotheses and repeating the process until only one hypothesis remains standing. 

In other words it involves keeping the facts and throwing away hypotheses!

This is true in the clinic as well as in the laboratory but this is not easy to do.  Many researchers get attached to their hypothesis and design studies to prove it not disprove it. Because of this, the literature is filled with studies defending hypotheses that could have been easily disproved in a properly designed study. 

All good researchers use strong inference to ask fundamental (basic) questions regardless of the size of the particle under study. Science administrators have struggled for decades trying to define the difference between clinical research and basic research but, as you can see, there really is none, methodologically speaking, if both are testing hypotheses using strong inference.

 It is easier to test hypotheses in the lab where experiments can sometimes be set up and completed in days or weeks compared to years for clinical studies.  

But there are some classical examples of fundamental (basic) research in the clinic in Bernard Fischer's studies testing the hypothesis that lymph nodes were not a barrier to metastases in breast cancer but a sign that a tumor had already spread (2) and in the experiments that proved you could cure childhood leukemia and advanced Hodgkin's disease with combination chemotherapy in adults (3, 4). 

    It is also much more difficult to design experiments to exclude a hypothesis in the clinic when the particles are whole humans who can talk back to you.

     When I was Director of NCI's Treatment Division, I reviewed about 1,500 of NCI's clinical protocols looking for those that were using strong inference. Only 5 to 10% of them were actually testing a hypothesis; the rest were applied science. There is nothing wrong with applied sciences as long as it is identified as such. 

    But when good scientists are offered examples of applied science as clinical research they are understandably confused at what passes for research by clinicians.

   Finally, translational research was a term introduced by my successor as NCI Director, Sam Broder. It simply refers to laboratory research that has visible potential applications in the clinic, although the time span from discovery to application is never clear. 

    At the time he coined the phrase, in the early 1990s, it was often difficult to see the clinical application of a study of what might have been an obscure molecule. 

    Translational research has lost much of its meaning today since virtually all laboratory science has visible clinical applications and most grants are categorized as translational research. But translational research is different from applied science because it involves the use of strong inference.

     So what are the major moving parts of Research 3.0? The most important recommendation was to urge the ACS CEO to double the funds devoted to research in the ACS budget over 5 to 7 years. That requires no explanation. It does require that the ACS raise substantially more funds.

     The extramural grant program will be the main beneficiary of any increase in funding and the recommendations of research 3.0 for the extramural research program are shown in Table 1. 

    There are two points to be made from Table 1. 

    The first is that 50% of extramural funds are to be devoted to basic science. Presumably, this means all studies asking fundamental questions , using strong inference, whether they take place in the laboratory or the clinic. 

    

    The second point is the awards in this category will be made only to those in their early careers, under the age of 45. The logic for this is that in order to assure the future of research we need to assure that young scientists are provided the stable support they need to encourage them to stay in the field.     

    But it can be argued that supporting young investigators is really the job of the NIH and NCI as the ACS's research program is too small to affect the nation’s long term needs of young scientists, and NIH and NCI have special programs for young investigators. 

    In addition, other organizations like the American Association for Cancer Research, the American Society of Clinical Oncology (ASCO) and the ASCO Foundation and others have substantial special grant programs for young investigators.

     It can also be argued that the ACS should be focused on discoveries that help us to eradicate cancer. In that case,discovery knows no age barrier and major discoveries have been made at both ends of the age spectrum.  By recommending age discrimination in awarding grants, the ACS could be hindering progress toward its basic goals. 

    Most of the movers and shakers in the cancer field are over the age of 45. With an age cut off they are excluded from access to ACS funds. Removing the age limit does not exclude young investigators from applying and the best of them do very well.

     My favorite example of great research at the nether end of the age spectrum was the discovery that information is transmitted by DNA not proteins which laid the foundation for Watson and Crick’s work on the structure of DNA and the molecular revolution that followed (5, 6).

     It was made by a retired scientist at the Rockefeller University, Oswald Avery, and has often been referred to as the most important discovery that never won a Noble Prize. Linus Pauling won his Noble Prize for work he did in his 50s. And he was the close runner up to Watson and Crick for the discovery of the structure of DNA or he might have been the first person to win three individual Nobel Prizes. He continued working productively in the lab into his 80's. 

    E. Donnall Thomas and Joseph E. Murray won a Nobel Prize for the definitive and fundamental clinical research they did on organ transplantation while  in their 50s and 60s.

     True in mathematics, if you haven't done anything major by the time you are 40 you probably never will. Not so in biology. Biology is very complex and it takes time to develop the insight and wisdom to solve biological problems. Leo Szilard the famous nuclear physicist, who gave us the nuclear chain reaction, decided at age 47 to become a biologist. 

    After that, he quipped, "I never had a decent bath". While a physicist, Szilard thought through the mathematics of a problem while soaking in a bathtub and could solve complex problems in one bath.

     But when he became a biologist, he said, he often had to interrupt his bath to go look things up! 

   Senior physician-scientists do much of the best work in clinical investigations as was the case with Donnall Thomas and his work on allogenic marrow transplantation. They need years of experience to marshal the resources to design and carry out novel clinical experiments that use strong inference.

