Androgen-independent prostate cancer

When cancer advances despite primary hormone therapy

We often hear the term prostate cancer and assume it is one disease. Practically speaking, it is. On a molecular level, however, scientists are revealing a far more complex picture. Cancer has an innate ability to adapt to its surroundings. As it progresses, cancer cells tend to change, morphing to a point where the differences between tumor cells can be dramatic. That’s why some researchers believe late-stage prostate cancer is more accurately described as a mix of cancer cell types.

Each year, an estimated 25,000 men will find out their prostate cancer has changed enough to become resistant to standard androgen-deprivation therapy, also called hormone therapy. At this point, the cancer is classified as androgen-independent prostate cancer (AIPC) or hormone-refractory prostate cancer, meaning that the cancer is still able to thrive despite hormone treatment.* The first sign of AIPC is typically a rising PSA level, a shift that can be extremely distressing for patients, but not entirely unexpected. A majority of patients with AIPC will have already watched their PSA levels rise at two previous critical junctures: before their initial cancer diagnosis and after supposedly curative local treatment. When PSA levels rise again, despite primary hormone therapy, it represents a third critical decision-making point for patients.

*Note: The terms androgen-independent and hormone-refractory are evolving. Many experts, including our roundtable participants, use terms such as castration resistant and primary hormone-therapy resistant instead. For the sake of clarity, this article will use androgen-independent prostate cancer.

Hormone therapy, a mainstay of prostate cancer treatment for more than 60 years, has been shown to shrink tumors, reduce pain associated with bone metastases, and extend survival. Hormone therapy, which relies on drugs called luteinizing hormone–releasing hormone (LHRH) agonists, deprives the body of testosterone, the male hormone (or androgen) that fuels prostate cancer cell growth.* The drugs prevent the secretion of LHRH, which is the brain’s chemical signal to start testosterone production (see Figure 1).† Treatment causes testosterone levels to drop by up to 95%. Some doctors add a second drug, called an anti-androgen, to block the effects of any remaining testosterone on prostate cancer cells. When an LHRH agonist and an anti-androgen are given together, it’s called a combined androgen blockade.

Notes:

*Testosterone levels can also be reduced by surgically removing the testicles, a procedure called a bilateral orchiectomy. But given the irreversible nature and potential psychological impact of this procedure, medical hormone therapy is usually the treatment of choice.

†Because LHRH is sometimes called GnRH, short for gonadotropin-releasing hormone, LHRH agonists are sometimes referred to as GnRH agonists. To prevent confusion, this article will use the term LHRH agonists.

In some patients, hormone therapy may slow disease progression for more than a decade; in others, it may keep cancer in check only for a few months. Eventually, prostate cancer cells begin to resist the treatment. Why do responses to hormone therapy vary so much? How does the cancer become resistant? Is it resistant to all types of hormone therapy? What options do patients have in terms of treatment? To learn more about androgen-independent prostate cancer, the Harvard editors invited three experts from Harvard Medical School to address these questions and offer insight into this phase of the disease and ways to manage it. The panelists were

  • Glenn Bubley, M.D., a medical oncologist and director of Genitourinary Oncology at Beth Israel Deaconess Medical Center. He has been a principal investigator for studies looking at cancer cell biology and the effectiveness of therapies in prostate cancer patients. He is an associate professor of medicine at Harvard Medical School.
  • William Oh, M.D., a medical oncologist and clinical director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute. He has served as a lead investigator for numerous studies on therapies for prostate cancer, including investigational chemotherapy regimens. He is an associate professor of medicine at Harvard Medical School.
  • Mary-Ellen Taplin, M.D., a medical oncologist at the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute. Her research focuses on molecular changes in prostate cancer cells as well as novel, second-line hormonal and chemotherapy regimens. She is an assistant professor of medicine at Harvard Medical School.

Marc B. Garnick, M.D., moderated the session.

Figure 1: Testosterone production and cell growth

Testosterone production and cell growth

  1. Testosterone production begins when the hypothalamus secretes luteinizing hormone–releasing hormone (LHRH).
  2. LHRH signals the pituitary gland to release luteinizing hormone (LH), which travels through the bloodstream. When it reaches the testicles and adrenal glands, it binds to specialized cells that produce testosterone.
  3. Testosterone flows through the bloodstream. Some tissues rely on testosterone for peak performance, but can function without it. Other tissues, such as the prostate gland and prostate cancer cells, depend on testosterone for survival.
  4. Once testosterone enters the prostate cell, the enzyme 5-alpha reductase converts it into a more powerful androgen called dihydrotestosterone (DHT), which stimulates sites in the cells called androgen receptors. These receptors help direct cell growth.

Understanding the nature of AIPC

How do you define AIPC?

OH: With AIPC we’re talking about men who have been on hormone therapy or who have had a bilateral orchiectomy and whose testosterone levels have dropped to less than 50 ng/dl,* and who subsequently show evidence of disease progression. This can be in the form of rising PSA levels or bone or soft tissue metastases.

*Note: The abbreviation ng/dl stands for nanograms per deciliter. It’s equivalent to 1 one-billionth of a gram (454 grams make a pound) in one-tenth of a liter (1 liter is approximately 1 quart).

