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The Information You Need When Considering Whether a Clinical Trial is Right for You!

Tom Beer, M.D., is a medical oncologist who leads a research and clinical trial program at Oregon Health and Science University in Portland, Oregon. He has been directly involved in over 100 clinical trials and has treated many hundreds of cancer patients. He has led trials at all phases, including those that use a medication previously only tested in animals for the first time in people, as well as large international trials that compare treatments to each other that, when successful, change the standard of cancer care. It is Tom’s hope is that this book will help readers enter into the often mysterious world of clinical trials armed with information and well prepared to make needed decisions. Larry Axmaker, Ph.D., is a retired psychologist, teacher, and writer who has cancer (prostate) and has participated in several clinical trials. He recently published a book about prostate cancer entitled Real Men Get Prostate Cancer Too that chronicles his sometimes serious, sometimes humorous journey with his cancer.

Preface	p. xv
Introduction	p. xvii
Cancer and Cancer Treatment Basics
What Is Cancer and How Is It Treated?	p. 3
What Is Cancer?	p. 3
The Six Hallmarks of Cancer	p. 4
The Three Mainstays of Cancer Treatment	p. 5
Surgery	p. 6
Radiation Therapy	p. 8
Medical Therapy (Medications)	p. 9
Evolution of Medicine: From Systematic Knowledge to Evidence-Based Medicine and Toward Personalized Medicine	p. 14
The Bottom Line	p. 17
What Are Clinical Trials and How Are They Organized?
What Is a Clinical Trial?	p. 21
A Brief History of Clinical Trials	p. 21
Dr. Lind's Plan	p. 22
Modern Medicine	p. 22
The Key Ingredients of a Clinical Trial	p. 23
Clinical Trials Versus Standard Care	p. 25
The Eligibility Checklist Process	p. 26
Informed Consent	p. 27
Information About You	p. 28
Statistics in Clinical Trials	p. 28
What Is Risk Reduction?	p. 29
What Is a Survival Benefit?	p. 31
What Does "Significant" Mean?	p. 32
The Bottom Line	p. 34
The Types of Clinical Trials: Four Phases and More	p. 35
Phase I: Safety Testing	p. 36
Blood Level Studies	p. 37
Variations of Phase I Testing	p. 38
The Biologically Effective Dose	p. 39
Why Would You Want to Participate in a Phase I Study?	p. 40
Phase II: Initial Efficacy Testing: Does the New Drug Work?	p. 40
Types of Phase II Studies	p. 41
What's in a Phase II Study for You?	p. 41
Phase III Trials: The New Treatment Compared to Standard Care	p. 42
Why Would You Volunteer for a Phase III Clinical Trial?	p. 43
Phase IV Studies	p. 44
What's in a Phase TV Study for You?	p. 44
Phase 0 (Zero) Studies	p. 45
A Word About Other Types of Studies	p. 45
Why Would You Consider Participating in a Clinical Trial That Doesn't Involve a Treatment Intended to Directly Treat Cancer?	p. 46
The Bottom Line: The Advantages and Disadvantages of Various Types of Clinical Trials	p. 46
Randomized Trials and Placebos	p. 49
Randomization: Letting the Computer Decide	p. 49
Randomization in Today's Clinical Trials	p. 50
Comparing Active Treatment to No Treatment	p. 51
Blinding and Placebos	p. 52
Benefits Can Be Hard to See Without Blinding	p. 54
The Appropriate Role of Placebos in Clinical Trials	p. 55
The Placebo Effect	p. 56
Placebos in History	p. 57
Why Are Randomized Trials So Large?	p. 58
What Happens If a Study Shows a Benefit Even Before It Is Finished?	p. 58
Did I Get the Best Treatment?	p. 59
How Can I Be Sure I Get the New Treatment?	p. 60
The Bottom Line	p. 62
