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November, 2001

Comparison of PubMed Statistics from Cincinnati and Six Other Cities

This contribution to our newsletter has been written while I was in Sarasota for treat-ment of my prostate cancer with EBRT (External Beam Radiation) - 3D/IMRT (3 Dimensional/Intensity Modulated Radiation Therapy). In three weeks radioactive seeds will be implanted.
I went to Florida for several reasons. First, my health insurance plan allowed me to do this. Not all health plans are like mine - but if you are on Medicare, going to Sarasota would be an option. Second, Dr. Dattoli and his colleague Dr. Sorace have an excellent reputation, and tend to work on the more difficult cases. They have treated thousands of prostate cancer patients, and the equipment in their clinic is top-of-the-line. Another reason for going to Sarasota was because Dr. Dattoli had published extensively about his clinical results. He also edited an authoritative book on brachytherapy that was published recently.
Publications are important: they apparently influence what patients do; they partially control the flow of grant money, create an institution's reputation, and make it possible to compare medical institutions or even cities.
The objective of this month's PCNG article is to compare the number of publications (citations in the parlance of PubMed) on cancer and prostate cancer from seven cities including Cincinnati.

Titles and abstracts of publications can be found in 'PubMed', the National Library of Medicine's data base providing access to over 11 million citations: http://www.ncbi.nlm.nih.gov/entrez/.
1.38 million citations in PubMed are on cancer, and about 2.5% of those are on prostate cancer. If one enters as keywords 'cancer' or 'prostate cancer' and 'Cincinnati', the number of all citations on cancer or prostate cancer and with Cincinnati in the address of the first author would be listed after clicking on 'Go'.
PubMed added in the late eighties an address to the name of the first author, and thus only information from the last 10 years, 5 years and 2 years respectively was collected (on November 2, 2001). It took about an hour to collect the numbers shown in this table (with a DSL connection), and to enter them into a spread sheet:

0: No Location Specified; CVG: Cincinnati –  COL: Columbus –  CLE: Cleveland –  IND: Indianapolis –                                                                PIT: Pittsburgh –  DTW: Detroit

The first graph shows the number of all Pub-Med citations for each city for the last 10 years. The lines begin therefore at 0. The highest value indicates the numbers of citations in the 1991-2001 period; the second highest value is the 10 years total minus the 2 years total, and the third value is the 10 years total minus the 5 years total.
It is noticeable that the seven cities cluster in only two groups: Cleveland, Pittsburgh and Ann Arbor in one group, and Cincinnati, Columbus, Indianapolis and Detroit in the other group. The first group published twice as much as the second group, and the publication totals of the respective members of each group are so close that the lines merge together!

The second graph shows the number of citations on prostate cancer per city. What a spread! Cincinnati is, unfortunately, at the very bottom, with 1/6th of the number of prostate cancer citations in Cleveland and 1/12th of those in Detroit.
Columbus was as productive as Cincinnati five years ago, but is now almost twice as productive.
There are two reasons for the low number of prostate cancer citations from Cincinnati: a) the percentage of citations on cancer is less in Cincin-nati than elsewhere, and b) prostate cancer is about the least studied cancer in Cincinnati.

The third graph  shows the citations on cancer as percentage of all PubMed citations from a city:
In the last two years only 9.4% of the citations listed in PubMed and originating in Cincinnati dealt with cancer. The trend is downward, as in the other cities - with the exception of Cleveland, and Columbus in the 1991-1996 period. But this trend is downward nowhere as consistently as it is in Cincinnati.

The fourth graph shows the prostate cancer citations as a percentage of the citations on cancer. About 4% of all citations in PubMed on cancer from the last ten years are on prostate cancer. This percentage has been increasing slowly during the last five years. Ann Arbor, Detroit, Cleveland, and Pittsburgh publish relatively more, but in Cincinnati the number of prostate cancer citations is less than half of that in PubMed - and this percentage has been decreasing.

The number of PubMed citations is in all likelihood correlated with various other assessment parameters to determine the standing of a medical center, such as research, grants, number of clinical trials - in summary, the quality of medical care in a city. Prostate cancer patients in Cincinnati have some reason to travel to another city!
Some may question this correlation, arguing that patients should not worry about the PubMed numbers because what really should count, at least in their opinion, are the clinical studies (dealing with the treatment of patients). Research papers and statistical studies would be interesting but not particularly relevant for patients needing help now.

Of the 24 citations on prostate cancer produced in Cincinnati during the last ten years, 10 dealt with clinical studies; 2 reported the results of a rather unsuccessful clinical trial (chemotherapy); 2 were on pain, and 6 were on radiation therapy or nuclear medicine. The other 14 citations were on research (9) or statistics (5).
Last year I wrote to Dr. Steger, president of UC, expressing my concern about the citation decline in prostate cancer. His response was that "…the UC Medical Center has to focus its research and resources to be excellent in its efforts…."
As a university is basically a zero-sum institution (a gain in one area means a loss in another area), excellence at UC in one area apparently implies negligence in another area. Unfortunately, from our perspective, the area in which we are most interested is definitely in the latter category.
Let's hope that this will change!

Kees DeJong, 11/18/2001

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October, 2001

A Thoughtful Approach to Prostate Cancer
(based on the Prostate Forum Web Site)

Background
In 1994, Dr. Charles Myers accepted the position of Director of the Cancer Center at the University of Virginia. At that time, the Cancer Center was a Basic Science Center. In the years since his arrival, the Center has more than doubled its funding from NCI and is now an approved Clinical Center. During this same time, UVA has become one of the leading centers for prostate cancer research.
Dr. Myers' current major activities revolve around prostate cancer treatment and research. His laboratory research is focused on why a diet high in animal fat appears to foster
progression in prostate cancer. Recently his research group has demonstrated that a fatty acid, arachidonic acid, common in meat, dairy products, and egg yolks promotes the survival and growth of human prostate cancer cells. They have shown that arachidonic acid is converted to a hormone, 5-HETE, which appears to fos-ter the spread of prostate cancer.
Dr. Myers has long been popular among prostate cancer patients as a speaker because of his ability to explain science and medicine in easy-to-understand language. For some years his other responsibilities limited the number of speaking engagements he could accept. In an attempt to address this problem, Myers and his wife, Rose, started a newsletter, Prostate Forum, in the summer of 1996 (see back page for more info).