BUBLEY: Typically, when we talk about hormone therapy, we’re referring to the primary hormone therapies, which are the LHRH agonists leuprolide (Lupron) or goserelin (Zoladex). We confirm that the patient has been compliant in taking his medications, and we test his serum testosterone level to rule out the rare chance that the medication hasn’t dropped the testosterone far enough. If the PSA level starts rising in a low-testosterone environment — what we call a castrate environment — we know the patient has entered a new phase of prostate disease: AIPC.

Has the clinical presentation of AIPC been changing?

TAPLIN: It is evolving. About three-quarters of the patients I see have rising PSA levels after initial primary treatment without evidence of metastatic disease, or what we call biochemical failures, which is an increasing proportion. We are also picking up very small metastases due to improvements in imaging techniques. So we’re spotting signs of progression much earlier than in the past.

OH: Over the last decade, as PSA levels have been more closely monitored, therapies have started earlier. Ten years ago, we would typically wait for patients to have radiographic evidence of metastases, such as a positive bone scan, or symptoms of disease before starting hormone therapy, regardless of PSA doubling time. Because men are now frequently starting hormone therapy based on rising PSA levels, some are developing hormone-refractory disease, or AIPC, before they develop visible metastases.*

*Note: See “Who is the typical AIPC patient?” below.

How is AIPC different from prostate cancer that has not yet been treated with hormone therapy?

OH: Androgen-independent prostate cancer is very heterogeneous, and we don’t fully understand the biology of it, but it does tend to present in different ways. It commonly spreads to the bones, but it may also spread to other organs or the lymph nodes. PSA levels tend to rise faster in cases of AIPC than they do in patients with earlier stages of the disease. This is likely due to increased tumor burden. But it may also reflect the type of cancer cell we’re dealing with. That’s a big focus of current research.*

*Note: See “Hormone naïve prostate cancer.”

Hormone therapy represses cancer by lowering androgen levels, particularly testosterone. How does the cancer eventually become resistant to this therapy?

BUBLEY: One of the evolving concepts in androgen-independent prostate cancer is that it’s actually not androgen independent. There’s a belief that residual androgens, even in minute amounts, may be enough to trigger the androgen receptors, parts of cells that bind to androgens to fuel cell growth.* Though LHRH agonists do a good job of limiting testosterone production by the testicles, the adrenal glands, located near the kidneys, continue to produce weaker androgens. And in the case of AIPC, the androgen receptors appear to become increasingly adept at using these adrenal androgens, along with other mechanisms and growth pathways, to maintain sufficient levels of androgen or androgen-like hormones to keep the tumor alive and promote cell growth.

*Note: See Figure 2.

TAPLIN: We believe the androgen receptor remains a player in prostate disease progression, and it may do so in a variety of ways. About a third of tumors have androgen receptor hypersensitivity, which means they can use very small levels of androgens more efficiently. About a quarter of patients have androgen receptor point mutations, which allow the androgen receptors in the cancer cells to bind with and use molecules such as other hormones, anti-androgens, or other medications to grow. As Dr. Bubley mentioned, we think that these tumor cells may latch on to weaker androgens from the adrenal glands or elsewhere, and then convert them into more potent androgens. In addition, prostate cancer cells are able to make their own androgens rather than relying on testicular or adrenal androgens. There are probably many other pathways, including genes that may work independently or with androgen receptors to fuel tumor growth, particularly in the late stages of very advanced cancers.

Figure 2: How AIPC develops

How AIPC develops

  1. Hormone therapy kills tumor cells by limiting their exposure to testosterone (cells in illustration with white centers, for example). The tumor shrinks.
  2. Remaining tumor cells either morph or have special characteristics that allow them to survive in a low-testosterone environment. Androgen receptor sensitivity, represented above by cells with gray centers, or a mutation, represented by cells with red centers, may allow for continued cell growth. Researchers are trying to identify other pathways and genetic changes that may also play a role.
  3. Resistance to therapy builds, androgen-independent cells proliferate, and the tumor grows. At this point, even though the cancer is considered androgen independent, it may respond to a second-line hormone therapy.

Can you predict who will develop AIPC?

OH: Patients who are cured with initial local therapy, such as radical prostatectomy, and don’t develop a recurrence, won’t develop AIPC. We can predict at the time of the original diagnosis which patients are likely to relapse using their Gleason scores, rate of PSA increase, and other clinical information. Patients who relapse are more likely to go on hormone therapy and subsequently to develop AIPC.

TAPLIN: PSA doubling time is a very good indicator of how quickly a cancer is progressing and a patient’s chances of survival. In patients whose PSA level doubles within three to six months after local therapy, the cancer tends to progress more quickly. So, we intervene earlier in these cases with hormone therapy.*

*Note: PSA levels are used as markers of prostate cancer aggressiveness and to predict AIPC. For more information, see “Rising PSA levels.”

Considering that hormone therapy has some significant side effects and eventually leads to androgen independence, how do you decide when to prescribe it in the hormonally naïve patient?

BUBLEY: In patients who have PSA doubling times of less than six months, I tend to intervene pretty quickly because we know that these patients have cancers that are advancing at a faster rate. For patients with doubling times greater than a year, I tend to delay hormone therapy. In fact, I have some slow doublers who have PSA levels in the hundreds and do not have any signs of metastatic disease. I’ve followed them for years and have not treated them with hormone therapy.

