Treating High-Risk Prostate Cancer

Approximately 90 percent of men diagnosed with prostate cancer have disease that is localized to the prostate by examination and scans. Therefore, most men should be cured with radiation or surgery.

Unfortunately, 30 to 40 percent of men suffer relapse, and too many men die of this disease despite treatment. Optimizing control of cancer in the prostate while effectively treating cancer that has escaped the prostate undetected is necessary to cure more men with prostate cancer.

Here we review who is at risk, how progression occurs and how research should lead us to cure more men with prostate cancer.

Risk of Relapse Despite Treatment

Effective therapy must first cure cancer within the prostate. A broad variety of treatment modalities may eradicate cancer within the prostate gland and the area immediately around it. They include the following:

• Radiation
  • External beam radiotherapy (EBRT)
  • Intensity-modulated radiotherapy (IMRT)
  • 3D-conformal radiotherapy
  • Hypofractionated radiotherapy (SHARP or Cyberknife)
  • Proton beam radiotherapy
  • Brachytherapy (± EBRT)
• Prostatectomy
  • Radical retropubic
  • Laparoscopic/da Vinci-assisted 
  • Perineal
• Combination
  • Androgen deprivation + radiotherapy
  • Prostatectomy with adjuvant radiotherapy
• Cryotherapy
   
• High-intensity focused ultrasound
   
• Alternative approaches
  • Active surveillance
  • Androgen-deprivation therapy alone  

These options reflect intensive and successful efforts to maximize cure while minimizing side effects. They typically include treatment focused on controlling cancer within the prostate gland, while limiting damage to normal organs nearby.  A critical component of the biology of prostate cancer which can thwart these efforts is the propensity for cancer to spread (metastasize) outside of the gland to other areas of the body, such as bone, lung or other organs. At present, the only therapy that has been adequately tested in clinical studies to treat prostate cancers that might have spread is androgen deprivation (hormone therapy). This is commonly used in combination with radiation therapy or after prostatectomy for men with metastasis to lymph nodes. Androgen deprivation lowers serum testosterone, depriving prostate cancer cells of a growth factor critical for their survival. 

Radiotherapy and prostatectomy are the most commonly used treatment modalities for men with localized prostate cancer. The other approaches outlined in the list above—including cryotherapy, high-intensity focused ultrasound and others—clearly have the potential to cure prostate cancer, but limited numbers of patients have been treated with these approaches compared to surgery and radiation, with short follow-up, and their utility in the long term is less certain. 

To predict the efficacy and the likelihood of cure with surgery and radiation, various tools have been developed to assist patients and providers in deciding on therapy. These include the Kattan nomogram, the D’amico prognostic system and others. (See the articles “Biochemical Outcome After Radical Prostatectomy, External Beam Radiation Therapy or Interstitial Radiation Therapy for Clinically Localized Prostate Cancer” and “The Partin Tables.”)

The pretreatment prostate-specific antigen (PSA) level, clinical stage by digital rectal exam, Gleason score, and extent of disease on biopsy are the main factors that predict the likelihood of cure, as defined by the ability to suppress and maintain low levels of PSA without androgen deprivation. These studies have shown that patients with advanced (Stage T2b or greater) or high-grade cancer (Gleason score 8 to 10) or pretreatment PSA level greater than 20 ng/mL, are at a high risk of biochemical progression (that is, further cancer growth), regardless of whether they received surgery or radiation. 

Many men with intermediate-grade disease (Gleason 7) or stage T2a cancer or PSA level of 10 to 20 ng/mL also have an unacceptably high risk of relapse. These pretreatment factors are a general means of assessing the volume and biologic aggressiveness of cancer with an associated propensity for spread of the cancer outside of the prostate. Other researchers have evaluated how the “PSA doubling time,” or rapidity with which PSA is rising, before treatment affects cure in men diagnosed with prostate cancer. Some studies have found that an increase in PSA of greater than 2 ng/mL in the year preceding the diagnosis predicted a higher risk of cancer recurrence and the likelihood that cancer would cause a man’s death despite therapy.