     The remaining half of funds, as shown in Table 1, will be in support of grants in response to RFAs that will attempt to align our supported research with ACS mission critical questions. But notice that half of those funds will go to mission critical questions in "applied research" or, strictly speaking, applied science. These monies will not support fundamental research, the lifeblood of discovery. 

    In this category of applied science no age restriction will apply. Finally, the other half of funds allocated in response to RFAs will go to support in areas designated as mission critical but these funds will also be restricted to young investigators receiving research scholar awards. 

    All in all, 75% of ACS extramural research funds will be allocated to young investigators. The 25% for which scientists of any age are eligible would be funds devoted to the application of the results of research, or applied science, not discovery. 

    

    Much of research today is called “Big Science” because addressing major issues often requires millions of dollars typically not provided in small research grants like research scholar awards provided by the ACS. The type of support instrument to foster discovery has been a subject of heated debate for years. At the NIH the preferred grant instrument is called the RO-1. The RO-1 grant has supported investigator-initiated research, ideas springing from the fertile mind of a single scientist, and is typically a grant to support a small laboratory run by a single investigator. 

    ACS research scholar awards are similar to RO-1 grants.  Research 3.0 recommended the ACS reexamine the use of large program project grants to  accommodate the collaborative nature of science these days. 

    These grants would support teams of scientists each doing a part of a project focusing on one area, or a specific tumor. These kinds of grants are large and expensive and their resurrection will depend on the ability of the ACS to raise the funds to support them or require a reduction in the support for research scholar grants.

     There is often conflict between program directors who want to see the science of their programs advance quickly, and need a more structured approach and those who feel that investigator initiated research remains the future of science. 

     This is not a new issue. Years ago, when the author was Director of the NCI and the National Cancer Program, the institute faced criticism for syphoning monies away from RO-1 grants into other instruments to support research. The other instruments were Program Project grants (PO-1), of the type recommended by the Research 3.0 group, and even research contracts, an instrument generally disliked at the NIH and research universities because it implies external direction of the scientist doing the work.

    To address this question we designed a special study (7). The NCI assembled a panel of elite scientists who were experienced in both laboratory and clinical sciences and asked only that they meet and deliberate to identify what they thought were the ten to fifteen most important advances in cancer science and medicine in the preceding 20 years. 

    After several weeks of in person and phone meetings, they identified 13 different discoveries. We then thanked them for their work and disbanded the committee and hired an external contractor to work backwards from each discovery, and the papers they produced in the scientific literature, to the funding instrument that supported the initial work. As a measure of the quality of the selected topics, scientists in six of the thirteen areas selected have since gone on to win a Nobel Prize for their work. Since at the time ACS was the source of support for only 4.3% of the identified work, only NCI funding instruments were studied.

     The results were surprising. No single grant mechanism dominated. Many different mechanisms supported the traced work. This is shown in Figure 1. It shows the percent of NCI supported trace papers by funding mechanism and type of advance. For studies considered laboratory based, three mechanisms dominated; the RO-1 grant, the NCI Intramural Program and the surprising one, the research contract. But even the P-30 grant, which is the cancer center support grant, through its pilot project grant mechanism, supported the initial work of one investigator who went on to win a Nobel Prize. Only the R-10 grant, which supported the clinical trials program, did not, by definition, play a role in laboratory based studies. 

    For the clinical advances, the dominant grant was the program project grant, the P-01, followed by the R-10, the P-30 and NCI intramural program and only then the RO-1 grant which has not been a support instrument that has worked well for clinical investigations. 

    Finally, fundamental advances in epidemiology were most often supported by research contracts with equal but lesser support coming from PO-1 and RO-1 grants and even cancer center core grants.

     Actually this was a data rich study and is presented here in its most simple form to illustrate the central message that research flourishes when there are multiplicities of ways of supporting it. This is due to the fact that different kinds of projects require different types of support to carry them out at different times in their evolution. One shoe doesn’t fit all. This is especially true in the era of big science.

    The most surprising finding was how often the research contract, often considered an inferior instrument, played an important role in the identified projects. This may be due to the tight focus and flexibility contract support provided to investigators that allowed research projects to move forward more rapidly. 

    These findings highlight the importance of the recommendation that the ACS re explore different grant mechanisms to match the needs of modern research.

   There is another important point about larger project grants. While more senior scientists  generally direct them, because they have the experience to coordinate complex projects, they often include support for young scientists as part of the project. This important means of support is often overlooked and needs to be considered one of the other ways to support young scientists in the age of modern science. 

    The Research 3.0 recommendation that 25% of funds go to support mission critical areas in applied science, with no age restriction, is important but needs clarification of the definition of applied research to be sure it includes projects that support fundamental research with clinical application, or translational research, not just applied science.

    Everything we do that works was developed through research.

 As volunteers for the ACS we need to be reminded of this when the temptation is to shy away from research support in favor of programs to provide access to care.

    As sophisticated as cancer care has become it is still what Louis Thomas referred to as “half way technology” (8). In this sense, cancer is unique as a discipline. Other fields are much more settled in their ways, able to focus on one organ or a small group of disorders affecting one organ, not the hundreds of entities affecting every organ in the body . The cancer field is unsettled and is likely to be that way for some time. 

     While the ACS spends about fifteen percent of its budget on research only about ten percent is devoted to its most visible component the extramural research grants. Yet the majority of donors think their donations are going to support research. 

    There could be a better balance of resources between what we know works and the allocation of resources to research programs that can deliver the next generation of advances.