TAPLIN: I think PSA doubling times between six months and a year present a gray area. In these cases, it really depends on the patient’s goals and acceptance of side effects. But in general, if a patient has a PSA doubling time that’s longer than a year, we take a watchful waiting approach and follow him with periodic bone and CT scans.

OH: One retrospective analysis found that for patients with rapid PSA doubling times, starting androgen-deprivation therapy before the PSA reached 10 ng/ml was associated with a better outcome than waiting until the PSA rose beyond 10 ng/ml. For patients whose doubling times were slower, early intervention with hormone therapy didn’t make as much difference in overall survival. I think it just points out that we don’t have any solid data about exactly when to start hormone therapy.

Who is the typical AIPC patient?

The typical AIPC patient has experienced rising PSA levels prior to diagnosis, after initial surgery or radiation, and when levels rise despite hormone therapy. However, the time between these rising levels often spans many years. When levels rise or radiographic evidence shows progression after hormone therapy, second-line hormone therapies may again drop those levels for months or sometimes years. How each patient responds to a given therapy varies, sometimes greatly. This is important to keep in mind when looking at statistics.

When prostate cancer advances, patients may experience pain (particularly bone pain if the cancer has metastasized to the bones), spinal cord compression, urinary complications, and side effects from medications. Newer approaches to treatment, such as the use of antinausea medications during chemotherapy, have made treatment regimens more tolerable. But it’s important for the patient-doctor dialogue to be open and honest about what to expect and how best to go forward.

Once a patient begins hormone therapy, is there any way to tell how long it will work before resistance to the treatment occurs?

BUBLEY: Patients with a PSA nadir, or low point, less than 0.2 ng/ml are going to have a much longer response to treatment, whether using continuous hormone therapy or intermittent therapy, which involves taking breaks from the medication.* The patients who are more likely to develop androgen-independent prostate cancer, or develop it sooner, have a less robust PSA response, and that means a PSA that fails to drop below 4.0 ng/ml. And it doesn’t matter what PSA level they start at — 100 ng/ml or 10 ng/ml. The more important thing is how low the PSA goes. People with low nadirs are going to have a longer response to primary hormone therapy.

*Note: See “Can resistance to hormone therapy be delayed?” below.

What about the rate of PSA decrease after hormone therapy is initiated?

OH: We’re actually looking at this right now. We’ve found, paradoxically, that patients who have the shortest time to their nadir PSA value after hormone therapy may actually have a worse prognosis. I’m speculating, but the patients who have a more rapid response in the beginning may have cells that are ultimately more resistant. It was an unexpected finding. The study was prompted by an observation in a patient of mine whose PSA dropped from somewhere in the 400 to 500 ng/ml range to 0.2 ng/ml in three months; six to eight months is typical. So we’re trying to study this phenomenon in other patients in our database.

Hormone naïve prostate cancer

Prostate cancer that has become advanced and has not been treated with hormone therapy previously is considered “hormone naïve.” Unlike androgen-independent prostate cancer, hormone naïve tumors continue to rely on normal testosterone levels for growth. Therefore, a patient with advanced, hormone naïve prostate cancer may present with a similar tumor burden as a patient with AIPC, but will most likely benefit from first-line hormone therapy. Although this response can be short, on occasion, it can be quite durable. However, whether the disease is androgen sensitive or androgen independent, these cancers have an increased ability to morph and become resistant to therapy.

Making treatment decisions

If a patient is already taking hormone therapy and his PSA starts to rise, what’s the next step?

BUBLEY: When a patient on Lupron starts to have rising PSA levels, I usually will take some baseline measurements and restage the disease. I typically start with a bone scan and CT scan, and sometimes I’ll add a chest x-ray. As I mentioned before, I’ll check serum testosterone levels to confirm the cancer is progressing in a castrate environment. If PSA levels are rising in this setting, there is a need to consider intervention because the timeline, in terms of development of metastases, is much faster.

Rising PSA levels

Prostate-specific antigen (PSA) is a protein made by prostate cells. A PSA level that rises to a certain threshold after initial prostate cancer treatment indicates that a patient is experiencing a biochemical recurrence, or progression of the disease without symptoms. The threshold varies depending on the type of treatment. The rate of change in PSA, or the PSA velocity, indicates how aggressive a cancer is. If PSA levels double in six months or less after local treatment, patients typically begin hormone therapy to prevent or slow metastases. PSA levels that double more slowly usually mean that a patient has a slower-growing cancer.

Ideally, hormone therapy decreases the PSA level to below 0.2 ng/ml. If PSA levels begin to rise or are hard to suppress with hormone therapy, it is likely that the cancer is becoming androgen independent.

How do you counsel patients when they first get a diagnosis of AIPC?