Testing for Metastasis

When men are found to have high Gleason scores, high PSA, or extensive prostate involvement on biopsy, there may be additional studies done to determine if cancer is outside of the prostate or has spread to other areas. These tests may include computed tomography (CT) scans of the abdomen and pelvis, bone scans, or magnetic resonance imaging (MRI) of the pelvis. Many centers, including Seattle Cancer Care Alliance (SCCA), are testing other means of finding cancer using new types of positron emission tomography (PET) scans.

As a standard of care, other imaging tests have not been shown to be helpful in deciding whether cancer remains in the prostate and surrounding tissues. Sometimes oncologists may recommend that lymph nodes around the prostate be checked for metastasis in order to design treatment appropriately.

At SCCA and University of Washington Medical Center, a long-term effort has identified cells in the bone marrow that have originated from prostate cancer, even in the absence of other evidence of spread. These studies, in concert with those being offered to men with advanced prostate cancer, are attempting to identify which men are at the very highest risk of relapse of their cancer.

Radiation, Surgery, or Both?

The decision about treatment for prostate cancer at high risk of relapse is dependent upon many factors, including technical issues, such as whether it is safe for men to undergo an operation or whether the prostate is the appropriate size and in the appropriate position for brachytherapy.

Other considerations include whether men have many urinary tract symptoms, which may be worsened by some types of radiation treatment. The long-term side effects of surgery and radiation treatment differ, with an overall greater risk of erectile dysfunction and urinary incontinence immediately after surgery, and a greater risk of damage to the bladder and rectum with radiotherapy. 

Having discussions with experts who provide these treatments is the best way to estimate the likelihood of side effects and design the optimal approach for men facing this decision.

Prostatectomy provides the potential for cure by attempting to remove all obvious evidence of cancer in the prostate and surrounding tissue and lymph nodes. An important but evolving area of study is the determination of whether more extensive removal of lymph nodes outside of the standard dissection area will improve the staging and curing of prostate cancer. This is referred to as an “extended lymph node dissection” and is routinely performed by urologists at SCCA for patients with high-risk prostate cancer.  

Radiation therapy in the form of external beam radiotherapy, intensity modulated radiation therapy (IMRT), proton beam, hypofractionated radiation therapy (SHARP or Cyberknife), or brachytherapy provides the potential for cure by exposing prostate cancer to high doses of damaging radiation.

Radiation has the potential to treat the prostate, the surrounding tissue, and the lymph nodes within the pelvis. There have been no randomized studies comparing radiation to surgery in men with intermediate- or high-risk prostate cancer; therefore, the answer about which approach provides a better likelihood of cure is uncertain.

Many physicians treating men with prostate cancer rely on cure rates that come from men treated by a particular oncologist at a particular institution, and these results are very difficult to apply to men who are treated elsewhere. The most broadly applicable results are those that come from phase III studies, which reflect treatment by many providers at many institutions. Some researchers have attempted to compare very similar patients treated with radiation versus prostatectomy, taking only the factors available at the time of treatment into consideration.

Two series, one from researchers participating in the community provider network called CAPSURE and another from Memorial Sloan-Kettering Medical Center, both suggest that prostatectomy reduced the risk of metastasis and death from prostate cancer by 70 percent compared to radiation therapy. This effect was particularly pronounced in men with high-risk prostate cancer. Although this information is compelling, these studies are not randomized and cannot establish prostatectomy as a better standard of care in men with high-risk prostate cancer.

Radiation therapy has been the most commonly used approach in men facing high-risk prostate cancer, in part because of a concern that surgery may not be able to remove all the cancer in the prostate in some men. In many cases, hormonal therapy or androgen deprivation will be used with radiation therapy, as this has been shown to be helpful in treating men who are at high risk of relapse.
 
Another approach to the treatment of high-risk prostate cancer is to treat men with surgery, and if indicated to add radiation therapy immediately after surgery. This is called adjuvant radiation. It is designed to kill any cells in the area that might have been left behind after the prostate was removed. Two large studies have shown that immediate radiation therapy reduces the risk that PSA relapse will occur compared to radiation delayed until the PSA has risen substantially or to no therapy. 

One study demonstrated that immediate radiation reduced the risk of metastasis or the risk that patients will die from their prostate cancer. No studies have compared immediate adjuvant radiotherapy to radiation performed when the PSA becomes detectable but is still very low. Some studies suggest that radiation done when PSA is very low has a reasonable chance to bring PSA back under control, and as a result, there is controversy about whether radiation should be given right away after surgery or when PSA starts to rise.    