Clinical Trials That Have Changed Cancer Care	p. 65
Surgery Cures More Women with Breast Cancer When Supported by Chemotherapy	p. 66
When Less May Be More	p. 67
Does Surgery Really Help Men with Prostate Cancer?	p. 68
A Sum That Is Truly Better Than Its Parts: Combining Chemotherapy Drugs	p. 68
Location, Location, Location	p. 69
A Successful Revolution: Targeting Mutations That Cause Cancer	p. 70
Hormones and Cancer Prevention	p. 71
Boost Your Immune System	p. 72
Debunking a Medical Bias	p. 73
When Our Basic Beliefs Are Challenged	p. 74
The Next Breakthrough Study-What Will it Be?	p. 75
The Bottom Line	p. 75
Deciding Whether to Participate in a Clinical Trial
Is There a Clinical Trial That's Right for Me?	p. 79
Deciding Whether to Participate in a Clinical Trial	p. 79
What Should You Know Before Choosing a Clinical Trial?	p. 80
What Potential Benefits and Risks Should You Consider Before Choosing a Clinical Trial?	p. 80
The Effects of Attitudes, Emotions, and Reality in Choosing a Clinical Trial	p. 81
"I Just Want to Be Left Alone!"	p. 82
Cancer Support Groups	p. 83
Choosing the Right Trial for Your Needs	p. 84
I'm Interested. What Do I Do Next?	p. 84
Start Close to Home	p. 85
Know Your Disease State, Stage, and Prior and Current Treatments	p. 85
Searching Online-The Basics	p. 86
Advanced Searches	p. 88
I've Done My Homework…Now What?	p. 90
The Bottom Line	p. 92
Who Is Looking Out for You and What Can You Expect?	p. 93
How Are Studies Overseen and Regulated?	p. 93
The Power of the FDA	p. 94
Not One, but Two Animal Tests!	p. 95
Truly Independent, Ail-Powerful Oversight: The Data Safely Monitoring Board	p. 95
What Can I Expect From My Doctor and Investigative Team?	p. 97
What If I Have Concerns and I'm Not Sure Where to Go for an Answer?	p. 98
Am I Free to Quit If I Want To?	p. 98
What If I Have Side Effects? How Will I Know If I Should Be Concerned?	p. 99
What If Something Goes Wrong?	p. 100
How Do You Get Through the Red Tape?	p. 100
Why Are There Delays?	p. 101
A Concern You May Have: "If I Start a Clinical Trial, and the Trial Medications Don't Work, I Could Be Wasting Valuable Time."	p. 102
The Bottom Line	p. 105
Who Pays for Clinical Trials-And What Can They Cost?	p. 107
What Costs Are Involved in Clinical Trials?	p. 108
Who Pays for These Costs?	p. 108
Costs of Your Care and Insurance Coverage of Cancer Clinical Trials	p. 109
Medicare Comes Through	p. 111
Traditional Health Insurance	p. 114
The Bottom Line	p. 121
Medical Treatment of Cancer Now, and in the Future
Cancer Drugs Currently in Use and Being Tested in Trials	p. 125
Chemotherapy Drugs	p. 125
Antimetabolites	p. 127
Alkylating Agents	p. 128
DNA Cross-Linking Platinum Derivatives	p. 128
Antitumor Antibiotics	p. 129
Topoisomerase Inhibitors	p. 129
Microtubule Assembly and Disassembly Inhibitors (Mitotic Inhibitors)	p. 129
Hormonal Agents	p. 130
Testosterone- and Estrogen-Lowering Drugs	p. 130
Hormone-Blocking Drugs	p. 131
Testosterone Conversion/Activation Blockers	p. 132
Small-Molecule Targeted Drugs	p. 132
Monoclonal Antibodies	p. 134
Immunotherapy	p. 134
Differentiation Therapy	p. 135
Gene Therapy	p. 136
A Last Word About Drugs	p. 136
The Bottom Line	p. 137
The Future of Cancer Treatment and Clinical Trials: Personalized Medicine	p. 139
Targeted Therapy	p. 139
Personalized Therapy	p. 140
Pharmacogenomics	p. 142
The Bottom Line	p. 142
A Final Word	p. 144
Tell Us What You Think	p. 144
Glossary	p. 145
Resources	p. 155
General Clinical Trials Information	p. 155
Information Specific by Tumor Type	p. 156
Index	p. 157
Table of Contents provided by Ingram. All Rights Reserved.