BUBLEY: If they had a low PSA nadir with a primary hormone therapy, then I can tell them with a bit of certainty that they’re likely to respond to a number of newer, and even older, anti-androgen and anti-adrenal therapies. This is why I often use the terms Lupron resistant or primary hormone-therapy resistant rather than androgen independent. These patients, in most cases, haven’t tried and are not necessarily resistant to a variety of second-line hormone therapies.* In many cases, although a cancer becomes Lupron resistant, it’s often not resistant to ketoconazole, diethylstilbestrol (DES), estrogen (Premarin), or high-dose bicalutamide (Casodex). All three of us, I’m sure, have had patients who’ve had a year and a half of response to ketoconazole, and another year of response to estrogen before we’ve had to think about chemotherapy. Some of my patients have had very long responses, with months turning into years. Beyond that, chemotherapy has been shown to improve survival. And then the field is replete with a number of investigational therapies.

*Note: See Table 1.

TAPLIN: We approach it the same way at Dana-Farber. We educate patients about secondary hormonal options followed by chemotherapy options. And we try to have clinical trials available every step of the way. We have one or two clinical trials of second-line drugs under way now. And we have ongoing trials that focus on various types of chemotherapy, both first-line chemotherapy and what is termed salvage chemotherapy. For patients who have had chemotherapy, we’re looking at salvage hormone therapy, which involves the use of newer agents that are in clinical trials to try to lower testosterone further.

OH: I would just echo this point: there are many therapeutic options available, and some patients have fantastic long-term responses to additional hormone treatments, even after chemotherapy. Today there are relatively long-term survivors of androgen-independent prostate cancer, which is really a change from five or 10 years ago.

Do you continue primary hormone therapy after a patient has been diagnosed with AIPC?

BUBLEY: The clinical trials mandate that we continue it. We can’t get them on any of the clinical trials if they’re not castrate surgically or compliant with a therapy like Lupron or Zoladex. I know there are conflicting opinions about whether or not it makes any difference to continue LHRH agonists. But if the patient has been taking the drug for a number of years, he may never recover testosterone secretion, so it’s likely a moot point.

OH: There were two studies performed many years ago that formed the basis for this general practice. One of them showed that there was really no benefit to continuing an LHRH agonist in the setting of hormone-refractory disease progression. The other showed a slight survival benefit to continuing it. There are some patients who may not be a candidate for a trial and want to take a break from medication. We can check their serum testosterone levels and consider restarting the LHRH agonist if their testosterone levels do rise.

In the same vein, what do you do with patients taking anti-androgens as part of a combined hormone blockade?

BUBLEY: We always stop the anti-androgen.

OH: You have to stop the anti-androgen because patients can have what’s called an anti-androgen withdrawal response.*

*Note: For more information, see “The anti-androgen withdrawal response.”

When do you consider chemotherapy?

OH: Chemotherapy has been proven to provide a modest survival benefit for patients with metastatic androgen-independent prostate cancer. And typically I will initiate it for such patients. I think it’s clearly beneficial for patients who are symptomatic. But even if they’re not, we know that there’s a survival benefit.

What do you consider to be the top five chemotherapeutic agents for AIPC?

OH: My list would include docetaxel (Taxotere), paclitaxel (Taxol), mitoxantrone (Novantrone), carboplatin (Paraplatin), and vinorelbine (Navelbine).*

*Note: For a list of chemotherapeutic agents and their side effects, see Table 2. For a list of articles that review the use of chemotherapy for AIPC, see “Chemo for prostate cancer.”

BUBLEY: Mine would be similar. I think we would all start with docetaxel. I’m not sure I’ve seen a lot of people respond to paclitaxel who haven’t responded to docetaxel, but I’m sure there’s a small subset who do. And Dr. Oh showed that a subset of patients who are resistant to docetaxel respond to carboplatin.

OH: Quite a number of patients have responded well to docetaxel but eventually experienced disease progression. That’s when adding a second-line chemotherapy like carboplatin may play a role. Studies show it has modest activity, but it can actually be quite dramatic in some patients. So, we’re trying to identify the subsets of patients who have the best response.

Can resistance to hormone therapy be delayed?

Cancer cells tend to adapt to existing conditions, including a low-androgen environment. Considering this, some researchers theorize that changing the environment using intermittent hormone therapy (IHT), the cycling of treatment and nontreatment periods, may delay the progression of disease to an androgen-independent state. The theory is that maintaining some testosterone may prompt tumor cells to retain androgen-dependent characteristics, making them susceptible to apoptosis (cell death) when testosterone is taken away.

Some smaller studies have shown that patients with PSA-only progression may benefit more from IHT than continuous hormone therapy. Studies have shown little difference in long-term survival rates, but patients experience a lessening of side effects with IHT. Clinical trials may shed more light on the subject in coming years.

The agents mentioned so far are commercially available. What about investigational therapies?

OH: Some of the more promising investigational chemotherapy drugs for AIPC are probably, like carboplatin, in the platinum-compound family. Satraplatin is not FDA-approved, but it has been shown to be effective at limiting progression, as well as reducing pain. Though survival is the traditional endpoint for approval of chemotherapy drugs in the United States, many investigators who saw the results of the SPARC (Satraplatin and Prednisone Against Refractory Cancers) trial think that the drug is promising and that the platins may have a role.

BUBLEY: The field is also moving toward combining therapies. For example, the effect of docetaxel, although real, is modest. Can we make the effect more dramatic? Studies of docetaxel plus other drugs are looking at that question.