Dr. Myers' Philosophy
There are several issues that make prostate cancer difficult for patients and physicians. The most important problem is that prostate cancer is variable. In many men their cancer grows slowly and does not spread beyond the prostate gland. In these men, this is a cancer that men die "with and not of." For these men, diagnosis and treatment may offer no advantage and may cause considerable distress. How slowly does cancer in these men grow? The cancer can be doubling every five to ten years. At the other extreme are men with cancer that doubles every 10 to 14 days. These cancers are growing as fast as the most aggressive cancers known, such as acute leukemia. These facts alone mean that no single approach is appropriate to all prostate cancer patients.
The second major problem is that prostate cancer occurs, for the most part, in men over the age of 50. These men may have a wide range of other medical problems that must be taken into consideration. Some of these men may be in their fifties and in vigorous health. Such men may well live to age 90 if prostate cancer can be surmounted. In contrast, other men may well be over 80 years of age with a wide range of medical problems that are more serious than prostate cancer. For example, newly diagnosed diabetes mellitus, a recent heart attack or emphysema may well be more life threatening than many prostate cancers. Thus, it is important to consider prostate cancer in the context of a patient's overall medical situation.
One final problem arises from the fact that none of the treatments for prostate cancer is perfect and none has been proven effective. For early prostate cancer, we have a choice between surgery, radiation therapy, hormonal therapy or watchful waiting. Serious questions re-main about the effectiveness of each of these approaches. Additionally, each of these approaches is accompanied with complications that can be serious. Dr. Myers believes there is no single right choice for all men. He believes that the appropriate approach is for the patient to view the physician as a carpenter who can build a ranch, colonial or split-level home and tell you how life is in each of these. Only you can decide which housing style matches your needs.
Unfortunately, many patients face this cancer while under the care of a specialist who uses only one approach. It is true that if your only tool is a hammer, everything begins to look like a nail! The patient hears the specialist passionately champion a single approach to this disease and takes the recommended course with-out considering the alternatives. Later the patient may discover that another approach might have fit his needs and personal goals much better. This process has created many angry patients!
Dr. Myers believes the only solution to these problems is for each patient to understand the nature of his cancer and the options for treatment in depth. The role of the physician should be to aid the patient in selecting the treatment that best fits the patient's needs. The Prostate Forum is specifically written to assist patients in decisions of this kind.

Treatment Options for Prostate Cancer
If you expect Dr. Myers to now tell you the choices are surgery, radiation therapy, or hormonal therapy, you are wrong. These are only tools, the real major decisions occur at a different level. There are several major approaches that can be used to manage prostate cancer and you need to understand these before even considering specific treatments.

These basic approaches are:
---go for a cure,
---kill as many cancer cells as possible ("debulking") and then do what you can to slow the reemergence of this cancer,
---slow the disease as much as possible without compromising your quality of life, or
---ignore the cancer for as long as possible.

If you decide that you want to try for a cure, then you can immerse yourself in the complex decision of whether to chose radical prostatectomy, external beam radiation therapy, radioactive seeds, cryosurgery or some combination of these treatments such as external beam radiation and radio-active seeds.
Dr. Myers believes that the available evidence indicates that many men diagnosed today have cancers that are not going to be cured by surgery or radiation therapy. All too often, men undergo these procedures only to experience a relapse after a period ranging from several months to several years. At this point, they again confront the issue of whether to simply slow disease progression or try an experimental approach that might offer cure.
Lately, he has become quite impressed by the tools we have to slow or arrest the growth of prostate cancer. We now have a range of relatively nontoxic drugs able to slow the growth of prostate cancer. Dr. Myers thinks this approach will come to play a large role in the management of prostate cancer.

Final Note: if you think Dr. Myer's philosophy makes sense then you may want to consider subscribing to his monthly publication, Prostate Forum, or perhaps purchasing specific back issues on subjects of particular interest to you. Both of these are available through the website, www.prostateforum.com. Several of us have found his material to be very helpful.

Fran Stanton, 2001-10-12

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September, 2001

Donald S. Coffey: Similarities of Prostate and Breast Cancer: Evolution, Diet, and Estrogen

      There has not been sufficient time for biological selection to evolve a proper defense for human DNA against the insults perpetuated by the modern Western diet. This may result in nutritional diseases such as prostate and breast cancer. Both prostate cancer and breast cancer primarily occur later in life, often after the optimum age for reproduction, thus severely limiting the evolutionary selection process against cancer. This medical dilemma appears to be enhanced by the speed of technology that enhances the imbalance between the rapid rate of changes in our food processing and dietary patterns, which far exceeds the slower rate of evolution of adequate biological defenses.
     This interplay of many dietary components, such as phytoestrogens, can induce hormonal changes that may contribute to the carcinogenic insults of our lifestyle on prostate and breast tissue. Insights into the development of the concept presented here have been derived from attempts to formulate plausible biological explanations of the following features and enigmatic phenomena observed in prostate and breast oncology:
1.     Species specificity of prostate cancer. A significant incidence of spontaneous prostate cancer is ob-served only in humans and the dog. Of the thousands of other species of mammals with prostates, none that age in zoos or captivity have a significant incidence of prostate cancer that results in clinical diagnosis, metastasis, and death. Except for the dog, prostate cancer is also absent or extremely rare in all aging pets such as cats, hamsters, guinea pigs, and horses.
2.    Tissue specificity of cancer. Prostate cancer is most common in humans; however, there are other adjacent reproductive organs that never present with cancers such as the vas deferens, epididymis, and bulbo-urethral gland, or even the seminal vesicles, where it is extremely rare. ...
3.    Geographical Variations. Compared with the United States, the incidence and age-adjusted mortality rates of both breast and prostate cancer can be >10-fold lower in Asian countries. When Asians migrate to the United States, their prostate and breast cancer rates tend to increase, with time, toward levels seen in the native US population. …
4.    Similarities in epidemiological factors. There appear to be very similar lifestyle risk factors accompanying both prostate and breast cancer, including a lower risk associated with high intake of fruits, vegetables, fiber, and soy products and, alternatively, a higher risk associated with increased intake of red meat, animal fats, dairy products, and steroid exposure, as well as body mass and birth weight. This similarity does not exist with other cancers, such as stomach cancer.
5.    Early events are common. In contrast to clinical cancers, small incidental foci of prostate cancer, as well as early pathologic changes and benign prostatic hyperplasia, appear to have relatively high incidences with aging in both the United States and Asia. This suggests that promotion and not initiation may be the critical difference between the clinical rates of prostate cancer in different geographical areas.
6.   Similarities between prostate and breast. Both glands have many similarities with regard to physiology, endocrinology, benign tumors, and the age-adjusted incidence and mortality rates of cancer that appear to be correlated in various countries.
       It is the purpose of this overview to suggest unifying concepts that might provide a common denominator between the mechanisms involved in the above 6 observations. This has been accomplished by involving the roles of evolution, diet, and estrogens as central and interactive factors in the above biological and pathological processes. If this proves to be true, then the acquisition of both prostate and breast cancer may be primarily an acquired nutritional disease and may, be prevented by lifestyle modifications that return us to the type of diet to which humans had evolved during the time preceding the recent technological changes that have altered our diets in such a dramatic manner. ..
      When 21 countries with excellent cancer registries report their incidences and age-adjusted rates for prostate cancer, the correlation coefficient is highest between prostate and breast cancer at 0.81, endometrium at 0.78, and ovary at 0.72.
      This may implicate the study of estrogenic factors, because the breast, endometrium, and ovary are estrogen-responsive tissues, and estrogen exposure has been shown to affect carcinogenesis…
There are striking similarities between the features of both breast and prostate cancer within the United States. The annual age-adjusted death rates are almost identical at approximately 25 per 100,000, and both glands also have a high incidence of both benign disease and small incidental cancers as well as early preneoplastic lesions. Both cancers also metastasize to the bone and can cause osteoblastic lesions. Both tumors require gonads for development and can be treated by hormonal manipulation. Both glands contain estrogen, androgen, and progesterone receptors. Reviews have pointed out that many prostate tissue markers, such as prostate-specific antigens, are also present in the breast, where they are also under androgenic regulation. ...
      Can diet affect the development of prostate and seminal vesicle cancer in a different manner? Insight may be available from studies of evolution. In 1859, Charles Darwin, in The Origin of Species, stated, "Species of the same group differ from each other more widely in the secondary sex characteristics than in any other part of their organization". It is recognized that all of the thousands of different species of male animals have a prostate gland; thus, this is a common denominator.
     However, mammals that eat meat, such as dogs, cats, and sea lions, do not have a seminal vesicle whereas those that eat primarily plants, such as the great apes, horses, bulls, and rodents, do have a seminal vesicle. It is apparent that during evolution, diet is associated in some way with the selection for the presence or absence of the seminal vesicle. Can diet also be involved in why humans do not get seminal vesicle cancer but do get prostate cancer? What is confusing about the above analogy is that the human appears to be an exception in that we eat large quantities of meat but we still have a seminal vesicle. … This apparent exception may be the result of a very recent change and diversion in our diet and food processing from the plant and fruit diet used over the main part of human evolution.
     Approximately 7 million years ago humans evolved from a common ape ancestor, with our closest relative being the pigmy chimpanzee called the bonobo. Like the other great apes, the bonobo eats primarily fruit and vegetables and no meat. … Even in humans, highly effective hunting was not the major source of high meat caloric intake until later in human development. When early hominoids such as "Lucy" came down from the trees 4 million years, ago and began to roam the savannas, they picked up the ability to become hunter-gatherers.
      This hunting was still at the most primitive level until approximately 12,000 years ago when the dog was brought into the human hunting society, which tremendously increased the ability to catch animals, owing to the dog's speed and olfactory abilities. The dogs chased and corralled the game at bay for the human to subsequently kill, and the human then shared the kill with the dog. … This sharing of diet between human and dog allowed the dog to be domesticated and trained to herd animals. This major shift in food style occurred only about 10,000 years ago, when humans became farmers and domesticated both plants and animals.
     The technology quickly evolved into a tighter focusing of human diets from wild fresh vegetables and fruits to an eating pattern toward limited plants that could be domesticated and grown in great quantities and stored, like wheat, rice, barley, corn, potatoes, and other tubers. This resulted in approximately 20 plant types rapidly replacing the high diversity of >3,000 .plants and fruits that were earlier eaten fresh as they came into season and were gathered from the wild. With large-scale domestication and breeding of cattle came a high meat intake, and this was combined with storage, curing, drying, and cooking as well as a propensity to use milk and cheese from dairy processing. Cooking, burning, and smoking produce high levels of heterocyclic molecules, many of which make adducts to DNA, and are carcinogens. Since separating from the great apes and chimpanzees approximately 7 million years ago, humans evolved into Homo sapiens sapiens that are very similar to our present form in as little as 150,000 years. However, we dramatically changed to a Western-style diet only in the very recent past (ie, 15,000 years) ---at a pace much faster than we could biologically evolve. This Western diet consists of high meat and fat; dairy products; stored, processed, and cooked meats; and low fruit and fiber intake, along with a more sedentary lifestyle.
     In summary, we were not biologically selected by the evolution process to eat the way we do today, and the damage is manifested in prostate and breast cancer. Indeed, all of the present suggestions of the National Cancer Institute and the American Cancer Society as to how Americans might reduce their chances of getting prostate and breast cancer revolve around adapting dietary changes in our lifestyle back toward the early human diet of more fruits; a variety of fresh vegetables and fiber; less burning, cooking, and processing; diminished intake of dairy products, red meat, and animal fats, as well as decreasing weight and increasing aerobic exercise. That is, we must return to a diet and lifestyle that more closely matches the first 135,000 years before technology modified our lifestyle and diet.

