The Science of Prostate Cancer

The Science of Prostate Cancer

by Peter Hahn

Copyright 2014 Peter Hahn

Smashwords edition

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Table of Contents

Preface

Chapter 1: Introduction

The Prostate Gland

Prostatic Intraepithelial Neoplasia (PIN)

PSA

Treatments

Biopsy

Gleason Score

Tumor Staging: TNM Categories

Early Detection and Treatment

Risk Assessment

Nomograms

Statistics: Probability and Risk

Bibliography

Chapter 2: The PSA Era

The PSA Test

Clinical Trials

Prostatectomies for Low-Risk Prostate Cancer

SPCG, Scandinavian Prostate Cancer Group Study

PIVOT The American Study

The Slippery Slope

Conclusion

Bibliography

Chapter3: Treatments for Low-Risk Disease

Radiation or Surgery?

Survival Odds

Risk Level Determination

Treatments

Biochemical Failure

Side Effects – Radiation vs. Surgery

Diet and Exercise

Smoking and Prostate Cancer

Bottom Line for Treatment Decisions

Bibliography

Chapter 4: Locally Advanced, High-Risk Disease

Prostatectomies and High-Risk Disease

Radiation for Locally Advanced Disease

Hormone Therapy

Age Considerations

Specific Factors that Influence Prognosis

Lymph Node Positive Disease

Subcategories of Locally Advanced Prostate Cancer

Bibliography

Chapter 5: Metastatic Disease

Prognosis

PSA Biochemical Failure

Micrometastases

Failure of Local Control

Metastatic Disease

Prognosis: Biochemical Failure

Hormone Therapy, Androgen Deprivation, Orchiectomy

The Drugs

Salvage Radiation Treatment

Adjuvant Hormone Therapy

Clinical Trials: Hormone Therapy, When to Start

Node Positive Prostate Cancer

Seminal Vesicle Involvement

Biochemical Failure and Initiation of Hormone Therapy

Intermittent vs. Delayed Hormone Therapy

Conclusion

Bibliography

Chapter 6: After Hormone Therapy Stops Working

Prognosis

Treatments: Docetaxel

Experimental Treatments

Clinical Trials of Experimental Drugs

Abiraterone

Sepuleucel-T

Palliative Care

Hospice

Bibliography

Chapter 7: Medical Decision-Making

Why Men Get PSA Tests

Expert Recommendations on PSA Testing

The Patient’s Decision

The Primary Care Physician’s Decision

The Urologist’s Decision

Dying from Surgery vs. Dying from Prostate Cancer

The Money

Bibliography

Chapter 8: Biology of Prostate Cancer

Molecular Biology

The Molecular Biology of the Androgen Receptor

TMPRSS2-ERG Fusion and the ETS Family Fusions

Clinical Implications

PTEN

CADM2

STAT3

Ploidy

Late Stage Hormone-Resistant Disease

Bcl-2 Overexpression

Conclusion

Bibliography

Chapter 9: Imaging

Imaging in the Initial Screening (and Biopsy)

Imaging and Radiation Therapy

CT Scans

Imaging and Active Surveillance

MRI (and MRSI)

Imaging and Metastatic Disease

Bone Scans

PET Scans and SPECT

Conclusion

Bibliography

Chapter 10: The Future

Experimental Treatments

Nanoparticles

Cryotherapy and Hyperthermia

Targeted Therapy

Oncotype

Conclusion

Bibliography

Chapter 11: Recommendations

PSA Testing

Risk-level and Treatment Choices

Radiation vs. Surgery

Metastatic Disease

Prostate Cancer Survivors

Prostate Cancer Survivor Support Web Sites

Online Nomograms

Glossary

Acknowledgements

I would like to gratefully acknowledge my editor, Susan Hahn, who spent countless hours scrubbing out the overly complex sentence structures. I would also like to thank Drs. Gabe Haas, Chad Dawson, and George Hahn for critically reading version of this manuscript.

I would also like to acknowledge the Department of Defense (DOD) Congressionally Directed Medical Research Programs (CDMRP). This program has a long history of funding Prostate Cancer Research. Serving many years on the grant review panels has been critical to my understanding the issues facing both the medical/scientific community and the prostate cancer survivors.

Preface

Evidence-Based Medicine: My goal for this book is to provide prostate cancer patients and their families access to what is known about prostate cancer and prostate cancer treatments. In this book I review the scientific literature and discuss the many studies that have been done to try to determine the best prostate cancer treatments. This is not a simple subject. Prostate cancers vary from almost harmless to deadly. The treatments have serious side effects. Deciding which treatment is right requires that you first understand your disease. You then have to choose one of many possible treatments.

There have been many studies following thousands and thousands of prostate cancer patients. The goal of these studies is to determine whether one treatment or approach works better than another and for which patients. The best of these studies divide patients into two large groups that are then given different treatments and followed for many years. Mostly these studies focus on whether one group lives longer, on average, than the other group. Some of the results will surprise you.