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From Chapter 2: What Is a Clinical Trial?

Modern Medicine
We now live in an era of evidence-based medicine. Evidence of success, usually collected in clinical trials, is now expected before a treatment is adopted as safe and effective. We use such evidence to understand the risks and benefits of medical treatments, and to make sound decisions about what treatments are best.
Clinical trials define the gold standard of care—the best treatment available. Medical science advances through clinical trials, even if progress is slow at times. Remember, it took more than 40 years for Dr. Lind’s breakthrough results to become widely accepted. No area of medicine is more in need of advances than cancer care, and hundreds of novel treatments are currently being evaluated in cancer clinical trials.
CALL-OUT: Clinical trials define the gold standard of care—the best treatment available.
The Key Ingredients of a Clinical Trial
Although clinical trials have grown large, complex, expensive, and tightly regulated, the principles of a sound experiment are universal. The basic ingredients from Lind’s eighteenth-century clinical trial remain the same in twenty-first century clinical trials:

• All trials begin with a hypothesis—an idea or a new theory—about what the researcher thinks will happen. For example, Dr. Lind’s hypothesis was that lemons and oranges might cure scurvy. The rest of the trial is all about testing the hypothesis. You prove it to be right, wrong, partially right, or partially wrong. Hypotheses can be as simple as this: the new drug ABC-123 will shrink cancer tumors (most new drugs begin with a boring name that resembles a license plate number!). Hypotheses can also be more complex: new drug ABC-123 will shrink tumors; it will also produce acceptable side effects up to a certain dose, above which the side effects will become unbearable, but it might work really well against some incurable cancers at a dose just shy of unbearable. You get the idea.
• The trial is designed and carried out to test the hypothesis. This is the experiment, the core of the trial (Dr. Lind used six groups of volunteers to test his hypothesis). The experiment, of course, has many parts, which we will explain in detail.
• The results—what everyone is after. Did it work? How well? A little? For which people? Can the results be duplicated with a larger group? Will it lead to a new approved medication or treatment, and, most importantly, did it or will it help you? At the outset, no one knows what the end results will be. That’s why it’s called a trial.