    Research 3.0, in its totality, represents the beginning of a major new thrust for ACS in the area of research support. If the society can double the funds in the research program in the next 5 to 7 years, and broaden the ways it supports research to match the extraordinary pace and opportunities of modern research, it will play an increasingly important role in unraveling the mysteries of cancer and fulfill our mission to create more birthdays, and meet the expectations of our donors and volunteers.

    If we want to finish the fight we need to devote more money to research and fund the movers and shakers who are doing the cutting edge research in the field.

References

1) Platt JR. Science, Strong Inference -- Proper Scientific Method (The New Baconians). Science Magazine 1964;146(3642)

(2) Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233-41.

(3) Frei E III, Karon M, Levin RH, et al. The effectiveness of combinations of antileukemic agents in inducing and maintaining remission in children with acute leukemia. Blood 1965;26:642-56.

(4) DeVita VT Jr., Serpick AA, Carbone PP. Combination chemotherapy in the treatment of advanced Hodgkin’s disease. Ann Intern Med 1970;73:881-95.

(5) Avery OT, Macleod CM, McCarty M. Studies of the chemical nature of the substance inducing transformation of pneumococcal types: induction of transformation by a desoxyribonucleic acid fraction isolated from pneumococcus type III. J Exp Med 1944;79:137-58.

(6) Watson JD. The Double Helix – A Personal Account of the Discovery of the Structure of DNA. 1968.

(7) An Assessment of Factors affecting Critical Cancer Research Findings; NIH Publication No. 90-567, May 1990.

(8) Thomas, L. The Lives of a Cell: Notes of a Biology Watcher, 1974, Viking Press.

My Induction as President of the American Cancer Society

On November 15, I had the honor of becoming President of the American Cancer Society in its 100th anniversary year.

My induction took place during the Society's Nationwide Volunteer and Staff Leadership Summit in Atlanta. Gary M. Reedy, worldwide vice president of government affairs and policy at Johnson & Johnson and an active Society volunteer for twelve years, was installed as chair of the Board of Directors during the same ceremony. We also added eleven new officers to the board: Pamela K. Meyerhoffer, F.A.H.P., of Litchfield Park, Arizona, chair-elect; Tim E. Byers, M.D., M.P.H., of Arvada, Colorado, president-elect; Robert E. Youle, of Evergreen, Colorado, vice chair; Douglas K. Kelsey, M.D., Ph.D., F.A.A.P., of Zionsville, Indiana, first vice president; Enrique Hernandez, M.D. of Penn Valley, Pennsylvania, second vice president; Daniel P. Heist, C.P.A., of State College, Pennsylvania, treasurer; Robert R. Kugler, Esq. of Haddonfield, New Jersey, secretary; W. Phil Evans, M.D., F.A.C.R., of Dallas, Texas, immediate past president; and Cynthia M. LeBlanc, Ed.D., of Richmond, California.
 
I'm sure you'll be hearing a lot more about my work with Gary, the board, and the ACS over the course of the next year.

Oh, and the mystery man in the picture is my brother, Ernie, who flew in for the occasion.

UK Citizens denied Ipilimumab

"Not so NICE" has done it again. On October 14, NICE, the UK's National Institute of Clinical Excellence, announced that it will not approve the use of Yervoy (ipilimumab), for the treatment of unresectable stage III and IV melanoma, despite a randomized trial showing improvement in survival in a situation where there is no effective treatment.

NICE used it's usual excuse: "It is not cost effective."

Almost twice as many patients treated with Yervoy are alive at one year. But, in a news release, NICE chief executive Andrew Dillon criticized the results of the study, saying that Yervoy (ipilimumab) had not been compared to the drugs currently used to treat stage III or IV melanoma.

In U.K. practice, like the rest of the world, this is carboplatin-based chemotherapy, dacarbazine, or supportive care. Will everyone who has seen a good response to the above treatment please raise their hands? I haven't in years, and neither has anyone else.

Where do a bunch of inexperienced bureaucrats get off telling the world's experts how to treat their patients?

Ipilimumab has already been approved by the US FDA and EMA. Very exciting things are happening in melanoma treatment these days and if you have the disease, you want to have the chance to be around to benefit from recent advances. Yervoy (ipilimumab) is one of them.

I guess Britons with advanced melanoma will have to watch from afar. Do they understand that they're being denied the right to live?

The National Cancer Institute's Broken Clinical Trials Program and The New York Times

There was an editorial in The New York Times last week on a report by the Institute of Medicine on the NCI's clinical trials program and its difficulties. The editorial made the point that the clinical trials effort is at the heart of transferring technology to cancer patients, and that it needs fixing.

The IOM report and the editorial missed the major problem, however. So did the letters to the editor on Sunday 2 May from Drs Doug Blayney and Alan Lichter, on behalf of the American Sociey of Clinical Oncology, and from Dr  Bruce Chabner, Clincal Director at Massachusetts General Hospital Cancer Center in Boston.

Blayney and Lichter extoll the virtues of the clinical cooperative groups and claim that the problem is money. They are underfunded, they say. True. Chabner points out that the  NCI's cooperative group program is no longer the main instrument for developing new treatments anyhow. Also true. (In fact they never were. But that's another story.)

But everybody missed the main source of the problem: over regulation.

