Prostate Cancer terms and treatments- Things to know
It's important to remember that it can't be one-stop shopping for the treatment of prostate cancer. You've got to factor in the stage of the disease, the Gleason grade is a very important predictive factor, prostate -specific antigen (PSA) level, health status, and so forth, and then decide on surgery, radiation, brachytherapy, watchful waiting, or use bisphosphonates.
Slide 5. Advanced Prostate Cancer-Classification Refinements Within the A-B-C-D Staging System
Several years ago, Dr. Blumenstein and I reported on a new stage of prostate cancer, which we called D1.5, which is a rising PSA after failed local therapy. This is biochemical failure. This is the most common way we're seeing advanced prostate cancer present. And it's a real challenge and a subject of a lot of debate -- what to do, when to do it, how long to do it, and so forth.
Slide 6. Metastatic Disease: Goals of Treatment
Most of the patients live about 3 years. They go into a hormone-refractory state and the goal, when that happens, is prolonged survival if we can manage symptoms and maintain a quality of life. And that's what our patients want from us.
Skeletal-Related Events: Definition and Impact
Slide 7. Impact of Skeletal-Related Events (SREs)
SREs are skeletal-related events. These are debilitating, painful, and have an impact on the patient with prostate cancer's life and life expectancy. We know that prostate cancer has a predilection for bone. We're going to hear a little bit about that, why it is, and what you can do about it.
Slide 8. Remember
This is just my way of remembering it, to prevent an SRE, get a Digital Rectal Exam (DRE).
Slide 9. Summary
Bone metastases are common in prostate cancer. We know that. And indeed, if you look at most patients with the disease, when it progresses, 65% to 75% of them have significant bone disease.
SREs are important and they are debilitating.
Slide 11. Strategies Would You Typically Attempt Before Administering Chemotherapy or Referring
We asked them what do you do when somebody fails hormonal therapy? And the answer, the first one, was withdraw anti-androgens, which obviously makes sense. A number of people will respond. The average time is 3 months.
Lots of other things happen. Adding an anti-androgen, ketoconazole, prednisone, and various other things. We all know that once somebody's hormone refractory, that in fact we're not prolonging their survival with quality of life. Hopefully, some of the new chemotherapy studies that are ongoing will be helpful. We have one with Taxotere (docetaxel) and M/Cip vs mitoxantrone and prednisone, which is considered the standard. We may see some improvement in survival rate, and that's going to be important to make that first step.
Slide 2. Disease Stages
This slide is an attempt to introduce sort of what I think at least is the overview of the epidemiology of prostate cancer in the United States in the year 2002. So, this is specifically focused on patients who present with localized disease, which represent somewhere between 85% and 90% of cases of prostate cancer that are diagnosed today in the US.
A patient comes in and has several treatment options. They elect a treatment option. We won't get into how or why they do that. And if they fail that treatment option, how do they fail? About 90% of patients who fail either radiation or surgery will do so within the first 7 years of follow-up.
So then recurrent disease, the majority of cases is detected as a biochemical failure with a rising prostate-specific antigen (PSA). And the most common therapy, obviously, at that time, is androgen-deprivation therapy.
The average patient spends between 3 to 5 years in a hormone-sensitive state and then progresses to the androgen-resistant state. And what happens generally, again, the PSA is the marker that detects it and at that point, the patient is reevaluated and has a median survival of about 8 months.
Patients can enter at the metastatic state and progress more rapidly to androgen-resistance, but that's roughly the algorithm of how prostate cancer is managed today.
Slide 3. Metastatic Disease: Treatment Options
What are the treatment options that currently exist? They're fairly well understood by most urologists. In the setting of advanced disease, the options include some form of androgen-deprivation, either medical or surgical castration, with or without the combination of an anti-androgen agent. For patients who fail androgen-deprivation, some form of systemic chemotherapy is used. Taxanes were mentioned, mitoxantrone. And then supportive care options, which include radiopharmaceuticals like strontium, treatment of local symptoms with either pain control, radiation, or surgery. And then a new category of medications that have been around for quite some time, but they really haven't shown efficacy in this setting, and that's intravenous bisphosphonates.