Donald S. Coffey, Ph.D. is a Professor of Urology, Oncology, and Pharmacology and molecular Sciences at the Johns Hopkins University School of Medicine, and the Director of the Research Laboratories of the Department of Urology. Dr. Coffey was appointed as the Catherine Iola and J. Smith Michael Distinguished Professor of Urology at the Johns Hopkins School of Medicine. He was President of the American Association for Cancer Research for 1997-1998, past-President of The Society for Basic Urologic Research and has served on several major editorial boards. For 19 years Dr. Coffey served as a member of the National Prostatic Cancer Program of the National Cancer Institute and served as National Chairman from 1984-1988. He has published over 200 research papers.

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August, 2001

Intensity Modulated Radiation Therapy (IMRT)

Treatment planning in radiation oncology has undergone major evolution since the first therapeutic use of x-rays in the early 1900's.  With a better understanding of cancer biology and normal tissue reactions as well as improved diagnostic imaging tools, radiation oncologists are better able 1) to define the targets for treatment and 2) deliver focused beams of radiation to those targets.  One recent advance began with the introduction of CT scanners, as these images could be transferred to target planning computers where tumor volumes and normal tissues were defined for development of radiation beam arrangements.  The process, known as "three-dimensional conformal radiation therapy" (3D-CRT), has proliferated as a method of giving higher tumor dose and minimizing effects on normal tissue.
      The development of a treatment plan using 3D-CRT has been performed traditionally with a "forward planning" process, where beam arrangements were tested more or less by trial-and-error, until a satisfactory dose distribution was produced.  For complex cases, this process can be very time-consuming because of the number of beam parameters that can be modified.
      In contrast, IMRT relies on "inverse treatment planning" and non-uniform radiation exposures to optimize the dose distribution to the target.  In inverse treatment planning, the radiation oncologist enters clinical parameters, such as desired dose to the target volume and dose-limits to normal organs, into the targeting computer, which then "back-calculates" from the desired dose-distribution and develops an optimal treatment plan to conform to those parameters.         
       An IMRT targeting computer also adjusts the intensity of the radiation beam across the field, depending on whether the tumor or sensitive normal tissues lie in the beam path.  The availability of inexpensive and powerful computing equipment has made the sophisticated optimization process practical and relatively automated.  In addition, the advent of multileaf collimators (MLC) on modern linear accelerators has permitted the delivery of multiple and complex portal geometries necessary for IMRT.  Multileaf collimators can move in and out of the beam portal under precise computer guidance while the radiation is on, thereby generating the desired nonuniform fluence (intensity) patterns that produce a uniform dose to the target.

Planning of IMRT

The planning process for IMRT involves several steps: 1) position and immobilization, 2) patient data acquisition, 3) target and normal tissue definition, 4) dose prescription and dose limits, 5) beam optimization, and 6) treatment plan evaluation.

Because IMRT delivers radiation in a precise fashion, patient positioning and immobilization are crucial elements in the planning process.  Certain tumor sites, such as head and neck cancer, brain cancer, and prostate cancer, are well suited for IMRT given their relatively stable position in relation to bony anatomy and close proximity to critical normal structures.  New devices have been implemented for 3D-CRT and IMRT.  For prostate cancer, some form of body immobilization either using thermoplastics or vacuum cast is implemented.  In some centers, the prostate gland can be better localized using a rectal balloon, transabdominal ultrasound, or intraprostatic radio-opaque markers.

Treatment planning for IMRT relies on CT images of the patient in treatment position.  Fixed marks are placed on the patient or the immobilization device and lined up with lasers such that every point within the patient can be localized in three-dimensional space.  In the next step, target volumes and normal tissue are outlined on the CT images by the radiation oncologist and dosimetrist.  In IMRT, multiple targets can be specified, each with a unique dose prescription if necessary.

One of the greatest strengths of IMRT is its ability to limit dose to normal tissues at risk for radiation damage.  For prostate cancer, these organs commonly include the rectum, the bladder, and the femoral necks.  Once these volumes are defined, doses are prescribed to targets and dose-limits are assigned to normal tissues.