Apparently this is too much of a lightning rod for people to discuss in public. Over regulation, in the name of patient safety, affects both cooperative group and industry studies. In the name of protecting patients from harm they stifle new developments and instead "protect" patients from access to new treatments.

I refer the reader to an editorial I wrote on this subject in 2009 for Nature Reviews Clinical Oncology and reprinted on this blog shortly thereafter. Pumping money into the archaic mechanisms of doing clinical trials in NCI's cooperative groups won't do an ounce of good if the structural problems aren't fixed first.

A Possible Breakthrough: Personalized Treatment for Hodgkin's Disease

My friend and colleague, Jose Costa, and I recently had an opportunity to write an editorial about  an exciting paper by Steidl et al.  published in The New England Journal of Medicine on March 11, 2010. I thought it would be worthwhile reprinting some of our commentary here because I think the data may be what we've been looking for when it comes to changing the direction of the treatment of Hodgkin's disease. 

The data provided by Steidl and his colleagues, in fact, offer the breakthrough we have been looking for to select patients with a particularly poor prognosis, regardless of stage, for more-aggressive treatment and bring more logic to the treatment of this very curable malignancy.

Steidl and his co-authors discovered a gene signature of tumor associated macrophages and monocytes in patients with Hodgkin’s disease that correlated with outcome. Remarkably, they were able to validate the correlation in an independent cohort of patients using CD 68—an immunohistochemical marker of normal macrophages. 

  
The correlation of CD 68 positive macrophages with outcome was striking. All patients with limited disease, minimally positive for CD 68, were alive and free of disease at the time of the report. The association of CD 68 positivity and disease specific mortality rates was strong in all subsets analyzed. In advanced disease the correlation between macrophage number and progression-free survival is significant.

This study provides a rationale for the use of molecular tools when effective treatments are available but we cannot prospectively separate those who will be cured from current treatment from those who will not respond. 

Hodgkin’s disease is a good example of this type of situation. For almost 40 years now, early stage disease has been curable by radiotherapy, and combination chemotherapy can cure both early and advanced-stage disease. Despite an overall cure rate of around 80%, treatment has stagnated in the past two decades because of the absence of precise markers that can predict response to therapy. As a result of this situation most patients, especially those in early stages of disease, are over treated— they receive radiotherapy and combination chemotherapy. As a consequence, long term toxicity from treatment is significant. 

In some studies where young women have received both chemotherapy and radiotherapy, the incidence of beast cancer reaches almost 30% at 15 years after treatment. Almost all patients with classic Hodgkin disease will go into remission with initial treatment but about 30% of patients with advanced disease and almost 15% of those with early stages of disease will also relapse. Early relapses in patients with both advanced and localized disease treated with chemotherapy defines a drug resistance subset of Hodgkin’s lymphoma. This group carries a very poor prognosis through all subsequent treatment approaches including high-dose treatment with stem cell support.

It is of considerable interest that early relapse from complete remission carries the same poor prognosis in all tumor types where remission is possible, suggesting a common mechanism of resistance across tumor types. If at the time of diagnosis we could identify the small subset of Hodgkin patients who are destined to fail to respond to chemotherapy, most patients could be spared the use of a combination of modalities as initial treatment, especially radiotherapy, that is associated with long-term toxicity.    

The Reed–Sternberg (R-S) cell is unique amongst lymphoma cells in that a number of important signaling pathways have been shown to be constitutively activated, including the JAK-STAT, receptor tyrosine kinases, NF-kappa B and other pathways^. The R-S cell also secretes numerous cytokines, including granulocyte-macrophage colony-stimulating factor, which may be responsible for the assembly of inflammatory cells in involved lymph nodes. It has been termed the master regulator of the surrounding inflammatory response.

Almost all tumors types are invaded by macrophages and it was once thought that this invasion represented a host immunological response to the tumor. However, most evidence now links tumor-associated macrophages (TAM) with a poor prognosis, as demonstrated in the study by Steidl and his colleagues. Termed ‘tropic macrophages,’ TAMs bear a close resemblance in function to embryonic macrophages associated with cell migration during development.These macrophages have been shown to mediate blood vessel formation by regulating the angiogenic switch through secretion of VEGF and hypoxia inducing factor.

Migration of macrophages to areas of the tumor seems to be a late event in Hodgkin disease. It is difficult to explain the impact of trophic macrophages on response to treatment unless at some point in the evolution of the disease, a critical pathway to apoptosis is crippled in the R-S cell and this is associated with the secretion of a cytokine that leads to macrophage infiltration of the tumor. Such an event could inhibit cell death in response to cytotoxic treatments. 

Rationing Health Care is Bad for Cancer Patients

       The current bill before  the house and Senate does a disservice  for cancer patients. It is not correct to say,  " it's true that some people are covered well, but many are not" as I have heard said by people who should know better. It's more correct to say that ,"most Americans  are covered well in the current system." This is especially true of cancer patients. So be careful what you do to change it.
      Cancer patients suffer most when they try to change jobs and are denied health care in a new job because of a preexisting  condition or when the amount they can spend on health care is capped. Like most Americans, they are also concerned about cost of insurance as well.