OH: People are optimistic about combining chemotherapy with angiogenesis inhibitors like bevacizumab (Avastin), which target tumor blood vessels. The optimism stems from some of the promising phase II data from the multicenter CALGB (Cancer and Leukemia Group B) trial. But it also comes from our knowledge of the kind of broad activity that the combination has had against other diseases, including colorectal, lung, and possibly breast cancer.

Table 1: Second-line hormone therapies for advanced prostate cancer

Drug name Side effects Comments
ketoconazole
(Nizoral)
Nausea, fatigue, swelling, skin rash, abnormal liver function An antifungal medication; rapidly lowers serum testosterone levels; used with hydrocortisone. Should not be taken with alcohol.
bicalutamide
(Casodex)
Hot flashes, fatigue, breast enlargement, mild nausea An anti-androgen; can be used as part of a primary combined androgen blockade and, in higher doses, as a second-line hormone therapy.
estrogen
(Premarin)
Breast enlargement, hot flashes, fatigue Suppresses luteinizing hormone (LH) secretions, which inhibits testosterone production.
diethylstilbestrol
(DES)
Breast tenderness, breast enlargement, deep vein thrombosis (blood clots in the legs or pelvis) Generally avoided due to cardiovascular side effects. If given, should be combined with a blood-thinning agent to prevent clots.
Drugs are listed in order of approximate frequency of use.

Do you treat a patient with AIPC and a rising PSA differently than one with symptomatic, metastatic disease?

OH: For those who present only with rising PSA levels, it is more of a gray area. Chemotherapy, which is the only FDA-approved treatment for androgen-independent prostate cancer, is really indicated for those with metastatic disease. That doesn’t stop us from treating patients who only have PSA progression, because we have a wealth of evidence that second-line hormone therapy may help.

TAPLIN: Another example of when treatment might differ is if there are bone metastases. Bone-building medications, such as zoledronic acid (Zometa), are specifically approved for men with metastatic disease. So, we might start zoledronic acid for patients with metastases, whereas for those with PSA progression only, we wouldn’t.

Doctors can use a genetic test called Oncotype DX to predict how patients with breast cancer might respond to a particular treatment. Is there a similar genetic test for prostate cancer patients?

OH: A lot of companies and organizations are interested in creating a similar test for prostate cancer that could accurately predict treatment outcomes in subtypes of patients. Ideally, it would help determine which treatment a patient should receive. For instance, is a patient likely to benefit most from hormone therapy, chemotherapy, or radiation after local treatment? We’ve never really understood why hormone therapy may work for many years, even a decade or longer, in some patients, and in other patients, it may work for only six months. A great deal of research is being done to better understand how genetics may help answer questions like this.

One study we were involved with found three inherited differences in genes related to androgen metabolism that accurately predicted how long hormone therapy would work. What that suggests is that the kind of machinery we’re born with probably has an impact on how well certain therapies will work. And I think we will begin seeing more genetic and molecular tests that can make these predictions.

Chemo for prostate cancer

Chowdhury S, Burbridge S, Harper PG. Chemotherapy for the Treatment of Hormone-Refractory Prostate Cancer. International Journal of Clinical Practice 2007;61:2064–70. PMID: 17956560.

De Wit R. Chemotherapy in Hormone-Refractory Prostate Cancer. BJU International 2008;101(Suppl 2):11–15. PMID: 18307687.

Oh WK, Tay MH, Huang J. Is There a Role for Platinum Chemotherapy in the Treatments of Patients With Hormone-Refractory Prostate Cancer? Cancer 2007;109:477–86. PMID: 17186531.

Doctors often say that the median survival time for a patient diagnosed with AIPC is two to three years, but many men live much longer. How do you explain that?

OH: I think there are two populations with androgen-independent prostate cancers. There are patients who develop metastases quickly and progress quickly, and there are patients who have slower-growing cancers. As we discussed, many of our patients are diagnosed with cancer before the advent of metastases because we’re monitoring their PSA levels so closely. And we know that often those patients will live five years or longer after diagnosis of AIPC. The survival statistics give an average that includes both patients who progress quickly and those who progress more slowly. This makes it difficult to predict how long an individual patient will survive. Beyond averages, we don’t have a lot of good data.

The anti-androgen withdrawal response

Patients who use a combined androgen blockade (an LHRH agonist and an anti-androgen) for an extended period may experience anti-androgen withdrawal syndrome. This paradoxical effect occurs when androgen receptors in the cancer cells mutate and use the anti-androgen, which is designed to block growth, to promote growth instead. When the anti-androgen is withdrawn, 25% to 30% of people using the LHRH agonist alone experience shrinking tumors and dropping PSA levels. This response to withdrawal typically lasts from six to eight months, but in some patients can last as long as two years.

What are your thoughts on the Provenge vaccine* and the FDA’s delay in approving it?

*Note: See “A vaccine for prostate cancer?” below.

TAPLIN: Patients are definitely justified in wanting it to be available, but it hasn’t been definitively proven to work.

BUBLEY: We’d all like to see treatments like sipuleucel-T (Provenge) approved so we’d have more treatments to offer our patients. But we haven’t seen data proving that it is effective. That said, I’m enthusiastic that there may be a role for vaccines in the treatment of prostate cancer. I tend to think vaccines would be most effective in the early stage of micrometastatic disease, when the immune system has the best chance of controlling a cancer, and in combination with primary treatments such as surgery.