Slide 4. Metastatic Disease: Goals of Treatment
The goals and treatment for the patient with metastatic prostate cancer are really 3-fold. One is to prolong quantity of life, survival. And that's the typical endpoint in most oncology trials: how much time is the patient offered by the treatment?
But more importantly perhaps is, the majority of patients have a median survival of roughly 8 months once failing hormone treatments, and the goal is to maintain a quality of life. So it's quantity and quality, and managing the symptoms that have been associated with advanced prostate cancer, particularly in reference to the bony symptoms.
Slide 5. Metastatic Disease: Complications
The complications of metastatic disease, the way I, at least, think of them, are really in 2 major categories. One is the complications related to the disease itself, and the other is the complications that are related to us, the physicians, offering treatments.
The disease-related complications fall under a term called skeletal-related complications or SREs. A brief definition basically is a complication from the disease that affects the skeletal bone, including bone pain, which is the most common; fractures, often in terms of pathologic fractures; spinal cord compression from either vertebral body collapse or direct tumor impingement upon the spinal cord; and then radiation to the bone or an operation performed for one of these events.
Other non-skeletal-related complications of the disease itself include urinary tract obstruction, either hydronephrosis or bladder outlet obstruction, as well as cachexia, weight loss, and anemia.
Treatment-related complications are important. Medication may actually have an effect on both of these - disease-related and treatment-related. And the most common one, androgen-deprivation therapy, has some classic side effects, including osteoporosis, hot flashes, loss of libido and impotence, and anemia.
Advanced Prostate Cancer and Bone Metastases
Clinical Importance, Prognosis, and Diagnosis of Bone Metastases
Today in the United States, the epidemiology of prostate cancer is fairly well understood. It's the most common malignancy in men. It accounts for roughly 185,000 new cases of cancer every year. It's the second most common cause of cancer death, second only to lung cancer.
What's a little bit less clear is what's called the prevalence of prostate cancer. And that basically is defined simply as how many people are walking around today in the United States with the diagnosis of prostate cancer? So that's accumulation of the incidence of prostate cancer. And at least in 1999, which is 3 years ago now, there were about 1.5 million patients in the US. Based on the incidence and the average life expectancy, that number's probably over 2 million.
So there are more than 2 million patients with prostate cancer today in the United States in all various forms of remission, treatment, or relapse. And probably somewhere on the order of 30% or 40% of these people are failing local therapy, and another 10% presenting with metastatic disease. So this is a large target audience. There are a lot of patients at risk for SREs and that's why this is probably a very significant population to be aware of and one that we're not quite comfortable with right now because we don't have a lot to offer them.
Here's the classic detection in metastatic disease. Here's a bone scan that shows a solitary vertebral metastasis.
Here's a slightly more advanced picture, oftentimes referred to as a super-scan. This is multi-focal bony metastasis in an androgen-resistant patient who presented with a rising PSA after medical castration.
How do we diagnose bone metastasis? This is just a typical state-of-the-art review. Right now, the most common way to diagnose a bone metastasis is a bone scan, radiopharmaceutical technetium scan. A plain x-ray is oftentimes used to detect osteoblastic lesions, and an MRI, particularly in the case of spinal cord compression, can also be used. When these fail, or if these are equivocal, a bone biopsy will be required, but that's not the standard.
Slightly more controversial is when to look for bone metastases. And depending on who you ask, these answers will be different, but in general, patients with PSA greater than 10, and that's a continuous numerical value. So the higher the PSA, the more likely they are to have bone metastases; patients with poorly differentiated cancers, Gleason 7, 8, 9 and 10; patients who have failed primary therapy and are presenting with a relapse in biochemical or otherwise; and those patients who have clinical suspicion, with or without any of these variables, such as bone pain or a new fracture.
PSA test results report the level of PSA detected in the blood. The test results are usually reported as nanograms of PSA per milliliter (ng/mL) of blood. In the past, most doctors considered PSA values below 4.0 ng/mL as normal. However, recent research found prostate cancer in men with PSA levels below 4.0 ng/mL . Many doctors are now using the following ranges with some variation:
- 0 to 2.5 ng/mL is low.
- 2.6 to 10 ng/mL is slightly to moderately elevated.
- 10 to 19.9 ng/mL is moderately elevated.
- 20 ng/mL or more is significantly elevated.