      In prior postings I exposed the numbers game used by those who support this bill for what it was, a bogus use of numbers to scare the American people into reform they don't need and don't want. There are not 47 million Americans uninsured. Even President Obama has begun to use a lower figure, 30 million,  a little embarrassed , I think , to be caught  using a number no one bothered to check ( this is still an overestimate). The American Cancer Society should feel some embarrassment for doing the same thing.

     But what is as clear as can be is that there is no way the current House and Senate proposal can stay within budget without rationing care. And people I know close to the administration say to me " get real, Vince, rationing is coming". They barely hide this although they don't trumpet it for fear of scaring more people away. They do admit to the need to cut billions from Medicare though.
     The preferred method to decide what to ration is to use "Comparative Effectiveness Research"(CER) to decide what should be approved. A billion dollars has been allocated in the bill for this. The best way to characterize CER is to say that it compares yesterday's therapy with that of the  day before yesterday. It is always behind the curve. The newest approaches need not apply. Cancer patients always get the short end of the stick when care is rationed.
      Look at the UK's National Institute of Clinical Excellence ,(acronym ,NICE -British doctors refer to it as "not so nice"). Their decision to deny coverage for the use of the drug Erbitux in patients with head and neck cancer was one example of  a feckless disregard for cancer patients. There are more. Studies have shown an enormous, statistically significant, difference in survival for those who are irradiated with Erbitux compared with those who don't receive it. Yet they denied coverage.  They actually don't even question the data, they just say it is not cost effective to use it. In other words if you have the misfortune of having head and neck cancer in the UK, you are not worth saving.
      This is the system the bill tries to emulate. It includes commissions to determine standard of care ( in the cancer field, " standard of care" is a moving target ) and authorities to the secretary of HHS that would allow her to limit the use of new technology even without  CER, as NICE did in the UK with Erbitux. The new drug from Plexicon, to which every patient with metastatic melanoma should have access, wouldn't even be considered for CER.
      They know they will need to ration care to pay for this version of health care reform. At the most exciting time in the history of cancer research, when new clinical advances are being made every day in the cancer field these provisions would  stop clinical innovation in its tracks.

      What is needed for the cancer patient is a stepwise approach that preserves the best of the current system and provides more security . Like most people I could write a bill in  ten pages to do this, not the  2,700 pages in the current bill.
      Prevent denial of coverage for a preexisting conditions, remove caps on the amount of coverage and allow insurance to be purchased across state lines. This would do it for cancer patients and save hundreds of millions of dollars as well.
       It's the many mandates included in some state's policies that drive up cost. Purchasing across state lines would allow more people to buy less expensive policies that suit their purposes. This might mean giving up some of our precious  mandates but  isn't it is better to cover more cancer patients well, than force policies on them with too many mandates that are too expensive to buy? 

      Frankly I don't see any organizations purported to be speaking for the interests of cancer patients telling the congress the specifics of what they need and, most especially ,what they don't want. We need the three things mentioned above and we do not want  a system that will require rationing of care .

     Oh , and by the way, the Congressional Budget Office estimates the new bill would still leave 10 to 19 million people uninsured , which is more than are truly uninsured now.

What happened to the merit sytem in NIH peer review?

There was an article in the New York Times on 22 September by Gardner Harris entitled “Debate flaring over Grants research”.It was based on a recently released report by the GAO on how NIH manages its grant program.

The essence of the NYTs articcle was whether or not NIH grants administrators are right to reach down to “make exceptions “to fund grants with worse scores, to support new young investigators. They say the average age of investigators has risen from 35 in 1980 to 41today, so such steps are necessary. The American Cancer Society goes even further. Anyone over the age of 45 need not apply.

 What happened to the merit system? If your goal is to find new knowledge that leads to the eradication of disease shouldn’t we be funding the best and the brightest whatever their age?

Harris says “ There has been a growing chorus of complaints over the years that the agency's scientific review process is deficient-that is fails to finance high risk research; that projects must effectively be half done before financing is approved; that cliques control the process; and that reviewers are rarely the field’s leading lights”.

Anyone involved in the NIH grant system knows all these complaints are true. I speak from experience; I ran the largest chunk of that grant program at the NCI for 15 years.

The essence of the problem is that universities are addicted to Ro-1 grants. The grant system has become an entitlement program. Without a Ro-1 grant it is difficult for an investigator to attain tenure. What has surprised me, even shocked me, and is that what an investigator does with those grants is often secondary to the fact that they got them. Supporting high-risk research is not the major goal.
The grant peer review process has become the major arbiter of tenure. And incumbents do have an unfair advantage. Peer review committees, each made up of grantees, give the edge to established investigators like themselves. And, scientists will always admit to other scientists, (but not in public) that they don’t submit their best and newest ideas in a grant but ideas that have some data to support them- . It’s a bit of grantsmanship.

Left to their own devices, young investigators do well on their own. Their ideas are often fresh and, in a purely merit system, they can out compete an incumbent. But the way the system is now constructed they are at a disadvantage but it is a disadvantage of NIH’s own making.

The NIH distorts the system even further. It decries “targeted research” but it regularly influences the research process by issuing Request for Applications in specific (targeted) areas with set aside funds. The areas selected are what the Congress or some NIH staffer, or a board of advisors, thinks is the best way to spend grants monies. I have watched young investigators change their research interest not because they thought an RFA identified an interesting area but because they needed to follow pools of money to get a grant. So much for NIH's storied primacy of “investigator initiated research”.