Table 2: Chemotherapy for advanced prostate cancer

Drug name* Common side effects Comments
docetaxel
(Taxotere)
Hair loss, nausea and vomiting, drop in blood cell count, numbness and tingling (usually in the feet) These anticancer drugs may be used alone or in combination with other chemotherapeutic agents, such as estramustine and carboplatin. Studies are looking at the effect of combining these agents with other types of drugs, including the angiogenesis inhibitors bevacizumab and thalidomide, which target the blood vessels that supply cancer cells.
paclitaxel
(Taxol)
Hair loss, fatigue, drop in blood cell count, numbness and tingling in hands and feet (usually after long-term use)
mitoxantrone
(Novantrone)
Nausea and vomiting, hair loss, fatigue, drop in blood cell count Often used in men who do not respond to docetaxel.
vinorelbine
(Navelbine)
Nausea, vomiting, fatigue, constipation, diarrhea, tingling in hands and feet, hair loss, muscle aches, drop in white blood cells Increased risk of infection; fever and chills should be reported to a physician.
carboplatin
(Paraplatin)
Low blood counts, nausea, vomiting, taste changes, hair loss, weakness, constipation, diarrhea Used as a single agent and in combination with paclitaxel and estramustine. Also used as a second-line therapy for patients who have become resistant to docetaxel.
estramustine
(Emcyt)
Blood clots, nausea and vomiting, fatigue, headache, drop in blood cell count Often combined with other agents in clinical trials, but the risk of blood clots and other complications make estramustine unlikely to become a standard treatment.
satraplatin Changes in blood cell count, nausea, vomiting, diarrhea, infection Satraplatin with prednisone is emerging as an active treatment regimen for those whose cancers have progressed on docetaxel or paclitaxel.
*This is a partial list, reflecting the more promising chemotherapeutic agents in clinical practice and in clinical trials. It does not include all agents or those in early stages of development. Some have not been endorsed or approved by the FDA, and may not be covered by health insurance. Drugs are listed in order of approximate frequency of use.

What about other novel therapeutic approaches? What can we expect in the future?

TAPLIN: We believe the most effective way to battle prostate cancer will likely involve a multitargeted approach. New medications are being developed to target androgens from the adrenal glands to drop testosterone levels to less than 1 ng/dl, and there are new androgen receptor antagonists in clinical trials. As the effectiveness of those treatments is evaluated, our definition of what we consider a castrate level of testosterone may change. A variety of inhibitors are also being developed to block androgen receptor function. And various other approaches, including gene therapy, are in development. In the future, we foresee combining these therapies with current approaches to maximize our ability to control tumor growth.

A vaccine for prostate cancer?

The prostate cancer vaccine sipuleucel-T (Provenge) was designed to use a patient’s own white blood cells to prompt the immune system to attack tumor cells. The FDA delayed approval of the vaccine in 2007 after a phase III trial showed it had little effect in delaying tumor progression compared with a placebo. The same study did show a modest improvement in survival. When the FDA receives additional information about the vaccine’s effectiveness, perhaps later this year or next, the agency will reconsider approval for sipuleucel-T.

SOURCE: Small EJ, Schelhammer PF, Higano CS, et al. Placebo-Controlled Phase III Trial of Immunologic Therapy with Sipuleucel-T (APC8015) in Patients with Metastatic, Asymptomatic Hormone Refractory Prostate Cancer. Journal of Clinical Oncology 2006;24:3089–94. PMID: 16809734.

It has to be difficult for a patient to hear that he has AIPC. What emotional issues do patients and their families face?

TAPLIN: Being diagnosed with any kind of cancer is usually very stressful for the patient and for family and friends. Patients have to deal with the psychological aspects of the cancer diagnosis and concerns about life expectancy. They have to deal with the side effects of the hormone therapy, including sexual side effects and the newly appreciated cardiovascular risks. They have to deal with doctor’s visits. And there’s a lot of work that patients do to understand their situation and the choices that are put before them, including learning about clinical trials and deciding whether to enroll in one.

OH: I think men with prostate cancer are a unique population. Many of them are used to being providers for their family. There are often issues with communication, both with their physician and with their partner and their family. I think we probably do undertreat these issues and underutilize resources, partly because the patients themselves may not be very forthcoming about how devastating all of these issues really are. And while they look to us for treating the cancer, I think it is important to address what are sometimes considered ancillary needs, but needs that are at the core of what the patient is going through emotionally.

BUBLEY: And it’s not just the patient who’s suffering from prostate cancer. His wife or partner is suffering from prostate cancer, and his children are suffering from prostate cancer. The best we can do is the old-fashioned closed-door talk. We find out what their needs are and try to be aware of all of the resources that are available.

What kinds of support services are helpful for patients diagnosed with AIPC?

BUBLEY: Often medical centers have specialized cancer support programs. Patients who don’t have access to this type of program should talk to their physician about what resources are available in their community. A referral to a psychiatrist, psychologist, or social worker can be very helpful, and there should be no stigma attached to seeing one. This is a very difficult time. Taking an antidepressant may be in order. I also think family therapy is a good idea.