There are a number of methods to specify dose parameters. One method is to assign a dose goal or dose limit to a structure, and a tissue weighting, which reflects the relative importance of constraining to the specified dose.  Typically, the tumor and critical organs receive the highest weighting.  In other treatment planning systems, the dose limits incorporate a volume constraint; i.e., the volume of the rectal wall receiving more than 70 Gy should be 40% or less.

Following the specification of the dose criteria, the treatment-planning computer performs an iterative search to develop an optimized beam configuration and intensity pattern.  The dose criteria must be realistic, or the planning computer may fail to produce an acceptable plan.  Once the planning computer produces an optimized plan, a dose distribution is calculated and evaluated by the radiation oncologist.  If the dose distribution could be improved, the radiation oncologist can modify the dose specifications to "tweak" the plan to his or her liking.
 

Delivery of IMRT

The delivery of IMRT has been facilitated by the introduction of MLCs.  Instead of rectangular edges in the beam aperture of earlier linear accelerators, an MLC consists of narrow leaves that are under computer control and can form custom-shaped portals.  During IMRT, the leaves may also slide during radiation exposure, thereby adjusting the intensity of one portion of the beam. The implementation of IMRT may be performed using two distinct methods: multiple fixed gantry positions or a rotation gantry.

With a fixed gantry technique, multiple beam angle and table configurations are chosen which should optimize radiation delivery.  At each position, radiation delivery occurs through the appropriate portal shape and in an optimal fluence pattern.  The fluence pattern can be adjusted by dynamic (moving) MLC, also known as a "sliding window" technique, or by delivering multiple "segments" of radiation at each gantry position.  With the latter technique, the radiation intensity for each segment is constant, while the confluence of the multiple segments produces the modulated fluence profile.

With a rotation gantry technique, the gantry (linear accelerator treatment head) swings around the patient in an arc configuration while the radiation is on, and the field shape and intensity are continually modified.  The first available IMRT system divided the target volume into thin slices, and treated each slice sequentially in one arc.  After each arc, the patient is moved horizontally, and the next slice is treated; hence, the term "sequential arc" IMRT.  The MLC in this system is a special hardware device that treats a relatively thin slit rather than a full field.  Since linear accelerators are now equipped with full field MLC, this adaptation allows full field IMRT with a rotating gantry.  Because the intensity pattern is often complex and may not be feasible with a single arc, the treatment can be divided into multiple arcs, with each arc treating a particular "segment" of the beam profile.  This method is known as "intensity modulated arc therapy."

Clinical Applications of IMRT

Radiation therapy has been a mainstay of localized prostate cancer therapy for several decades.  Technological advances in treatment planning have permitted higher doses to the prostate and better shielding of the rectum and bladder.  IMRT is particularly suited for dose escalation in prostate cancer, as this technique provides avoidance of rectum, bladder, and femoral necks to minimize potential morbidity.  There is good rationale for dose escalation in prostate cancer, based on evidence from randomized trials from M.D. Anderson Cancer Center and a phase I trial from Memorial Sloan Kettering Cancer Center.  By increasing dose from 70 to 78 Gy, intermediate-risk prostate cancers were more likely to be controlled.  In addition, doses of 81 Gy resulted in a 7% positive biopsy rate compared with 45% or more with lower doses.  Many centers with both 3D CRT and IMRT capabilities have adopted IMRT as the preferred treatment planning method for prostate cancer.
 

Limitations of IMRT

The implementation of IMRT can be a tedious task, even for radiation oncology facilities equipped with 3D-CRT.  IMRT requires special hardware and physics expertise as well as some amount of re-training for radiation therapists.  With greater experience, it is possible for IMRT to become a very efficient treatment technique.  Because of its recent introduction to clinical radiation oncology, many more years of study will be necessary to determine the true therapeutic impact of IMRT on tumor control, toxicity, and patient survival.

 July, 2001

Recent Research In Treating Prostate Cancer
Andrew C. von Eschenbach, MD

"The Auditorium of Sarasota Memorial Hospital was the scene of the first annual Distinguished Lecturer Series sponsored by The James F Mullen Memorial Fund, Inc., successor organization to Man To Man, Incorporated. This gathering represented the culmination of the dreams and hopes of Jim Mullen, who in 1990 founded the pro-gram known as Man To Man, now the property of the American Cancer Society."
Dr. Andrew C. von Eschenbach of the MD Anderson Cancer Center in Houston (TX) presented in January "Recent Research In Treating Prostate Cancer".
In our Newsletter we present the last part of his lecture.

…… we know that the progression or behavior of the cancer cell, and specifically a prostate cancer cell, is dependent upon two things. It is dependent upon changes that are occurring within that cancer cell itself, and it is also dependent upon that cancer cell's interaction with it's environment. Both of these factors are important.

Oncogenes and tumor-suppressor genes
Some of the things that are occurring within the cancer cells themselves have to do with things that promote the growth of the tumor. This growth is under the control of a number of genetic alterations that influence how these cancer cells behave. Some of these genes are called oncogenes; they are like the accelerator in a car. When there is a problem with an oncogene, it is as if the accelerator in the car is stuck in the open position; the cells are driven to increase. Some of the other genes that affect cancer cell growth are called tumor-suppressor genes. These act like the brakes on a car. If there is a defect in a tumor-suppressor gene, it is like having no brakes and the car cannot stop. The cell is again, continuing to grow out of control. Some of the genes that we have recognized in the prostate that have to do with it's growth and proliferation are oncogenes like BCL2 and tumor-suppressor genes like P53.
When there is a problem with P53, it is a problem where there are not brakes in this cancer cell, and no way of stopping it once it is growing. One strategy we think about in being able to effect the cancer cell is, can we restore the defective brake within that cell? One way of doing that is by taking a normal P53 gene, and attaching it to an adenovirus. When the virus infects the cell, carrying along with it this normal P53 gene, that gene may be able to re-store the defective brake. We do this by injecting the viral P53 directly into the cancerous prostate, much the way we do brachytherapy, by using ultrasound control. We have learned that by doing this procedure before a radical prostatectomy, we could study the effectiveness under the microscope after the prostate had been removed. The P53 genes were there, putting on the brakes. That, in itself, did not completely destroy, or control, all the cancer in the prostate, but by restoring the brakes, we could potentiate some of the other treatments that also put brakes on the cancer cell, like androgen ablation and radiation therapy. One of our current protocols to-day, is to use P53 combined with radiation therapy as a way of biologically destroying the cancer cell.

Introducing Anti Angiogenesis
The other thing that we have learned is that in addition to cancer cells being able to proliferate, that in order for them to grow and develop into tumors larger than just the size of a pinhead, they have to be able to get oxygen, they have to be able to get a food supply. The way they do that is by tricking the body into bringing new blood vessels into the tumorous area so that these cells can get more oxygen, more food, and grow into a larger lump. This process of new blood supply is called angiogenesis. One of the strategies we have of blocking a tumor is to prevent this development of new blood vessels: anti angiogenesis.
We now have drugs that can block the effect of that tumor cell and prevent it from creating its new blood supply. Some of those drugs are ones that were used in the past, like thalidomide. That same thalidomide that had horrible complications when given to pregnant women precisely because the thalidomide blocked the development of limb buds in the fetus. Babies were born without arms and legs and other parts. We use that drug now, enabling us to stop the growth of tumor cells. We use thalidomide in combination with other drugs. We are also using it after radical prostatectomy and radiation therapy when patients show a rise in PSA but no clinical evidence of disease, in an effort to see if we can prevent the progression of small tumor cells that are obviously growing and were not completely destroyed by local treatment.