And more gamesmanship. To keep Congress anxious about how many grants are funded each year NIH artificially keeps the percentage of approved grants funded very low. NIH scores grants on a system of 1 to 5 with one being the best and 5 the worst score. A grant can also be disapproved. Few ever are. Many are , however, given scores of 3, 4 or 5 that indicate they shouldn’t be funded even if the investigator is young and money is available. Or expressed another way, no matter how much money we had, we could find better ways of spending it than funding grants with bad scores. Instead of funding only 21 % of all approved applications, many of which shouldn't be funded,  we are more often funding 40 to 50 % of the good applications. Not too bad really. Reaching down could get you into bad territory.
It would be interesting if data were available on the age distribution of the PI's of grants that score better than 2 compared to those that score worse than 2.

It is in the best interests of both universities and the NIH to leave the system as is. But, NIH has so distorted the peer review process that it is faced with dilemmas like funding young investigators just because they are young not because of the merit of their ideas. The grant system has become an end in itself instead of a means to an end.

A Churchill quote about Democracy is often paraphrased to defend the current system as “the worst system ever invented except for every other system”. This may be true for democracy but not the NIH peer review system.

MORE ON THE NUMBER UNINSURED IN THE US

There was an exchange on the floor  of the house chamber between the President and Congressman Joe Wilson last night that bears on the figure of the number of people who are uninsured in this country.
The data used comes from the US census bureau and is 47 million.  I used the 47 million  figure to point out the various groups that make up this number using the same census bureau data. The 47 million figure includes 10 million people who , according to the Bureau , are " not American citizens".
Last night the  President vehemently said that his plan would not include the funding of health insurance for illegal alliens.
The President's speech should now automatically  lead everyone to reduce the figure of those without insurance  to 37 million..  Will it? I doubt it since it would tend to  reduce the urgency  to take down our entire health system for a mere 37 million uninsured, made up of four additional groups whose probelms can be solved by simple legislation. Actually , this morning he actually increased it!
As I said in my recent footnote to that blog, when it was reposted, I use these figures as a way to  judge whether any speaker actually knows what he or she is talking about vis a vis the health care issue..
So far it is slim pickings and it doesn't include the President or his advisors..

Note: I worte the following post in 2007 using US census figures for that year but it is relavent today. I have found that anyone who uses the "47 million are uninsured "argument  is usually as wrong about everything else the say about the health care system so I have decided to re  post this.
VTD


 I am concerned about the direction of the current debate on the reform of our health care system. Most proposals for reform are based on two premises.

The first, is that our health care system is overrated and not equal to some that use a different model for health care , like the single payer systems of the United Kingdom and other European countries.
The second is that 47 million Americans are "uninsured".
Neither , in my view, is correct. Both come from the unfortunate tendency to tear something down when proposing something new. Afterall ,who will take a proposal to fix something seriously unless the something is totally broken.
It is the second premise I want to address here because the phrases "47 million Americans are uninsured", or " without insurance whatsoever" are used as if this was one homogeneous group to show that the american health care system is broken.
So , let's look at the makeup of the 47 million figure dervied from the US Census Bureau figures.
1. 27 % , or roughly 12.7 million people, are uninsured for only a part of the year in which they are counted but are ultimately insured. This is an issue or portability of health insurance. This group will need plan A to reduce their risk of becoming ill while not covered by insurance . But are they really " uninsured" in the way the term is usually used?
2. Roughly 10.3 million of the 47 million are listed as " not American citizens". They require Plan B which surely has more to do with immigration reform than reform of the health care system. Most proposals use the 47 million uninsujred total but ignore the fact that a substantial part of this group are illegal aliens.
3. The third group is made up of roughly 9 million people, half of which make between 50 and 75 thousand dollars a year and the other half more than 75 thousand dollars a year. Many of them are healthy young people who can afford insurance but do not wish, for various reasons, to buy it. This group, if they must be covered, would require a plan that required everyone to buy health insurance, say, Plan C.
4. In the 4th group, there are roughly 8 milion people of all ages, adults and children alike, who are actually eligible for health insurance under a variety of existing plans but don't take advantage of them , again, for a variety of reasons, sometimes out of ignorance. Surely we can solve the problems of educating people about the existence of these plans using Plan D.
That leaves the 5th group, roughly about 7 million people, who might be called the " hard core uninsured" or "without insurance whatsoever", certainly a tragedy for a country as rich as ours . This group will require Plan E.
But the 47 million uninsured figure is quoted as if all of them are hard core uninsured which is factually incorrect .
It is important , it seems to me, to examine the issues related to these groups separately, and to hear specifics about plans A through E so we do not apply " the general solution for the specific problem" and do more harm than good to the finest health care system in the world..

Speaking of New Orleans

There was a story today in the New York Times about how this magnificent city is clawing its way back trying  make itself better than it was before hurricane  Katrina and  with some success.
It reminded me of  a bad decision the leadership of the American Society of Clinical Oncology ( ASCO) made to  drop New Orleans from it's list of meeting sites.
When someone commented that New Orleans would no longer accommodate a meeting the size of ASCO, I checked with a colleague of mine in New Orleans and was assured it wasn't true. The convention center , hotels and New Orleans outstanding  eateries are well able to handle the meeting.