There is no specific normal or abnormal PSA level. The higher a man’s PSA level, the more likely it is that cancer is present. But because various factors (such as age) can cause PSA levels to fluctuate, one abnormal PSA test does not necessarily indicate a need for other diagnostic tests. When PSA levels continue to rise over time, other tests may be needed.
It should be noted that it is common for normal PSA ranges to vary somewhat from laboratory to laboratory.
The real question is why do we want to diagnose bone metastases? Because the standard of care for the androgen-naive patient is androgen-deprivation and for everyone else who's failed androgens, there's very little other than systemic chemotherapy to offer them. So, why does a urologist want to know about a new bone metastasis?
Skeletal-Related Events: Impact and Definition
SREs are serious. They're debilitating, painful, and severely affect the quality of life for a patient with a significantly decreased quantity of life.
The formal definition includes pathologic fractures, spinal cord compression, radiation to the bone or surgery to the bone for any reason, change of antineoplastic therapy if a patient fails a chemotherapy and goes back onto a new agent, and hypercalcemia of malignancy (HCM), which is rare in prostate cancer.
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For patients who have not been cured initially by their disease, about 65% to 75% of them will develop bone metastases and the prognosis is negatively affected by the presence of bone metastases. There's approximately a 25% 5-year survival and about a 40-month or 3-year median survival once there's evidence of bone metastases.
In general, cancer-related bone metastases can be osteoblastic, osteolytic, or mixed. And the classic teaching in urology has been that, in prostate cancer, there's a purely osteoblastic lesion, and I'm going to discuss with you that there's not only an osteoblastic reaction going on, but there's simultaneously an osteoclastic process that's going right along side of it, and that's what we're addressing with bisphosphonate therapy.
The etiology of the bone changes that occur when there are metastases include activation of osteoblasts and osteoclasts by substances that are released by the tumor cells once they're in the bone microenvironment.
Here's a picture of osteoblasts. These are the cuboidal lining cells that you can see here. And on the bottom half of this screen is bone that's been formed. This is the bone marrow cavity. And the osteoblasts, as you know, are the bone forming cells that are derived from stem cells in the bone marrow. The osteoblasts are responsible for producing type 1 collagen, which is the main structural protein of bone, and also produce growth factors that influence other cells in the bone microenvironment.
Osteoblasts are regulated by systemic hormones and local factors and as I said, in turn, secrete factors that act either by an autocrine or paracrine action in the bone to influence other cells, one of them being osteoclasts, which are shown here.
Osteoclasts are really specialized macrophages that, when they're mature, become multinucleated and they're responsible for digesting or resorbing bone. And as you can see here, Howship's lacunae are the excavated areas that have been taken away, removed by the osteoclasts, and they do their work by attaching firmly to the bone surface by secreting hydrogen ions into that space to dissolve the mineral part of bone and also by elaborating proteases like cathepsin B to digest the protein component of the bone matrix.
Impact of Bone Metastases in Prostate Cancer: From Pathogenesis to Treatment
Bone Remodeling
Slide 6. Normal Bone Remodeling
I want you to have an appreciation of the normal process of bone remodeling. During childhood and adolescence, when we're developing new bone, it's called modeling. And in adults, the process is called remodeling where old bone is broken down, degraded, and replaced by new bone. And it's continuously happening in the skeleton. At any 1 point in time, there's approximately a million different sites within the skeleton in microscopic units, called bone structural units, where this process is actively occurring. And in a normal adult, in approximately 10 years, the entire skeleton is remodeled. So there's a process of replenishment in adults that goes on and is quite critical.
You can think of the process in the upper left-hand panel as beginning with resorption, where cells that are going to be the osteoclasts or mature osteoclasts are recruited to the site of resorption. They go in and do their work where they digest and excavate bone. As you can see in the upper right-hand panel, there's a bone resorption pit that's created. And then there's a process of reversal followed by formation. If you look in the lower right-hand panel, you see that osteoblasts are located there. They're recruited to the site and they form new bone. Initially they secrete proteins in the organic part of the matrix called osteoid, and that later becomes mineralized to form mature bone. And at the end, you're left with the same volume of bone, but it's been replenished. And this is also, by the way, trabecular bone, if you see the structure of it.