Even the most complex clinical trials are made up of simple parts and are fairly easy to understand, at least for those conducting them. Dr. Lind had a hypothesis that lemons and oranges would help sailors overcome scurvy. He gave lemons and oranges to some sailors and something else to others in order to find out if he was right (the experiment), and he learned that he was right (the result). Hypothesis. Experiment. Results. That’s it “in a nutshell.”
To understand what you are getting into if you’re considering a clinical trial, you will need to understand the first two of these ingredients, hypothesis and experiment. Of course, you’ll also want to know the third as soon as possible. It would certainly be nice to know what will happen before you even consider the trial. After all, why would you want to take a drug that may or may not work?
While you cannot know the results of a clinical trial that has not been completed, it’s important to thoroughly understand why the trial is being conducted (the hypothesis) and how it’s going to be conducted (the experiment). You’ll also want to know how the clinical trial might benefit you: what is the expected—or hoped for—result. We will help you learn to ask the right questions of the right people to get these answers more quickly.
Clinical Trials Versus Standard Care
You may be thinking, “Why would I want to try a treatment that might or might not help me?” You may be right. If there is an effective standard treatment that works for you, there is no reason for you to enter into a trial. Here are some explanations that might help.
In many ways, clinical trials and standard care for cancer are similar. Both require you to visit doctors and nurses, take medications, have blood tests, body and possibly brain scans, have regular physical exams, have needles inserted in tender places, and undergo many other procedures and indignities. For those of you who are just beginning cancer treatment, there will be a great many unknowns, in both experimental and standard treatments. After all, you have not done this before. You will encounter a lot of new information, face new treatments and unfamiliar tests, and have unexpected experiences. You could look at it as a new adventure in your life, although not an adventure you ever wished for!
Whoever came up with the term standard treatment didn’t consider that although it may be standard procedure for your doctor, nothing could be further from what you might consider standard. The whole process can be frightening.
Treatment for cancer—whether standard or experimental—usually involves side effects, expenses, testing, and a lot of your time. Standard treatments become standard when they are shown, in large clinical trials, to be better than the previously accepted standard. By better we mean that the entire group of patients who received the standard treatment generally fared better than the entire group of patients who received the treatment it replaced. This does not mean that every patient benefitted equally, and some people may not have benefitted at all. Standard treatments may involve a fair amount of uncertainty as to your personal outcome.
Even when you are beginning a treatment that is considered standard for your type of cancer, you will likely hear that there is a certain chance that you will benefit from it, often expressed as a percentage of people who remain cancer-free or whose cancers are under control a number of years after treatment. Hopefully, the chances of success are high, but they are almost never 100 percent, and often they are disappointingly low.
New treatments are needed because we don’t yet have perfect cancer treatments. So, although there are more unknowns when you consider experimental therapy, they are often similar to those that you face when you receive standard therapy. It will be important for you to understand both options in order to make the right or best choice for you.
The Eligibility Checklist Process
Despite the similarities, clinical trials are certainly not the same as regular cancer care. Trials are much more carefully regimented. Even before you get started, you will have to qualify to be in the trial. The doctor or study nurse has a long checklist of eligibility criteria. You may or may not be shown this list, but it’s always part of any clinical trial.
This checklist—often 20 to 40 items long—lists all the criteria you will have to meet in order to qualify for a clinical trial that might or might not work for you. Thank goodness we are not subjected to such checklists in most of what we do in everyday life! We’d never get anything done.
While the checklist may seem like the “Great Wall of China” standing between you and your hope of joining a study, it is there to protect you, and to make sure that the study is carried out properly. Many of the criteria focus on ensuring that you are healthy enough or—in some cases—unhealthy enough to receive the proposed treatment. The criteria will likely include:
• Kidney function
• Liver function
• Heart function
• Blood counts