I was told by ASCO's  EVP Alan Lister, that it was primarily a financial decision . ASCO can make more money from the exhibits at the Chicago convention center than at New Orleans because of the way it's configured. But it turns out New Orleans is not suffering from discrimination .  ASCO is gong to be in  Chicago in perpetuity despite  good facilities at other cities as well.

Now don't get me wrong, I like Chicago-just not every year. Not to mention that ASCO could do it's part  by helping the economy of New Orleans.

I told the ASCO leaders that I thought if the ASCO members were polled  they would probably  have voted for  variety over Chicago in perpetuity.

Annoyance was obvious. I was told it was a board decision to make. As a member I disagree.
I was at the founding meeting of ASCO. The society was founded for the benefit of its members, and had as it's primary role  the dissemination of information, not to become a bank.
I don't suppose the annual budget to run  the society of 90 million dollars had anything to do with  this?

The Slippery slope

I read with great interest the story in the 30 August Sunday Magazine section of the New York Times  on the  tragedy at Memorial Hospital in New Orleans in the days following hurricane Katrina.
If the story is accurate , patients who would have been difficult to move or who had signed a " Do not Resuscitate Order" ( DNR) were euthanized by lethal injections on a grand scale.
The doctors involved justified it by saying the police told them if they were not out by 5 PM on that last day they would be left behind . And they wouldn't have survived anyhow.
There were clearly patients who were conscious and not ready to die  and those who had signed DNR orders as a statement, not because they were terminal.
Now the surgeon who administered the lethal doses of drugs is campaigning for laws that would exempt doctors from liability if they did these things under emergency conditions.
And, of course, the doctors were not indicted  even though euthanasia is illegal.  New Orleans politicians, it appears , had decided they had had enough bad  exposure.
I mention  this because it is an example of what can go wrong if you give doctors the right to judge who should live and who should die. I am a cancer doctor and know physicians who believe that patients who have metastatic cancer should be left to die anyhow, with dignity of course, but early. My worst nightmare has always been to wake up from a cancer operation and find one of these guys looking down on me. I would not have wanted to be a cancer patient at that  hospital after Katrina.
Giving doctors that power is a first step down a slippery slope, especially if we end up with a government run health care system and rationing.

Jim Watson's editorial in the NYTs

I read Jim Watson's editorial in the New York Times   a few weeks ago about the war on cancer , and actually agree with his thoughts about our ability now to design smart drugs.
This vision is better than the one he had  that saw cancer cured by Judah Folkman 's antiangiogenesis factors "in two years," 8 years ago, a prediction he repeated to no avail two years later at a meeting in Aspen. But clinical cancer is not Jim's strong suit.
Everything else was  wrong , as well , especially about how the money allotted to the war on cancer was spent.
He was also wrong about  why he was dropped from the Presidentially appointed National Cancer Advisory Board (NCAB). I was there and watched his interaction with Cancer Panel Chair, Benno Schmidt, who attended every board meeting.
 Jim expressed nothing but contempt for the new war on cancer  and the NCAB and showed it by coming to the board meeting with the New York Times , putting his feet up on the table , reading the paper and ignoring what was going on. When somebody said something about a program he  didn't like he would lower the paper and spit out an expletive. " This is a pile of  s** " was his favorite.
He made the mistake one day of saying that about a program and forgetting he was a major beneficiary .  Benno , in a way only the eloquent Benno Schmidt could do, pointed this out. Since this was a public meeting, it made the news. Jim was quiet for the next few board meetings
The President's Cancer  Panel had oversight function for the NCI and the NCAB, and Schmidt thought his behavior  was rude and non contributory  and was  hurting the program . He  asked for his removal  two years into a six year term and the White House complied.
 In truth , while I suppose I may have missed it somewhere, I never heard Watson  utter a single positive suggestion about  anything  to do with the National Cancer Program.
His constructive criticism of the NCI  that led to his removal , he said in his editorial ,was to put all the money into basic research but "instead" he said, " they went clinical". 
Eighty five percent of the money did go onto basic research. He wasn't paying attention.
The remaining 15 % is responsible for the declining national mortality rates from cancer we have been witnessing since  1990, something else he may have  missed.
My guess is ,the hundreds of thousands of people whose lives were saved would agree that Benno  Schmidt did the right thing.
But hey, 1 out of 3  is considered good in some sports.