Thwarting The Metastatic Process
Finally, one other important biologic strategy is to be able to interfere with the process of metastasis. We now know that cancer cells just don't haphazardly, randomly, spread to other body parts. They go there in a very precise and a very specific way. The precision has to do with the fact that these cancer cells are interacting with stromal cells, or the environment that they find themselves in, and that this environment then presents us an opportunity for being able to prevent metastasis. The behavior of the cell is now being determined, not by its own proper-ties of genetic alterations, but by the environment that it finds itself in. One of the questions that was being posed to us was 'why do prostate cancer cells have this very specific propensity to metastasize to lymph nodes and bones? What was it that was so special about this environment that makes it so likely to be a place for prostate cancer?'
When prostate cancer cells metastasize to bone, they cause the bone to form more bone and so in an x-ray it becomes white and chalky because of the calcium. Unlike most tumors when they metastasize, which eat away the bone; prostate cancer does just the opposite. We have known for a long time that this was a characteristic pattern of prostate cancer. What it was telling us was that the cancer cells were talking to the bone cells. What we know now is that the bone cells were talking to the cancer cells. The prostate cancer cells were sending a message to the bone to cause the bone cells to develop, but the bone cells were also sending a message to the pros-tate cancer cells causing them to develop. We know now that bone stromal cells make a bone protein, which is normally supposed to be a bone growth factor, which stimulates the growth of prostate cancer cells. The reason why we have prostate cancer going to bone in a favorable environment; there are growth factors and there is a food supply present that the prostate cancer cells like.
We now can exploit that by realizing that maybe we can change the bone environment and, in-stead of being hospitable to prostate cancer cells, make it just the opposite, and make it hostile. This is a trial that we just finished and has been published in Lancet <see abstract below>. Men who had hormone-independent progression of prostate cancer involving bone were treated with adriamycin, a chemotherapy drug. But some of them also got a drug called strontium 89, which directly affects the bone cells. The patients were randomized as to who got adriamycin plus a placebo and who got adriamycin and strontium 89.
In the men who had strontium, which affected the bone environment, there was a much bet-ter outcome than the patients who got only the adriamycin alone, affecting just the cancer cells. There was an 80% reduction in PSA in the former group versus 36% in the latter. There was also significant improvement in their time to progression, almost double, and some improvement in their overall survival; showing and demonstrating that altering the environment could significantly alter the outcome of the tumor. We now need to look at what we could do with altering the macro environment - not only the immediate environment of the cancer cell, but also the environment of the patient himself. What can we learn about nutrition, the immune status, and other hormones that can significantly influence the macro environment and alter the outcome of the tumor?

A Paradigm For The Future
The new paradigm for the future, whether we are talking about latent or clinically significant or advanced cancer, we are now learning the biologic steps that are controlling or regulating this process. With each of these biologic steps that we are learning about, we are opening up a whole new portfolio of treatment that we can use to be able to influence or prevent that progression. When we are able to do that, we then open up a whole net set of strategies that can help us be able to prevent a prostate cancer cell from progressing and growing to the point that it results in a painful and difficult death for patients. Some of those things will have to do with diet; some of those things will have to do with creating or causing these cancer cells to die. Some of these will have to do with the ability to prevent their growth or cause them to not become angry and aggressive in their appearance. But, the point I leave you with, is that the future is much more hopeful than the past because our approach to prostate cancer in these next few years will be dramatically different than it was in the past.

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June, 2001

http://virtualmeeting.asco.org/vm2001/

American Society of Clinical Oncologists
"….the ASCO Annual Meeting offers details on cutting edge technology and groundbreaking research results. This year, more than 1,700 scientific abstracts will be presented throughout the four day Meeting…."
Select first ASCO Abstracts, then 'Abstract Categories'  click on 'Prostate Cancer' in the 'Genitourinary Cancer' category and the titles of 139 abstracts will be shown. The full abstract is easily obtained. 
A few abstracts will be presented here; others will be discussed at the June 27 meeting.

A huge trial, with great results. Bicalutamide (trade name: Casodex) is also a much 'easier' medicine than LHRHs such as Lupron. But expensive it is: I pay $4 per month and my health insurer pays almost $1,100!

#705  Bicalutamide ('Casodex') 150 MG as Immediate or Adjuvant Therapy in 8113 Men with Localized or Locally Advanced Prostate Cancer. Manfred Wirth, William See, David McLeod, Peter Iversen, BoEric Persson, Kevin Carroll, Technical University of Dresden, Dresden, Germany; Medical College of Wisconsin, Milwaukee, WI; Walter Reed Army Medical Center, Washington, DC; University of Copenhagen, Copenhagen, Denmark; AstraZeneca (Sweden), Södertälje; AstraZeneca (UK), Macclesfield, UK.
INTRODUCTION: The efficacy and tolerability of bicalutamide (a nonsteroidal antiandrogen) as immediate therapy or as adjuvant to therapy of curative intent in localized or locally advanced prostate cancer has been evaluated in an international program of 3 prospective, doubleblind, placebocontrolled clinical trials. MATERIAL AND METHODS: A total of 8113 men with prostate cancer and negative bone scans were enrolled in the program which was carried out in N. America (3292 patients), Scandinavia (1218 patients), and Europe, S. Africa, Australia and Mexico (3603 patients). Patients were randomized to receive bicalutamide 150 mg/day (n=4052) or placebo (n=4061), in addition to standard therapy of radical prostatectomy, radiotherapy or watchful waiting. Objective disease progression was determined by bone scan, CT scan, ultrasound or MRI. Deaths from all causes were counted as objective progressions. PSA progression was not a criterion for objective progression. A planned, pooled analysis of all 3 trials was performed on an intenttotreat basis using a Cox proportional hazards regression model for progressionfree survival. RESULTS: At a median followup of 3 years, bicalutamide significantly reduced the risk of disease progression by 42% compared with placebo (HR 0.58; 95% CI 0.51, 0.66; p<<0.0001). Of 922 patients with objective progression, 363 progressed in the bicalutamide group compared with 559 in the placebo group. Reductions in risk were seen across the entire patient population, regardless of underlying therapy (radical prostatectomy, radiation therapy or watchful waiting) or disease stage. The most frequently reported side effects of bicalutamide were gynecomastia and breast pain. Survival data were immature with 6% overall mortality and less than 2% of patients dying due to prostate cancer. CONCLUSIONS: Immediate treatment with bicalutamide 150 mg, either alone or in addition to standard therapy, in men with localized or locally advanced prostate cancer significantly reduces the risk of disease progression.

You are diagnosed with prostate cancer and are considering RP  what is the relative risk of failure? Read this abstract! The authors are heavyweights from Harvard University.