Slide 7. Types of Bone Metastases
These are the types of bone metastases. There's osteoblastic, osteolytic, and mixed metastases. And prostate cancer is the main malignancy that has a prototypic osteoblastic reaction where there's excessive, new, but disorganized or woven bone that's formed. And this bone is being formed very rapidly and is structurally not as sound as healthy bone.
Osteolytic metastases occur, for example, in renal cell cancer, which is a tumor that you see as urologists. Also multiple myeloma and breast cancer have lytic lesions. And in this case, there's excessive bone resorption with pathologic destruction of bone. And then there are mixed lesions such as in breast cancer.
One of the key concepts that I would like to get across is that the classic teaching for prostate cancer is that the metastases are purely osteoblastic. And that is based primarily on the fact that on x-rays what you see is increased calcification. There's clearly a sclerotic process that's going on and the assumption has been that that's a purely osteoblastic type of reaction.
But in the past 10 years or so, we have different lines of evidence that indicate that there's simultaneously an osteolytic component going on right alongside the osteoblastic. Part of the evidence comes from bone biopsies taken from patients with prostate cancer where the bone metastases are, and it shows a very complicated picture that includes, obviously, the osteoblastic reaction where there's osteoblasts adjacent to tumor cells, but there's also osteolysis occurring.
Also, there are studies that show that markers of bone resorption, biochemical markers like urinary N-telopeptide and so on are increased in patients with prostate cancer who have bone metastases.
And finally, there's a common sense argument that's been put forward that, in order for bone metastasis within the skeleton to occupy an appreciable amount of space, that there has to be some destruction of normal bone in order for the cancer cells to proliferate and occupy space within the bone.
Slide 8. Cancer Effects on Bone Remodeling
Here's a general diagram showing the different types of bone remodeling processes that may occur. In the upper left-hand panel, there's a healthy bone where the process of bone resorption and bone formation is both coupled and balanced, and it's a stable process.
And then on the upper right-hand panel, you can see that bone resorption exceeds bone formation and there's a loss of bone. This is the situation with osteolytic metastases or, in a more common disease, osteoporosis.
In the lower right-hand panel, I think this is a fairly good diagram to show what happens with prostate cancer where, in the 2 sites, you see that there's excessive osteoblastic or new bone being formed and at the same time, nearby, there's excessive bone resorption going on right alongside it. And that's the situation I think that most closely approximates what's going on with prostate cancer.
And then there's uncoupled but balanced process where there's excessive bone formation and resorption and they're balanced, but they're not coupled.
Prostate Cancer Hormone Therapy – Anti – androgen
Anti - androgens are another class hormone therapy drugs that are used in prostate cancer treatment. Anti – androgens affect the receptors of the prostate cells’ nuclei and prevent the reception of testosterone. These anti-hormone drugs are sometimes used as monotherapy for prostate cancer patients who are in early stages with low risk tumor features. Anti - androgens may also be used in conjunction with either surgical or medical castration to ablate 100 percent of the body’s testosterone.
Anti - androgens work by blocking the testosterone receptors in the prostate cells. Normally, testosterone would bind with these receptors and fuel the growth of prostate cancer cells. Some researchers believe that men with a higher number of hormone receptors will more quickly experience hormone refractory cancer, which occurs when the prostate cancer cells grow resistant to the hormone deprivation. With the receptors blocked, testosterone cannot “feed” the prostate. Anti - androgen therapy does not eliminate testosterone and therefore may have fewer or less severe side effects than those associated with surgical and medical castration.
When patients stop benefiting from the use of anti-androgens, some patients have found stopping hormone therapy to be effective for combating prostate cancer. This phenomenon is referred to as the “anti – androgen withdrawal effect.” For this reason, some doctors will use intermittent hormone therapy, where patients use the drugs until their levels drop then stop, then begin the drugs again when testosterone levels rise. Other doctors prescribe six months on and six months off as intermittent therapy.
The three most common anti - androgen drugs used for prostate cancer hormone therapy are flutamide, bicalutamide, and nilutamide. These drugs are taken orally as either a tablet or a pill. A single dose usually contains between 50 mg and 150 mg, depending on the patient’s needs and doctor’s prescription. Doctors encourage their patients to take the drug around the same time everyday to ensure a steady stream of therapy. Patients who forget to take a dose and are close to a time where they usually take the next dose, should not take a double dose. Taking a dose around the same time each day will decrease the incidence of some side effects, such as nausea or vomiting.