On the Struggles of Cancer Centers
Vincent T. DeVita Jr. and Elizabeth DeVita Raeburn
My daughter, Elizabeth, and I are writing a book about the War on Cancer. So,I’ve been doing a lot of reflecting on how things have played out since the Cancer Act was passed in 1971. Cancer Centers were a major theme of the Cancer Act.
Before it was passed, we had three freestanding cancer centers. Now we have 63—the vast majority “matrix centers,” meaning they are integrated within the structure of university medical schools and hospitals. The matrix set-up helped us get new cancer centers up and running across the country much faster, and at less cost than building new, free-standing ones.
The downside, however, is that, historically, “matrix” centers have often run afoul of the departmental structure of medical schools. They are often centers in name only. More energy is often expended over turf struggles between the departments of medicine and cancer centers over the operation of the sections of Medical Oncology than over innovations in cancer care. This is a recurring theme that has dogged NCI cancer centers since their inception in 1972.
Was there a better model? Possibly. Columbia College of Physicians and Surgeons (C P&S) had the first University based freestanding cancer hospital. But even it was dogged by some of the problems that affect the matrix model.
In November of 2007, while researching the upcoming book, Elizabeth and I interviewed Dr. Alfred Gellhorn the first Director of the Francis Delafield Cancer Hospital.
Gellhorn was trained as a general surgeon but re trained himself in Internal Medicine. When we interviewed Dr. Gellhorn, he was involved in his fourth successful career since leaving the Delafield.
Here’s an excerpt of our conversation:
“Dr. Gellhorn how did the Delafield get started?”
“It started in 1952. A CP&S breast surgeon by the name of Christian Hagenson persuaded the city to build a cancer hospital. Hagenson could never find anybody in Internal Medicine who was interested in cancer because the Chairman of the Medicine, Robert Loeb, felt that this was a disease that a good internist would have nothing to do with, because you couldn’t cure it.
I had absolutely unbounded admiration for Bob Loeb. He was a magnificent clinician…and a wonderful teacher. I think he just had a blind spot when it came to cancer. I think that the reason that Medical Oncology got such a slow start had to do with the attitude of people in Internal Medicine.
Loeb would not consider rotating CP&S house staff through a cancer hospital, but we were able to eventually get approval for our own residency program. I was able to recruit some wonderful colleagues, like Paul Marks, Elliot Osserman, John Ultmann, Bernie Weinstein, Helen Ranney among others. And my first chief resident was Jim Holland.
I was then the Director of the Institute of Cancer Research. The Delafield was its clinical arm where we also had labs.
Loeb tolerated me. But he was fond of saying rather openly, “Alfred, you’re a part of the lunatic fringe.”
And then Loeb retired and an even more pessimistic and indifferent clinician came in as Chair of Medicine, Stanley Bradley. Stan Bradley sent two guys to replace me in ’68 who had no connection to cancer and it was closed shortly thereafter.”
Despite the obvious need for, and the success of the Delafield, two Chairs of Medicine closed it. Their actions set the template for most NCI matrix centers today. Delafield was a good model just not free standing enough.
CP&S received its NCI designation in 1974. Since then, like a lot of matrix centers, they have struggled to find their Cancer Center identity. I am sure, for those who knew of the Delafield, there have been many times when they wished they still had it.
Dr Gellhorn died peacefully in March 2008 at the age of 94. He was a great mentor and a pioneer in the cancer field. Not many people, having been told they were part of the “lunatic fringe” by one of the greats in medicine, would have had the fortitude to continue. He did. And for that, and all the many luminaries he trained, we all owe him a debt of gratitude. Thanks Alfred.

The Co-Directors of the Center for Management
Research in Healthcare at Vanderbilt,
David Dilts and Alan Sandler, reported a study
of an alarming nature to the National Cancer
Institute (NCI). The study was covered by The
Cancer Letter and documented that cancer
trials take an average of 800 days to start. The
clinical trials program in the US is broken and
apparently nobody has noticed: 800 days! Can
you imagine that? The response of the NCI
Director was a vow to cut the time to approval
in half. At 400 days the system would still be
broken. Dilts and Sandler reported that for
cooperative-group studies, a protocol takes
800 days from conception to activation, with an
additional 200 days at a cancer center. Even
an investigator-initiated trial at a cancer center
takes a median of 116 to 252 days, and if you
make amendments to a study it goes back
to the end of the line. Furthermore, the study
by Dilts and Sandler was conducted by two
cooperative groups at four centers selected
by NCI because they scored better than most
(in peer review) on the function of their clinical
trials programs. The solutions offered by
the authors of the study to rectify this situation
were not of much help (e.g. start fewer studies,
stop tweaking studies).
We live in an age where we are blessed with
bounteous information about critical steps
in the pathways that cancer cells use to outstrip
the growth of normal cells and information
about how their cell-death pathways are
broken. Although we have the specific agents
and the opportunity to capitalize on the whole
concept of ‘targeted therapy’ we find ourselves
unable to use these advances. If one looks
at past successes in treatment, they were
characterized
by the ability to test an idea
rapidly, and to tweak studies to allow swift
adjustment of protocols in response to events
happening in real time. I have not examined
the protocols in question directly, but I would
not hesitate to suggest that a study that takes
800 days to activate is hopelessly outdated
the day it starts. Furthermore, if investigators
are encouraged to avoid tweaking, then the
talents of our best investigators are either not
being used or are being wasted.
At my own institution I reside on many committees
involved in protocol review, and I can
say with authority that we are hopelessly
over-regulated.
Although cancer centers are
not perfect and have many problems of their
own, they are still where the knowledge base
is. The requisite talent to know the right way
to design and modify an ongoing study does
not reside on remote review committees at the
NCI or the FDA, yet those are the places where
the delays are greatest. Too many cooks are
spoiling the broth.
A step towards fixing this problem would
be to delegate the entire review and approval
process, at least for phase I and II studies,
to NCI-designated cancer centers with NCIapproved
clinical trials programs, with the NCI
and FDA only retaining audit responsibilities.
This was the role envisioned for cancer centers
by those who framed the NCI Act of 1971.
Most of these regulations have been imposed
on us by the US congress in the name of
patients’ safety. Review boards set up and
codified in regulations to protect patients are
doing just the opposite. They prevent patients
from having access to the fruits of the war on
cancer and the best we have to offer.