Systemic Therapy with Local Treatment

Systemic treatments for patients with cancer are designed to reach any place in the body that might harbor cancer. Almost any cancer can spread at some point during its development, although some cancers are at much higher risk for early spread. The likelihood for spread to other parts of the body with prostate cancer is higher if men have large amounts of cancer on exam or on biopsy or if the cancer has a high Gleason grade. High-risk prostate cancer requires additional treatment to treat cells that might have spread prior to diagnosis and therapy in order to improve outcomes. The most commonly used systemic therapy is androgen deprivation. This is typically performed by administering medications such as leuprolide (Lupron) or goserelin (Zoladex), or antiandrogens (flutamide or bicalutamide), which keep testosterone, the main growth factor for prostate cancer, from getting to its receptor and activating growth. 

Androgen Deprivation

Androgen deprivation is commonly given with radiation therapy when men are being treated for high-risk cancer because large studies have demonstrated clinical benefit for this combination. The benefits appear to be related both to the ability of androgen deprivation to make prostate cancer more susceptible to radiation-induced death, and by killing or suppressing cancer cells that might have already escaped from the prostate gland. Androgen deprivation by itself is not curative, and it has side effects.

Other systemic therapy, such as the chemotherapy drug docetaxel, provides benefits for men with advanced cancer, but it has not been adequately tested to see if it will benefit men with high-risk cancer localized to the prostate.

Because high-risk cancer spreads early and a significant component of recurrence is due to early spread, improving the systemic therapies that can be combined with surgery or radiation to eliminate cells that might have spread is a major focus.

New Research

Investigators at Seattle Cancer Care Alliance have been instrumental in performing laboratory and clinical studies to improve these systemic treatments. Most of this work has focused on trying to prevent resistance to hormonal therapy and targeting cancer cells that may already be resistant to hormone therapy from the outset by using chemotherapy early. If within each cancer there are prostate cancer cells resistant to hormone therapy at the outset, then treatments such as chemotherapy should be more effective at eliminating these “hormone-independent” cells that might have left the prostate. Investigators from SCCA are carrying out a study to determine if early chemotherapy after radical prostatectomy for prostate cancer can effectively kill any cells that might have spread prior to prostatectomy (Cooperative Studies Program study #553).  

Although hormonal therapy is among the most effective forms of systemic therapy available, it is rarely ever curative by itself.  Because for many years it was felt that prostate cancer would always become resistant to hormonal therapy, the lethal form of prostate cancer was called “hormone refractory” or “androgen independent.” Investigators at SCCA have shown that when cancers become resistant to lowering testosterone in the blood, it is because they have found out how to make their own testosterone within the cancer itself. For this reason, we believe that the majority of cancers are not hormone refractory but rather are converting other hormones in the blood, or even cholesterol, into testosterone within the cancer itself.

Fortunately new, more effective systemic therapies for hormone regulation are starting to be used in combination with surgery or radiation earlier in the treatment of high-risk prostate tumors. These include abiraterone (Zytiga) that blocks testosterone synthesis and blocks the ability of the tumor to metabolize androgens, cixutumumab that blocks signaling through the insulin-like growth factor pathway to the testosterone receptor, and enzalutamide (Xtandi) that prevents a tumor receptor from binding to androgens and translocating to the cancer cell’s nucleus. These second generation drugs have enhanced actions that lead to a more powerful suppression of androgen receptor signaling resulting in prolonged survival in patients with what was historically considered to be hormone refractory prostate cancer.

At SCCA, we have designed studies using these new drugs to better block the ability of cancer cells to make and use hormones. These drugs are being given to men with high-risk prostate cancer prior to radiation or surgery. In this way, men have access to drugs that are not otherwise available and that may more effectively suppress or kill cells that might have spread.   

There are several other studies available to men considering surgery or radiation. The combination of novel drugs given with definitive radiation or surgery may provide better control of cancer in the prostate and elsewhere. Participation in research studies like these has potential advantages and disadvantages, and must be carefully considered before deciding to proceed.  

Doctors at Seattle Cancer Care Alliance provide men who have prostate cancer with a range of options for therapy, including surgery, radiation and systemic treatments, through clinical studies in an effort to provide a long, healthy life.