Hormone therapy can involve unpleasant and, in more rare cases, dangerous side effects. Because there are multiple anti - androgen drugs available in United States as well as Canada and the United Kingdom, patients with serious side effects should speak with their doctors about possibly changing drugs. Some doctors may change the form of hormone therapy, but in other cases doctors will encourage their patients to continue. In some cases, the side effects will dissipate as the body gets used to the drug and the androgen ablation.
The use of castration in addition to anti - androgens is called combined androgen blockade(CAB). The use of anti - androgens a few weeks before LHRH agonists are started has been shown to significantly reduce the incidence of hormone flare that can be painful dangerous for patients with distant bone metastasis. Anti – androgens can also be used after surgical or medical castration stops being effective. There are a few studies that indicate using anti - androgens as monotherapy may be slightly less effective than medical or surgical castration as monotherapy. Other studies found no difference in the survival rates of people who had used only one form of treatment.
The majority of men who are deprived of androgens, either by means of luteinizing hormone-releasing hormone (LHRH) agonists or bilateral orchiectomy, ultimately progress to an androgen-independent phase where the initial androgen deprivation regimen no longer controls the tumor. As a result, treatment strategies are needed for men with androgen-independent prostate cancer (AIPC). A minority of men who have progressive disease after initial androgen deprivation respond to additional hormonal treatments. Prostate cancer that no longer responds to any hormonal treatment is referred to as hormone-refractory prostate cancer (HRPC). Older estimates of median survival for patients with HRPC range from 7 to 12 months, but more recent studies report a median survival of 16 months.[5,6] This improvement may be the result of better treatments or may be explained by stage migration and prostate-specific antigen (PSA)-induced lead-time bias. Historically, cytotoxic chemotherapy for prostate cancer induced low response rates, with an average objective response rate of 8.7%. Prior to the use of taxanes, no survival benefit supporting the use of chemotherapy was demonstrated. More recent studies of chemotherapy in patients with HRPC report benefits including reduced pain, improved quality of life, and decreased need for narcotics.
Prostate Cancer Hormone Therapy – LHRH Antagonist
Because the growth of prostate cancer is fueled by the male sex hormone testosterone, doctors can use chemical castration to ablate 90 to 95 percent of the body’s supply. Chemical castration interferes with signals in the brain that tell the testicles to start testosterone production. The hypothalamus in the brain first detects that levels of testosterone are dropping and releases Luteinizing hormone-releasing hormone (LHRH) also called Gonadotropin (GnRH). LHRH or GnRH act as a messenger and fill in receptors of the pituitary gland to report the lowering levels of testosterone. The pituitary gland releases luteinizing hormones (LH) that travel to the testicles.
An antagonist inhibits the action of a cell by filling in receptors. A LHRH or GnRH antagonist mimics the shape of normal LHRH then fills in the receptors on the pituitary gland. Not receiving the message from the hypothalamus, the pituitary gland does not release LH. The testicles never produce testosterone and the body’s levels drop.
LHRH and GnRH antagonists should not be confused with agonists. LHRH antagonists are generally used only for advanced prostate cancer with bone metastasis. Unlike the agonists, LHRH or GnRH antagonists do not produce hormone flare. LHRH antagonists, however, have been known to cause severe allergic reactions with a small number of patients. Because of this risk, LHRH antagonists are used only for patients with advanced prostate cancer or who refuse any other type of hormone therapy due to preference or other side effects.
LHRH antagonist is injected through the buttocks at a doctor’s office. The injection will be made by either a doctor or a nurse. Two weeks after the initial injection, the patient receives his second injection. Two weeks after the second injection, the patient receives his third injection. After this first month, the patient receives the antagonist only once a month. Patients are strongly encouraged not to miss appointments, and to schedule those appointments as close to exactly four weeks later as they can. After an injection, a patient will also wait at his doctors office for another 30 minutes to ensure that he does not have an allergic reaction.