#757 Estimating the Impact on Prostate Cancer Mortality of Incorporating ProstateSpecific Antigen Testing into Screening. Anthony Victor D'Amico, Richard Whitington, S. Bruce Malkowicz, Andrew A. Renshaw, John E. Tomaszewski, Christy Bentley, Delray Schultz, Sean Rocha, Alan Wein, Jerome P. Richie, Harvard Medical School, Boston, MA; Hospital of the University of Pennsylvania, Philadelphia, PA; University of Millersville, Millersville, PA.
Whether early detection using prostate specific antigen (PSA) and digital rectal examination (DRE) as compared to DRE alone will reduce prostate cancer mortality awaits the results of ongoing prospective randomized trials. However, the maximum impact that early detection could have on prostate cancer specific survival can be estimated by assuming that PSA failure following RP will translate into death from prostate cancer. The study population consisted of 1,274 men with clinically localized prostate cancer who underwent a radical prostatectomy (RP) in Boston, MA or Phila, PA between 1989 and 2000 and had a preoperative PSA greater than 4 but not more than 10 ng/ml. The main outcome measure was actuarial freedom from PSA failure. The relative risk (RR) of PSA failure following RP for patients diagnosed with a PSA of greater than 45, 56, 67, or 78 compared to greater than 810 ng/ml was 0.3 [95% confidence interval (CI), 0.2  0.5], 0.5 [0.4  0.8], 0.6 [0.4  0.9], or 0.9 [0.6  1.3] respectively. Based on the estimates of 5year PSA outcome, patients with a biopsy Gleason score of 5 or 6 (781/1,274; 61%) consistently benefited from RP performed when the PSA at diagnosis was greater than 47 ng/ml compared to greater than 810 ng/ml (93% vs 78%, p = 0.0002). A benefit to early detection was not found for patients who had a biopsy Gleason score 7 or higher. Therefore, early detection using both PSA and DRE based screening may benefit men who present with biopsy Gleason 5 or 6 prostate cancer and a PSA level of 47 ng/ml as compared to 810 ng/ml. This finding awaits validation from ongoing prospective randomized trials.

Is there anyone among us on ADT medicines who is NOT on Fosamax or Aredia? I hope not  the following abstract shows that "prostate cancer patients treated for at least 12 months with ADT had a 50% prevalence of vertebral fractures. Such fractures increase longterm morbidity and mortality but they can be reduced with appropriate therapies".

# 2420 A Comparison of the Prevalence of Osteoporosis and Vertebral Fractures in Men with Prostate Cancer on Various Androgen Deprivation Therapies: Preliminary Report. Shanu Modi, Lori Wood, Kerry Siminoski, Peter Venner, Cross Cancer Institute, Edmonton, AB, Canada; Nova Scotia Cancer Centre, Halifax, Canada; Endocrine Centre of Edmonton and Medical Imaging Consultants, Edmonton, Canada.
Although osteoporosis is gaining recognition as a complication of the hypogonadal state induced with androgen deprivation therapies (ADT) used in the treatment of prostate cancer, the incidence of vertebral fractures in this population has not yet been well defined. The few published data in this area would suggest a clinical fracture rate of 56%. Here we report early findings from an ongoing comparative study of different ADT and their respective incidences of bone loss, which reveal not only a high rate of osteoporosis in these treated patients, but also an unexpected high rate of asymptomatic fractures. As part of this study we assessed the prevalence of osteoporosis and vertebral fractures in men with advanced or metastatic prostate cancer receiving one of the following ADT for at least 12 months including luteinizing hormonereleasing agonists (LHRHA), LHRHA + antiandrogen, antiandrogen alone, steroidal antiandrogen, or bilateral orchiectomy. Assessments included bone mineral density (BMD) measured by dualenergy xray absorptiometry (DXA), metabolic markers of bone turnover, and vertebral morphometry to detect vertebral fractures (defined as 20% loss in vertebral height). Data on 26 patients (mean age 73 years) revealed that 10/26 (38%) had osteoporosis, 12/26 (46%) had osteopenia, 4/26 (15%) had normal BMD. Overall 13/26 (50%) had vertebral fractures. In relation to BMD, 10/10 (100%) with osteoporosis, 3/12 (25%) with osteopenia, and 0/4 (0%) with normal BMD had vertebral fractures (p=0.001). In summary, prostate cancer patients treated for at least 12 months with ADT had a previously unrecognized 50% prevalence of vertebral fractures. This was highly correlated with bone density. Asymptomatic fractures increase longterm morbidity and mortality. With published data showing that such fractures can be reduced with appropriate therapies, it is imperative to identify these patients and institute treatments as early as possible.

PC-SPES does has some advantages as an ADT medicine; absence of loss of BMD is one of them. A disadvantage is the $300/month cost which is not reimbursed by the insurance in the USA. In the Netherlands it is.

#2355 The Effect of the Herbal Supplement PC-SPES on Bone Mineral Density in Men with Prostate Cancer. Robert Waters Ross, Susannah Kussmaul, Eric J Small, University of California, San Francisco, San Francisco, CA.
Background: PC-SPES, a nutritional supplement consisting of 8 different herbs, has been shown to have activity in the treatment of prostate cancer, perhaps due to its estrogenicity. Bone mineral density (BMD) loss is a concerning side effect of androgen deprivation therapy (ADT), which might be avoided with more estrogenic treatments. Therefore, patients with androgendependent prostate cancer being treated with PC-SPES were evaluated for evidence of BMD change. Methods: Thirtythree men with progressive hormonedependent prostate cancer were enrolled in a prospective evaluation of PC-SPES treatment. Fifteen of these men had BMD measured by dualenergy xray absorptiometry (DXA) within a median of 4.5 months of starting therapy, and then again at a median of 11.2 months later. Results: Pretreatment median PSA level was 8.3, and median testosterone was 356.5 ng/ml. One patient had bone metastases. After 1 year of treatment, all patients had a >80% decline in PSA (median posttreatment PSA = 0.0) and decline in testosterone to anorchid levels (median =16 ng/ml) Bone density changes are summarized in the table below. There were no statistical changes in BMD in the spine, hip or femoral neck using both parametric and nonparametric tests; in fact, BMD rose nonsignificantly at all sites. Conclusions: In this sample of men with hormonedependent prostate cancer, treatment with PC-SPES did not significantly affect BMD over one year. As with other forms of ADT, both testosterone and PSA levels fell, but with standard ADT this fall is accompanied by a decline in BMD of 35% in the first year. Whether this BMDsparing effect of PC-SPES treatment reflects a true difference from other forms of ADT requires further study. A casecontrol study is underway.(diagram omitted)

Our own Dr. Barrett! His results are difficult to evaluate as the patient cohort was not broken down in subcohorts. A median follow up of 27 months is also relatively short. But we should be grateful to Dr. Barrett that he kept extensive data about his patients, and presented them in this abstract. Let's hope that this abstract will be followed by a lengthy article!