Most of us are familiar with this approach. For example, we are well aware of studies that have shown that men or women who smoke two packs of cigarettes a day develop lung cancer at a much higher rate than people who don’t smoke. Yet we all have heard of people who have lived to be 100 who smoked every day of their adult lives. There are also people who never smoked who die at an early age from lung cancer. Nevertheless, most people, including most smokers, accept that if we wish to live a long healthy life and not die of lung cancer we should not smoke. This is evidence-based medicine. Evidence-based medicine relies on current, verifiable information from scientific studies to inform medical recommendations and decision-making.

Someday tests will be available to tell doctors the best specific treatment for each individual patient. Such tests will usher in the era of personalized medicine. The patient’s DNA will be sequenced and cancer patients will also have their tumor DNA sequenced. Doctors will tailor treatments for each of their patients. We are a long way from that goal.

In the meantime we have statistical studies. Many thousands of similar patients are treated and then followed for many years. The results are analyzed statistically. These studies tell you the range of possible outcomes for patients like you. They tell you how likely you are to be helped or harmed by any particular treatment. These studies give you and your doctors the best information available to plan your treatment.

How to read this book: This book is designed to be a reference source. My assumption is that people will read the sections that specifically apply to their personal situation rather than reading cover to cover. You are certainly welcome to start at the beginning and read through to the end, but I suspect most people will jump around. As such, I have included many navigation aids to help people move from section to section and back again.

When an issue is relevant to more than one situation, I will discuss it in multiple chapters. For example, there are several studies that show that prostatectomies can save lives for men with aggressive high-risk prostate cancer who are under the age of 65. These same studies show little benefit of prostatectomies for men with low-risk prostate cancer of any age. These studies are discussed in both the chapter on low-risk prostate cancer and again in the chapter on high-risk prostate cancer.

Prologue

In the USA today, 16% of American men will be diagnosed with prostate cancer in their lifetime and perhaps 20% of these men will die of their disease. Dying of prostate cancer is not an easy death, and a huge effort has gone into developing a widely embraced early detection and treatment program. Unfortunately, 20 years into this program, there is no evidence that early detection and treatment has translated into saving lives.

What I am attempting here is to give a clear-eyed recounting of the latest scientific studies. Because prostate cancer is so common, we now have a pretty good idea of what happens to prostate cancer patients. These data are the basis of your physician’s statement that of 100 men in your situation... It is a statistical description, and cannot predict anyone’s future but it is the best information we have now.

A large number of studies published in the past year or two have questioned our current approach to treating prostate cancer. This evidence has led the US Preventative Services Task Force to recommend against using PSA testing to detect early stage prostate cancer. Their reasoning is outlined in a recent review in the Annals of Internal Medicine. Other recently published studies (e.g. PIVOT, Wilt et al., 2012) have concluded that most men who are diagnosed with early stage prostate cancer do not benefit from prostatectomies. These latest studies only add to the mounting evidence that strongly suggests that we need to radically rethink our approach to this disease.

Prostate cancer is different from other cancers. It is extremely common in older men, but at least in the early stages it grows more slowly than any other cancer. I discuss prostate cancer’s unique characteristics in the biology chapter. The incidence of prostate cancer is estimated to be almost as high as a man’s age. That is, 70% of 70-year-old men may have prostate cancer or its precursor. Most of these cancers will take more than 30 years to turn deadly. If you are an older man, finding out that you have early stage prostate cancer tells you little more than that you have a prostate.

The unusual biology of prostate cancer defeats the early detection and treatment strategy that has been one of the cornerstones of successful cancer treatment. The early detection strategy assumes that deadly cancers start out as relatively harmless and easily curable early stage cancers. Therefore, finding these cancers when they are still very small should be the key to saving lives. The strategy also assumes that the early stage cancers, if left untreated, will turn into the deadly late stage cancers that cut lives short. But prostate cancer is different. Most of the early stage prostate cancers stay that way.

A recurring theme of this book is that prostate cancer should be viewed as three separate diseases that require three different approaches. The majority of prostate cancers discovered by PSA testing fall into the indolent low-risk early stage of prostate cancer. Most of these cancers do not need to be treated initially and may never need to be treated. Another sizable group of prostate cancers are the high-risk locally advanced cancers. These need to be treated aggressively and can frequently be cured. A third and smaller group of prostate cancers are metastatic, meaning that the disease has already spread beyond the prostate region. These cancers can be treated to slow the disease but are invariably fatal. Although it is thought that these three groups represent a continuum it does not follow that the early stage disease will progress to the later stage disease.

Doctors could simply take out every man’s prostate when he turns 50 (or even 40). That would cut the prostate cancer death rate to near zero. Unfortunately, prostatectomies have serious potential side effects. Incontinence and impotence are the most common complaints. Most men are more than willing to suffer these consequences in exchange for significantly reducing their chances of dying from prostate cancer. However, it is becoming increasingly clear that the vast majority of men with early stage prostate cancer are barely at greater risk of dying of prostate cancer than their neighbor who has a normal PSA value. This is not as encouraging as it sounds, since 3% of those normal-PSA neighbors will die of prostate cancer. We need an effective way to identify the men at risk of developing the lethal form of the disease but we are much farther from that goal than most people, and even most physicians, realize. We also need better treatments. The current treatments are analogous to radical mastectomies, but what we need are effective lumpectomies.