OH: Some men may be hesitant to accept antidepressants or a referral to a psychiatrist. That is partly why I think peer groups, spouses, and families are important. In my practice, it’s often the wife or significant other who tells me that there’s a problem when the patient is saying, “I’m perfectly fine.” So I think it’s important for physicians, particularly oncologists and primary care doctors, to engage patients in this conversation and help them find resources at community hospitals. What’s key is that the patient has to take steps, too. Many of them won’t address emotions as a primary issue. They’re trying to deal with the cancer on a physical level. But what’s happening psychologically is a critical part of caring for the whole patient.

Any other advice for patients?

TAPLIN: We always suggest that patients check with their doctors about taking part in a clinical trial.* There are an increasing number of new therapies, and researchers continue to explore potential new treatment targets, particularly as we begin to understand more about the biology of prostate cancer.

*Note: For a primer on scientific studies, see “Clinical trials explained.”

BUBLEY: It’s a difficult time for patients, but it’s not as bleak as it used to be. Our understanding that the disease is not resistant to all hormonal therapies is changing our outlook and expectations. I counsel patients to take part in clinical trials because it gives them more treatment options. If they get an investigational drug and it doesn’t work, they can always stop taking it and continue on a standard therapy.

OH: There are patients who feel that without solid evidence of effectiveness, they would not use second-line hormonal therapies. But there are some patients who respond to them for years and have an excellent quality of life. Although randomized trials have not been done to prove a survival benefit, we do see improved survival. The studies just haven’t been done to prove it. In that regard, I like to give patients a sense of hope that there are multiple interventions to consider, and that there are more in development.

Clinical trials explained

Doctors often suggest that patients take part in clinical trials to gain access to the latest treatments and medications. Clinical trials begin when a treatment shows promising results in laboratory tests. Trials are grouped into four categories:

  • Phase I trials involve a small number of people and help assess the safety of a new treatment.
  • Phase II trials focus on the effectiveness of a treatment and usually involve fewer than 100 participants.
  • Phase III trials compare a new treatment with standard treatments. This can involve adding a new drug to a proven therapy to determine if the combination is more effective. The size of these trials ranges from hundreds to thousands of participants.
  • Phase IV trials gather information about treatments that have already been approved by the FDA for use in patients.

Randomized, double-blind phase III trials are considered the gold standard because of the large number of participants, the random assignment of patients to one treatment or another, and the fact that neither the doctor nor the patient knows which drug or type of therapy is being used. In some cases, the drug is actually a placebo, an inactive medication designed to look like the real one. Patients should know whether or not they are taking part in a placebo-controlled study, as there is often a 50% chance that they will not be receiving an active treatment.

To determine whether you are a suitable candidate for a trial, talk with your doctor. Trials currently enrolling patients, along with enrollment criteria, are listed at www.clinicaltrials.gov. You can also call the National Cancer Institute’s Clinical Trials Referral Office at 888-NCI-1937 (888-624-1937) for information.

Comments
13
Greg Edwards

I’m in the process of being diagnosed (CT, bone scan) with AIPC .. This follows 6 years of androgen suppreson treatment.. I’m very grateful for the information, treatment advice, and the positive tone of the article.. Sincer thanks to all involved from the Dr’s to all ancelory support staff who made it available..

Greg
Sun City AZ

F

I, 69 yr. old, 5’10”, 160lbs) was diagnosed with mPCA (pelvis and skeleton, no lymph nodes), totally asymptomatic at the beginning of 2016, Ashkenazi Jew with cancer (non-prostate) in both parents. PSA 28 on 01/02/2016, PSA 0.09 on 03/22/2016. BRCA2 mutation in biopsy sample. Have a germline normally only found in patients who have received chemotherapy.

Will start 6 rounds of docetaxel with carboplatins on 04/01/2016. Oncologists feels taht given the germline, the addition of carboplatins at the begining will be useful.

Any comments?

Andrew Campbell

I am about to start Lupron hormone treatment. What is the maximum recommended time between starting Lupron and starting Docetaxel?

david e seelye

DES, Prescott,AZ May 7,2016.
My PSA was 2.8 in December 2014, 5.2 June 2015 Primary doctor said nothing and I was dumb. New Primary January 11, 2016 PSA 334. Prostate biopsy January 26, 2016, out of 12 sample 1 3% Gleeson 6, sample 2 15% Gleeson 7, digital soft pliable!. CAT scan show numerous lymph node involvement. February started 6 month Lupron injection. Second opinion UACC showed positive PET scan, negative bone scan, two lymph nodes biopsied show positive for prostate cancer. Started Docetaxel April 7. PSA now 22, testosterone less than 20ng/Dl since March. 3 treatments done, 3 to 6 more on the horizon.
David

Dyke Davis

Great Article:
Learn everytime I read an article with this type format even though it covers little on the Immunotherapeutic side I was impressed with the therapeutic-response times and seeming understanding that it is best to consider any well researched therapy change, while the PSA is at its lowest point and begins to rise.
I say this because I am rising .070 ng/dL daily after seemingly nadir at .550 ng/dL that is now .690 ng/dL after a little over (2) weeks on combination Enzalutamide/Sipuleucel-T, but I think I maybe having an drug-drug interaction with my other medications and have begin to find precedents in stopping some and switching some to other types to improve my existing therapeutic potency.
Troubleshooting I am learning is part of the therapeutic approach before looking at failure or switching therapies…awaiting second PSA results since my .690 ng/dL rise and hoping for the best…Godspeed Everyone and Stay in the Fight…A THERAPY FOR YOU IS OUT THERE OR MAY BE ALREADY AVAILABLE, BUT YOU HAVE TO DO THE RESEARCH AND RISK!