#2370 Efficacy and Morbidity of Transperineal Radioactive Iodine 125 Seed Implantation for Prostate Cancer. William Lanon Barrett, University of Cincinnati, Cincinnati, OH.
Purpose: To assess the efficacy and morbidity of transperineal radioactive Iodine 125 seed implantation for patients with presumed localized adenocarcinoma of the prostate. Materials/Methods: Between October 1992 and September 2000, Two hundred consecutive patients were treated with permanent transperineal radioactive Iodine 125 seed implantation. Pretreatment PSA's ranged from 1.6 to 77 with a median of 7. Ten patients received external radiation therapy in addition. Forty two patients received neoadjuvant hormonal therapy. One hundred twenty one patients described being potent prior to seed implantation. Median follow up is 27 months (range 195 months). Biochemical failure was defined according to the ASTRO consensus statement. Patients achieving and maintaining nadirs less than 0.2, 0.5 and 1.0 were identified, excluding those who had received hormonal therapy. Preservation or loss of potency was ascertained by patient interview. Urinary and rectal toxicity were scored according to the RTOG morbidity scale. Results: Fourteen patients (7%) have experienced biochemical failure as defined by the ASTRO consensus statement. Of the 158 patients who had not received hormonal therapy, thirty percent have so far achieved and maintained a nadir of less than 0.2, 52% a nadir of less than 0.5 and 73% a nadir of less than 1.0. Eighty five percent of the patients potent prior to treatment have reported maintenance of potency. Eleven percent of patients have developed RTOG grade 1 or 2 rectal toxicity with intermittent bleeding and have been managed with topical steroids. Eighty two percent of patients have required medication (alpha blockers) for RTOG grade 2 or 3 urinary morbidity. Conclusion: Transperineal radioactive Iodine 125 seed implantation is efficacious and has acceptable morbidity in the treatment of presumed localized adenocarcinoma of the prostate.

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May, 2001

New Drug Against Metastatic Bone Disease 
May 3, 2001 press release by Novartis Oncology (http://biz.yahoo.com/prnews/010503/nyth042_2.html) 
Zometa(R) (Zoledronic Acid for Injection) First Bisphosphonate to Demonstrate Efficacy in Treatment of Bone Complications Across a Broad Range Of Tumor Types. 
Zometa Offers Greater Clinical Efficacy With Comparable Tolerability, In A Variety of Tumor Types Over the Current Gold Standard of Treatment.

Novartis Oncology announced today that its investigational drug Zometa® (zoledronic acid for injection) demonstrated statistically significant efficacy (proportion of patients demonstrating skeletal related effects) (SREs) compared to placebo in the treatment of bone metastases and prostate cancer. These results are part of the largest set ever to evaluate the efficacy and tolerability of bisphosphonates in bone metastases. These clinical trials studies also show that Zometa is effective and safe in multiple myeloma and breast, renal and lung cancer. In addition, the convenient 15minute infusion time of Zometa offers a significant advantage compared to two to four hours for the infusion of Aredia® (pamidronate disodium), the current gold standard of treatment. …. 
Study participants included more than 600 prostate cancer patients with a history of metastatic bone disease who had developed biochemical progression measured by increases in Prostate-Specific Antigen (PSA) levels. More than 250,000 patients worldwide suffer from bone complications from metastatic prostate cancer…..

CLINICAL TRIALS 

New drugs result from Clinical Trials -  see the press announcement on the previous page. Zometa will be available after approval by the FDA which is expected this fall. Earlier use is also possible if you are on Aredia, your physician can request Zometa on base of 'Compassionate Use' which, incidentally, was discussed during CBS '60 Minutes' Sunday May 6. 
New drugs such as Zometa can only be introduced after extensive clinical trials in this case more than 600 prostate cancer patients participated. 
What are clinical trials, how many enroll prostate cancer patients in Cincinnati, and who can participate? In this issue of our newsletter we'll discuss these questions.

What is a clinical trial? 
(information from http://clinicaltrials.gov/) 

A clinical trial is a research study to answer specific questions about vaccines or new therapies or new ways of using known treatments. Clinical trials (also called medical research and research studies) are used to determine whether new drugs or treatments are both safe and effective. What is a protocol? All clinical trials are based on a set of rules called a protocol. A protocol describes what types of people may participate in the trial; the schedule of tests, procedures, medications, and dosages; and the length of the study. While in a clinical trial, participants are seen regularly by the research staff to monitor their health and to determine the safety and effectiveness of their treatment.

What are clinical trial phases? 

Clinical trials of experimental drugs proceed through four phases: 
* In Phase I clinical trials, researchers test a new drug or treatment in a small group of people (2080) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects. 
* In Phase II clinical trials, the study drug or treatment is given to a larger group of people (100300) to see if it is effective and to further evaluate its safety. 
* In Phase III studies, the study drug or treatment is given to large groups of people (1,0003,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely. 

Who can participate in a clinical trial? 

All clinical trials have guidelines about who can get into the program. Guidelines are based on such factors as age, type of disease, medical history, and current medical condition. Before you join a clinical trial, you must qualify for the study. The factors that allow you to participate in a clinical trial are called inclusion criteria and the factors that keep you from participating are called exclusion criteria. It is important to note that inclusion and exclusion criteria are not used to reject people personally. Instead, the criteria are used to identify appropriate participants and keep them safe. The criteria help ensure that researchers will be able to answer the questions they plan to study. 

Who sponsors clinical trials? 

Clinical trials are sponsored by government agencies: such as the National Institutes of Health (NIH); pharmaceutical companies; individual physician investigators; health care institutions such as health maintenance organizations (HMOs); and organizations that develop medical devices or equipment. Trials can take place in a variety of locations, such as hospitals, universities, doctors' offices, or community clinics. What happens during a clinical trial? The clinical trial process depends on the kind of trial you participate in. The team will include doctors and nurses as well as social workers and other health care professionals. They will check your health at the beginning of the trial, give you specific instructions for participating in the trial, monitor you carefully during the trial, and stay in touch with you after the study. 

Clinical Trials Listed In Cincinnati? 

I searched for clinical trials on these web sites: 1http://clinicaltrials.gov/ct/gui/c/r (NIH's National Library of Medicine), 2http://cancernet.nci.nih.gov/trialsrch.shtml (CancerNet) and 3 http://www.centerwatch.com (Centerwatch) Enter prostate cancer and Cincinnati as search term in the first two sites, and twelve clinical trials open for new patients are listed. The second site provided a little more information about each trial than the first site, including the numbers by which most trials are known. The third site listed one trial. 

Active Clinical Trials in Cincinnati? 

Listing a clinical trial in a national data base does not necessarily mean that patients can actually enroll in that trial in a particular location. In Cincinnati only five trials are active, with a grand total of 6 patients. These numbers are changing constantly as trials are 'opening' (begin to accept new patients) or 'closing' (don't accept new patients). 

Who to call? 

Patients don't enroll in clinical trials  physicians enroll patients. The first person to contact and to ask questions is, of course, your own physician. But there are also patients who call one of the phone numbers listed below, speak with a physician and are eventually accepted in one of the trials. 

Which numbers to call? 

# 1: 5840436 (Allison Koch) UC Barrett Center Radiation Oncology Barrett Center Hematology/ Oncology 
# 2: 5840436 (Allison Koch) UC Barrett Center Radiation Oncology or 5850844 Cancer Center at the Christ Hospital 
#3 and #4: 5842606 (Patti Rose) or 5843238 (Liz Miagawa) UC Barrett Center Hematology/Oncology 
#5: 5844282 University Hospital Nuclear Medicine or 8887567032 (Centerwatch National Tel. No.) 

Clinical Study #1 (RTOG 9714) (3 patients enrolled at UC Barrett Center) "Phase III Randomized Study of Palliative Radiation Therapy for Bone Metastases From Breast or Prostate Cancer" Objectives I. Compare the ability of a single fraction of radiation therapy vs multiple fractions to provide complete pain relief in patients with painful bone metastases from breast or prostate cancer. II. Determine the frequency and duration of pain relief and narcotic relief after these treatments in these patient populations. III. Compare the effect on quality of life of these two treatments in these patient populations. IV. Compare the incidence of pathologic fracture within the treatment fields after these two treatments in these patient populations. Protocol Outline This is a randomized study. Patients are assigned to 1 of 2 treatment arms. Arm I consists of radiation therapy delivered in 10 fractions over 2 weeks. Arm II consists of a single dose of radiation therapy. Any retreatment does not occur until at least 4 weeks after prior treatment unless there is an increase of 2 points on the pain score. ……. 