Other parts of the checklist are designed to make sure that all participants in the trial are similar enough that the experiment and results will be valid. It would be difficult to know how well a drug performed in advanced prostate cancer, for example, if the study participants had many different kinds of cancer in all stages. So each trial defines the patient population for which it is designed. You will not know if you meet the trial’s criteria until the qualification process—also called the screening—is completed.
The rigid nature of a clinical trial does not end with your being admitted into the study. Once treatment starts, your care will follow a tightly scripted plan. The schedule of every blood test, scan, dose of medication, and doctor visit is dictated by the clinical trial protocol—it includes dates, times, places, and procedures. This can also be the case with standard cancer therapy, but although regular cancer therapy is thorough it can be relatively flexible. Clinical trial therapy is closely controlled and monitored, because skipping a test or not taking a medication as prescribed could affect the overall trial outcome.
CALL-OUT: The rigid nature of a clinical trial does not end with your being admitted into the study. Once treatment starts, your care will follow a tightly scripted plan.
Informed Consent
As discussed in detail in Chapter 7, clinical trials are tightly regulated and overseen by an independent oversight committee. One of the committee’s responsibilities is to make sure that all participants are thoroughly informed about the trial they are considering. Participation in a trial will begin with the reading of a detailed, and often exhaustive, consent form.
You need to read the consent form and understand it—even if it seems long and boring. While the concept of informed consent is not unique to clinical trials, in routine care it often consists of nothing more than a conversation between a doctor and a patient. Not so for clinical trials. You get at least one conversation, sometimes two (doctor and nurse or study coordinator), and a volume of questions and statements in fine print. You not only have to read it, but also sign it. It’s all quite a bit more formal than consenting to standard treatment.
Information About You
Finally, information about how you are doing with the trial medication goes into the medical record, as it does for standard care. It also goes into the study database, where it is combined with the experience of all the other trial participants. This is referred to as the study data. Generally, you will have access to your personal results (although there are exceptions), but you probably will not be given information about results from the overall database. If you are given this information, it may be a long time before you receive it.
In addition to routine information such as blood test results, the study may ask you to fill out surveys about how you are feeling, thinking, sleeping, eating, how your spouse is doing, and so on. Clinical trial studies often collect much more information about the daily routine in your life than doctors do in the course of routine standard care.
Whether there are five, 500, or 5,000 participants in the study, it is unlikely that you will know who else is in the trial. But you will know a lot about their type and stage of cancer, because it will be much like yours.
Statistics in Clinical Trials
Statistics are the tools used to interpret data from studies and discover if there is a real difference between two treatments. You need to have a basic understanding of statistics to evaluate what a clinical trial is seeking to accomplish. The same concepts will help you better evaluate standard treatments you may be considering. So, resist the urge to skip the following section and let us introduce you to a few key statistical concepts. This will help you know what to look for—and what to look out for—in order to understand your options and be aware of what you might expect from your treatments.
What is Risk Reduction?
All treatments seek to reduce the risk of something bad—death, cancer coming back, or some terrible complication, for example. The way this reduction in risk is described can leave you more confused than informed. Ideally, your risk would be reduced to 0—meaning the treatment was a reliable cure. If that were the case, we would not need statistics very much. In almost all cases, modern cancer treatments work for some people and not for others, and risk reduction statistics are how we talk about the results. You may hear that drug “X” reduces the risk of cancer coming back by 40 percent. That sounds good, doesn’t it? Not perfect, but it might make a big difference. Well, maybe, or maybe not.
CALL-OUT: In almost all cases, modern cancer treatments work for some people and not for others, and risk reduction statistics are how we talk about the results.

Most such statements focus on so-called relative risk. This is risk in the treated group compared to the control group (patients receiving some other treatment or no treatment). Whether, for example, a 40 percent risk reduction is great, or not so great, depends on the absolute risk—meaning the actual risk experienced by the control group. In many ways, an absolute risk reduction is probably the more accurate way to report results, but it never sounds as impressive.
As an example, let’s say that women with a certain stage of breast cancer have a 90 percent chance of cure with surgery alone. In this situation, the absolute risk of cancer coming back is 10 percent. A fantastic drug comes along that reduces the risk of the cancer coming back by 40 percent! Sounds great, right? Maybe, but it may not be as impressive when you realize that the drug reduces risk from 10 percent to 6 percent. The risk was reduced by 40 percent, but it was small to begin with. When you start with a risk of 10 percent, a 40 percent reduction means that risk is reduced by 40 percent of 10 percent. This is equal to 4 percent.
(A figure might be useful here)
We hope your head is not spinning right now, because this concept is really important. A 4 percent risk reduction in absolute terms could be quite significant, but it means that if we treat 100 women, 90 would have never suffered a recurrence in the first place, six would have had a recurrence anyway, and only four would have truly benefitted from the treatment—they would have had a recurrence without any treatment but don’t because they were treated. It would be ideal, therefore, to just treat those four women and leave the other 96 alone! Someday, we may be able to do just that (see Chapter 10), but right now we can’t tell in advance who they will be.
Understanding this can help you make decisions. A 4 percent reduction in the risk of cancer coming back may be a really important benefit for you. If so, the decision will be an easy one to make. However, if you have other health concerns and the potential side effects of the new drug are severe, you might make a different decision. If all you hear is that the reduction is 40 percent, you might not even think about it. QUERY: The preceding discussion of percentages might be a bit confusing. Please review for clarity.
When you see risk reduction numbers, ask yourself first: “What is the actual (absolute) risk to begin with?”

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Cancer Clinical Trials A Commonsense Guide to Experimental Cancer Therapies and Clinical Trials

Cancer Clinical Trials A Commonsense Guide to Experimental Cancer Therapies and Clinical Trials

098232197X

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