My original purpose in writing this book was to present an overview of where we are today in order to aid physicians and scientists to develop new approaches. However, it has become clear to me that the group that really needs to be more informed about prostate cancer is men over 50 years of age and especially the prostate cancer survivor groups. The survivor groups are organizations of men who have advocated for more prostate cancer research funds. They have been instrumental in shaping public attitudes towards prostate cancer. They need to help inform the average man about the complexities of prostate cancer so men can better negotiate the medical system.

The problem we face is that complex medical decisions about prostate cancer treatment are increasingly being left to the patient in the name of joint doctor/patient decision-making. The patients, collectively, are going to have to do the heavy lifting to provide direction for new treatments. In addition to continuing to lobby for more research to develop newer and better cures for the aggressive form of the disease, they will also need to aggressively confront the overtreatment problem.

Because I think that men over 50 need to be more involved, I have tried to make this text accessible to the average reader. As an over-50 year-old biologist I have been quite surprised by the personal implications of recent clinical studies. I also know many men – relatives, colleagues, friends and neighbors – who have been diagnosed with and treated for prostate cancer.

This again brings up the most important point of this book. If you have been recently diagnosed with prostate cancer, your very first step should be to understand which type of cancer you have. This is because your thinking about what treatment is right for you should be strongly influenced by how aggressive the cancer is. If you are diagnosed with the low-risk early stage disease, as are 70% of newly diagnosed prostate cancer patients, there is a 97% chance you will survive your prostate cancer for at least 10 years, even if you do nothing at all. If you get a prostatectomy, your odds go up to 99%, but your odds of living longer are not increased. (This seeming paradox is explained in multiple ways throughout this book) On the other hand, if you have the more advanced forms of prostate cancer, the different treatments can greatly extend your life.

The low-risk early stage prostate cancers are the ones that routine PSA screening uncovers. The PSA test is effective at doing what it is designed to do – to increase the rate of early diagnosis and treatment of prostate cancer. It should also be acknowledged that routine PSA screening is something that prostate cancer survivors have fought for and believe in. PSA testing has now become part of the standard of care, meaning that primary care physicians are subject to malpractice lawsuits if they don’t offer the test and it is likely they would lose the lawsuit. The test, by itself, is safe and harmless. There is also a great deal of health-care money involved. All of these facts mean that it is likely that we will be living with routine PSA testing for a long time.

One result of continued PSA testing is that we will soon create two very large groups of very unhappy men. One group, on the order of 100,000 American men per year, will be told that they have the very early stage of a terrible disease, but the best we can do for them is to keep an eye on it and hope it doesn’t get worse. If it does get worse, we will treat the disease aggressively, with all the potential bad side effects. The treatment may save their lives, but it may also be too late. The other group consists of the men who were treated aggressively following their physician’s recommendation, and who are experiencing the side effects of that treatment. Now they will read that exhaustive studies have failed to show any life-saving or life-extending advantage to the treatment. Both groups will likely regard this new situation with disbelief.

To support the conclusions in this book, I review the scientific data. As mentioned in the preface, the approach used here is evidence-based medicine. The focus is on what has – or has not – been shown to be effective in clinical trials. Clinical trials are studies organized by the medical community that follow thousands of patients and compare promising new treatments with the currently accepted best treatment. This is considered the gold standard for evaluating potential medical advances. Unfortunately, as we know, many promising treatments don’t work as well as hoped or cause more harm than good. PSA screening and prostatectomies for very early stage prostate cancer now appear to be in this group of promising new treatments that cause more harm than good.

In some quarters, evidence-based medicine is viewed with suspicion. It can be seen as a cost-control strategy to deny potentially life-saving treatments. If it takes 10 or 20 years to show that a treatment is effective, that might be 10 or 20 years the insurance company doesn’t have to pay for the treatment, and 10 or 20 years that patients are denied some life-saving benefit. In this case, however, we have been using (and paying for) this potentially life-saving treatment for over 20 years in the anticipation that the clinical trials would show a real benefit, but they have not. Now what?

For the scientists and physicians one thing should be clear. Once you subtract all the cures of prostate cancers that probably didn’t need to be treated in the first place (the 97% of the low-risk prostate cancers), we have made remarkably little progress in recognizing and/or treating the aggressive lethal form of the disease.

What follows is what we have learned in the past few years about prostate cancer. This information should be useful for anyone who is tempted to Google some medically-related prostate cancer issue. In particular, anyone who has been recently diagnosed with prostate cancer or just gotten the news that his PSA is elevated will try to find out everything he can. What you will get from searching the internet is a confusing array of opinions interspersed with dense scientific literature. In this book I try to summarize the scientific literature and place it in the context of the bigger picture. I have also provided references so you can check out individual studies if you have more in-depth questions or if you question my analysis.

Chapter 1: Introduction

The Prostate Gland

Prostatic Intraepithelial Neoplasia (PIN)

The PSA Test

Treatments

Biopsy

Gleason Score

Tumor Staging: TNM Categories

Early Detection and Treatment

Risk Assessment

Nomograms

Statistics: Probability and Risk

Bibliography

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