Clinical Study #2 (RTOG 9601) (1 patient enrolled at UC Barrett Center) "Phase III Randomized Study of Radiotherapy With Or Without Bicalutamide (=Casodex) in Patients With PSA Elevation Following Radical Prostatectomy for Carcinoma of the Prostate" Objectives I. Compare overall survival following radiotherapy with or without bicalutamide in patients with an elevated prostatespecific antigen (PSA) and no evidence of metastatic disease following radical prostatectomy for pathologic T3 N0 prostate cancer. II. Compare each regimen with respect to time to second PSAbased progression, time to distant failure, and diseasespecific survival in this patient population. III. Compare each regimen with respect to time to third PSA failure (or PSA progression on hormone therapy for second PSA failure) as a potential predictor for impending cancer death in these patients. IV. Allow for subsequent analysis of emerging molecular pathologic predictors of outcome with the prospective collection of paraffin blocks from the radical prostatectomy specimen. ……. 

Clinical Study #3 (SWOG 9346) (no patients enrolled in Cincinnati) "Phase III Randomized Study of Intermittent Versus Constant Combined Androgen Deprivation (Bicalutamide and Goserelin) in Patients With Stage D Prostate Cancer. Objectives I. Compare the survival of patients with stage IV prostate cancer responsive to combined androgen deprivation therapy (CAD) treated with intermittent vs continuous CAD……. 

Clinical Study #4 (SWOG S9916) (no patients enrolled in Cincinnati) "Phase III Randomized Study of Docetaxel and Estramustine vs Mitoxantrone and Prednisone in Patients With Advanced Hormone Refractory Prostate Cancer." Objectives Compare the overall survival and progression free survival in patients with hormone refractory metastatic stage IVA or IVB prostate cancer treated with docetaxel (=Taxotere)and estramustine vs mitoxantrone (=Novantrone) and prednisone. ……. 

Clinical Study #5 (2 patients enrolled at University Hospital) "This study is designed to assess the effect and safety of two dose levels of Quadramet administered intravenously every 16 weeks in delaying the development of pain associated with cancer spread to bones in patients with prostate cancer that is no longer responding to hormones" This study is randomized (i.e., similar to a coin toss), placebocontrolled and doubleblind (i.e., patient and assessing physician does not know treatment during the study). There is a 2:1 ratio between patients who will receive active drug and those who will receive a placebo. 

Too many technical or difficult terms? 

Ask your physician, visit http://www.phoenix5.org/glossary/glossary.html or come to one of our meetings. At least one of the six patients enrolled in Cincinnati in a prostate cancer clinical trial attends our meetings regularly. 

I think that the number of active clinical PC trials in Cincinnati and the number of patients enrolled in these trials is remarkably small. This is, unfortunately, not a surprise. 

Kees DeJong, May 19, 2001 
Assistance from Allison Koch collecting this information is gratefully acknowledged. 

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April, 2001

Report from the Cincinnati Prostate Cancer Forum

    I enjoyed the first Prostate Cancer Forum in Cincinnati on 3/24/2001. And I was not alone. Praise was abundant for the excellent organization (Dr. Barrett with Lydia Wocher and Linda Banks), the nice facilities, convenient parking and good food. 300+ men came to the Forum, as well as about 27 urologists and oncologists from the Greater Cincinnati area. 
For me the highlights included the bantering between Drs. Crawford (urologist from Denver -prostatectomy) and Wallner (radiologist from Seattle -brachytherapy). Dr. Crawford managed to show a Tom West (salmon) commercial with the hilarious encounter between a "bear" and a man. See it again at http://www.wilnet.org/Commercials/john-west.html. It's funny, although I am not sure what it had to do with prostate cancer
    From Dr. Wallner we learned that only when the line of a graph remains horizontal for a few years can definite terms such as 'cure' or 'freedom from impotency' be used. Until that moment all is preliminary. For example, it first appeared that impotency was much less after brachytherapy than after prostatectomy. According to Dr. Wallner, after a sufficiently long time period, impotency is about 60% for either treatment. 
    Dr. Wallner also showed slides of his seed implantations and admitted that some of them had been less than perfect. I thought it remarkable that a MD was willing to discuss his imperfections in public.
"Case Discussions" was an important part of the program. Text describing the medical data of a prostate cancer patient was shown on a screen, and a panel of experts gave its opinion. There was not much difference between the surgeon and the radiologist, both favoring an early application of hormonal therapy if the patient had advanced disease. 
    During one of the Case Discussions, Dr. Crawford mentioned that osteoporosis is a serious problem for men on hormonal therapy. He puts his patients on calcium + vitamin D, and many also on Fosamax 10 mg/day or 70 mg/week. I really liked to hear from such an authority that osteoporosis in men on hormonal therapy should be treated immediately. 
    One of us, while on hormonal therapy, could not get his urologist to take the risk of osteoporosis seriously. "My patients -on hormonal therapy- do not have problems with their bones", the specialist had said. His name was among those listed in the program and he was probably in the audience, making the Forum a learning experience not only for patients!
    Dr. Bracken was everywhere, with a kind word for his patients (and many of us are his patients because he refers more patients to the Wellness Community and PCNG than any other urologist). He had thought that it would be impossible to attract so many men to the Forum in a place such as the Kingsgate Conference Center, and was clearly happy that his prediction had been wrong. 
    I also liked talking to Dr. Wallner, the radiologist, whom I had met near the posters of the PCNG. We discussed a few things, and I noticed that he wrote my name on a piece of paper. When he gave his talk, Dr. Wallner apparently wanted audience participation, and asked me to give an interpretation of the graph data he was presenting. As I wrote above, that was not too difficult, and I succeeded to give answers feeling, however, rather sheepish. 
    The PCNG posters included numerical data about prostate cancer research and mortality in Cincinnati. I also asked Dr.Cecilia Fenoglio-Preiser (pictured below) to look at these data. Appointed as the Director of the Barrett Center in January, she spoke to the Forum about the plans of the Center. Her remarks were rather generic, and after the lecture I asked why she had not been more specific, as she certainly could have been aware that research on prostate cancer in Cincinnati was not doing too well. Dr. Fenoglio-Preiser (a pathologist) was indeed aware of the sad position Cincinnati has in prostate cancer research, but she intimated that major changes were in preparation. We will be looking forward to hear details of these changes.

    The importance of research was certainly emphasized by Dr. Bernard Aron who said that women with breast cancer involved in a research protocol did better than women not involved in a research protocol.
    Charles Seibert, who asked a question about this statement, kindly summarized his views on the role of research on the next page. 

Kees DeJong

On the Role of Research in the Care of Prostate Cancer Patients

    The Prostate Cancer Forum raised important questions about the role of research in the care and treatment of prostate cancer patients. Particularly interesting was the final 'Case Discussion,' including remarks of Drs. David Crawford and Bernard Aron. 
    While discussing the best care for a prostate cancer patient, I noticed a subtle shift of emphasis from therapy to enrollment of patients in a research protocol. This shift puzzled me, and I asked about it during the que