LHRH antagonists are usually not recommended for patients who have irregular heart beat, liver problems, or osteoporosis. Patients who weigh over 225 pounds are also not candidates for LHRH antagonists. Patients who have one or more of these physical criteria should speak with their doctors about whether LHRH antagonists are right for them. LHRH antagonists could exacerbate irregular heart beat and liver problems in addition to risking decreasing bone density. Researchers have found that weighing over 225 pounds could dramatically decrease the effectiveness of the antagonists.
After the first injection, patients should receive a blood test once every 8 weeks to ensure that his levels of testosterone have dropped to castrate level. Patients should also consider tests to monitor the functioning of the liver. Patients who undergo extensive LHRH antagonist hormone therapy run a higher risk of developing osteoporosis.
If patients experience a changing in the rhythm of their heartbeat or fainting, they should contact their doctor immediately.
Combined Androgen Blockade in Prostate Cancer Hormone Therapy
Combined androgen blockade is abbreviated as CAB and is a type of prostate cancer hormone therapy which combines an anti-androgen with either chemical castration or surgical castration. 90 to 95 percent testosterone is produced by the testicles while 5 to 10 percent is produced by the adrenal glands. Combined androgen blockade ablates 100 percent of the testosterone present in the blood stream. Combined androgen blockade is also known as total androgen blockade and combined hormone blockade.
Gleason Score:
In developing his system, Dr Gleason discovered that by giving a combination of the grades of the two most common patterns he could see in any particular patient's specimens, he was better able to predict the likelihood that that particular patient would do well or badly. Therefore, even though it may seem confusing, the Gleason score which a physician usually gives to a patient is actually a combination or sum of two numbers. These combined Gleason sums or scores may be determined as follows:
* The lowest possible Gleason score is 2 (1 + 1), where both the primary and secondary patterns have a Gleason grade of 1 and therefore when added together their combined sum is 2.
* Very typical Gleason scores might be 5 (2 + 3), where the primary pattern has a Gleason grade of 2 and the secondary pattern has a grade of 3, or 6 (3 + 3), a pure pattern.
* Another typical Gleason score might be 7 (4 + 3), where the primary pattern has a Gleason grade of 4 and the secondary pattern has a grade of 3.
* Finally, the highest possible Gleason score is 10 (5 + 5), when the primary and secondary patterns both have the most disordered Gleason grades of 5.
Partin Coefficient Tables:
Introduction
The following four tables give data which allow you or you doctor to predict the probability that prostate cancer has spread out of your prostate into the lymph nodes on the basis of your Gleason score, your PSA value, and your clinical stage. Be careful to use the table which is based on your PSA value.Example
Mike is a 62-year-old man with a PSA of 8.4 ng/ml and a Gleason score of 4 + 2 = 6. His doctor has categorized his clinical stage as T2b since he was able to feel a significant induration in one lobe of Mike's prostate on DRE and the biopsy and ultrasound indicated that the cancer had invaded more than half of that lobe but there was no sign of cancer in the other lobe.Using the table for PSA values between 4.1 and 10.0 ng/ml, we find that Mike has an 4% likelihood of prostate cancer which has invaded his lymph nodes. In other words, there are about 19 chances in 20 that Mike's cancer has not invaded the lymph nodes.
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| Gleason score | Stage T1a | Stage T1b | Stage T1c | Stage T2a | Stage T2b | Stage T2c | Stage T3a |
|---|---|---|---|---|---|---|---|
| 2-4 | ... | 4 | 1 | 1 | 3 | ... | ... |
| 5 | ... | 10 | 3 | 3 | 7 | 7 | 11 |
| 6 | ... | 23 | 7 | 8 | 16 | 17 | 26 |
| 7 | ... | ... | 14 | 14 | 25 | 25 | 32 |
| 8-10 | ... | 51 | 24 | 24 | 36 | 35 | 42 |
adjuvant therapy (A-joo-vant THAYR-uh-pee) Treatment given after the primary treatment to increase the chances of a cure. Adjuvant therapy may include chemotherapy, radiation therapy, hormone therapy, or biological therapy.
neoadjuvant therapy (NEE-oh-A-joo-vant THAYR-uh-pee) Treatment given before the primary treatment. Examples of neoadjuvant therapy include chemotherapy, radiation therapy, and hormone therapy.
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