Dennis Doyle

Wonderful Article. Revealed to me one should not be suprised or overly disappointed when first line hormone therapy stops working,.brings home the point of how tricky PCA can be whether you subscribe to the theory that you have androgen independent cells, or normal cells with ultra sensitive receptors that can live off low levels of testosterone.

Dora

What a wonderful informative complete article. learned a lot and it’s very positive and not scary. I also have a question. MY boy friend had his prostate removed in 2004 now he is getting lupron shots since sept of 2015. Ofcourse they are watching his levels. So my question is the latest blood test shows testostrone 880 and psa 0. His testostrone in feb 2016 was 8 and psa 0. He is going for another round of lupron. I am very happy that psa is 0 but also confused. would you please email me the answer what does this mean? thanks and keep up the good work

Debdas Mukerjee, Ph.D.

Very Informative article.

I am a cancer researcher. Currently retired and ‘am 83 years old. Apparently in good health, very active and walk every day more than 3 miles.

I had Glesson Grade 4 + 3 Prostate cancer diagnosed with PSA level 0.16ng/mL in 2007 and had prostactomy in 2008. I has survalance radiotherapy in 2013 when the PSA level was found to have raised.
April 2016 MRI revealed tumor nodules in the peritoneum. PSA and testosterone levels were 0.89ng/ml and 278 ng/dL respectively. No tumor in the bone. On May 20, 2016 I was injected with Firmagon 120 mg + 120 mg. I started taking 50mg of Bicalutamide by mouth daily from May 21, 2016.

On June 24, 2016 my testosterone level came down to 20ng/dL and PSA 0.89ng/mL. My oncologist started me with leuprolide 22.5 mg IM. I am continuing to take Biculatamide.

As I read the literature, I find that cytotoxicity of Taxotere overexpresses the androgen receptors and other adverse effects on the patients.

Realising that androgen independent prostate cancer cells can synthesise teatosterone from cholesterol, I would like to get your opinion on treating castration resistent prostate cancers for polyadenoside duphosphate ribose polymerase inhibition with olaparib. (Mateo J et al. N Engl. J Med 2015 Oct.29: 373(18):1697-708).

Beverley Vasquez

I am here to testifies on how Dr Odia help me to cure my sickness called CANCER OF THE LUNGS which has been eating me up for 2 years and 4 months, and when I go online I saw his email on how he cured so many people, so I emailed the Dr and tell my problems to him, and tell all his necessary needy for the healing, after that day he gave me an assurance of 3 days of his herbal healing, and said I should go for a medical check up on the 4th day of which I get to the hospital the new result now shows that the cancer was gone,And now am so happy and free from it thanks to Dr Odia. Please if there is any one in need of his help should kindly contact him on his email address ( drodiaherbalistcenter @ gmail . com )

J. Martin

I would like to second Greg Edwards comments above. Very informative and positive article. I am age 69, stage 4, with widespread metasis to bone and lymph nodes. PSA over 1,000. I have not started treatment yet due to recovery from a cancer enduced pulmonary embolism and now on anti-clot medication. I have a hematologist/oncologist and a urologist on my case. I am considering orchiectomy, but I will hear what my doctors recommend later this week. My wife and family are suffering emotionally and I can only hope that hormonal therapy will buy some time for us all. Thanks for the opportunity to express myself.

Ann Messina

My father now 91 has been on hormone therapy, Luron for over 10 years with two different “vacation” of sis months or more. Today for the first time it was discovered he now has a raising PSA and is Androgen independent. This article was very helpful moving forward in his diagnoses prior to visiting his oncologist. We will be informed!Thank you!

Deborah Sawicki

My husband was diagnosed with prostate cancer 3 years ago. He received radiation therapy ( 40 treatments ) and Lupron injections for 2 years. During this time his PSA was undectectable. He has been off the Lupron for over a year. In June his PSA level was .064, September it was .067, it was recommended that he start Lupron again. He opted to wait. In December he will have his PSA and Testosterone level checked. The radiation center said if his PSA goes to .1 then he will have to restart the Lupron. His initial biopsy showed positive for 3 sites in the prostate. Gleason score of 7 on 1 site so radiation and hormone therapy was the recommended treatment. After reading the article we arewondering if the Lupron should be held off for a while and use the watch and wait method. He is 69 years old. Would appreciate your thoughts. Thank you, Deborah Sawicki

Bob

Harvard as usual publishes comprehensive articles like this which are very informative. I’ve had questions about hormone therapy for which I’ve never been able to get answers . Now I have them even though as usual with this disease many questions have no definitive answers due to lack of data or the heterogeneous nature of this very complicated disease. I thank these doctors and all the others who toil to find answers , more treatments and hopefully more cures to this hideous disease.

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