Stages of Prostate Cancer

Learn how Texas Oncology treats prostate cancer at every stage, from early detection and active surveillance to advanced therapies for Stage IV.

Stage I Stage II Stage III Stage IV

Stage I Prostate Cancer

Overview

Prostate cancer is referred to as stage I if it cannot be felt in a physical examination and there is no evidence that cancer has spread outside the prostate. Stage I prostate cancer is further classified into the following depending on how it was found and how large it is:

T1a: The tumor (cancer) found when the prostate tissue is taken for some other reason and involves 5% or less of the prostate sample.
T1b: The tumor is found when the prostate tissue is taken for some other reason and involves more than 5% of the prostate sample.
T1c: The tumor is detected by needle biopsy, or because the patient has a high blood level of PSA.

Should All Patients Receive Treatment of Stage I Prostate Cancer?

If prostate cancer is truly confined to the prostate, it is curable with surgery or radiation. However, in order to benefit from curative treatment, a patient’s life expectancy may need to be 10-20 years from the time of prostate cancer diagnosis. This is because many prostate cancers are slow growing and men will sometimes die from other causes before they succumb to prostate cancer. Individuals may ask themselves: If cure is possible, is it necessary? Treatment of prostate cancer is a very personal decision; the choice of radiation versus prostatectomy is often based on weighing the possible complications of treatment and the relative inconvenience of the treatments. It is important to be seen by more than one physician to determine the likely treatment outcome associated with the various options available in your community. Before deciding on receiving treatment, patients should ensure they understand the answers to 3 questions:

What is my life expectancy and risk of cancer progression without treatment?
How will my prognosis be improved with treatment?
What are the risks or side effects of the various treatment options?

Primary Treatment Options for Stage I Prostate Cancer

Patients with stage I prostate cancer are curable and have a number of treatment options, including surgical removal of the cancer with radical prostatectomy, radiation therapy with brachytherapy or External Beam Radiation (EBRT) or active surveillance without immediate treatment. It is important for patients to obtain as much information as possible about the results of each treatment modality and to obtain more than one opinion on the matter, especially when deciding on surgery versus radiation therapy.

Before making treatment recommendations, physicians who treat prostate cancer consider a number of aspects about the patient’s health, life expectancy and the cancers risk of progression that help predict whether the cancer is truly confined to the prostate and how fast the cancer will grow. These include the clinical stage of the cancer, the prostate-specific antigen (PSA) level, and the appearance of the prostate cancer cells under the microscope (the Gleason score). Together they can be used to predict an individual’s risk of prostate cancer recurrence.

Low risk: PSA <10 ng/mL, Gleason score < 6 and clinical stage T1c or T2a
Intermediate risk: PSA >10 to 20 ng/mL or Gleason score of 7 or clinical stage T2b
High risk: PSA >20 ng/mL or a Gleason score of 8 to 10 or clinical stage T2c

In general, for patients with low or intermediate risk, early stage prostate cancer, treatment with radical prostatectomy, EBRT or brachytherapy appears to produce equivalent outcomes but these treatments are associated with different side effects. In patients with higher risk disease, however, treatment with EBRT or radical prostatectomy appears to produce superior results compared to brachytherapy however there is a significant risk of cancer recurrence and additional treatment strategies are being developed to improve outcomes.¹, ²

Radical Prostatectomy: Radical prostatectomy involves surgical removal of the prostate gland and a small amount of surrounding normal tissue. Surgical removal of the prostate is a very effective therapy if the cancer has not spread beyond the prostate and is a standard treatment for individuals with low, intermediate, and high-risk stage I cancer. Over 90% of patients with low-risk, and over 75% of those with intermediate risk prostate cancer treated with radical prostatectomy will survive greater than 10 years after surgery alone.¹, ³ Learn more about radical prostatectomy and its side effects.

Radiation Therapy: Radiation therapy is treatment with high energy x-rays that have the ability to kill cancer cells. Standard radiation therapy utilizes either external beam radiation (EBRT) consisting of daily treatments on an outpatient basis for approximately 6 to 8 weeks or interstitial brachytherapy, which involves permanent placement of radioactive seeds directly into the prostate gland.

Because radiation implants focus the radiation closely around the prostate, this form of radiation works best in patients with low or intermediate risk stage I prostate cancer. For high-risk patients another form of treatment may be better suited for the patient. In addition, patients with a large prostate gland, prior history of prostate infections or recent transurethral resection of the prostate (TURP) may not be able to undergo the implantation procedure for brachytherapy.¹, ⁴, ⁵ Learn more about the risks and benefits of EBRT and brachytherapy.

Active Surveillance: Some physicians and patients choose a strategy of delaying any treatment of prostate cancer until symptoms from the cancer appear. Because treatment with radiation or surgery may be associated with side effects, in addition to inconvenience, electing not to receive immediate treatment may be appropriate for selected patients especially those with other health concerns or a shorter life expectancy. This strategy may be described as “watchful waiting” or “active surveillance”.

Watchful waiting is based on the premise that some patients will not benefit from definitive treatment of the primary prostate cancer. The decision is to forgo definitive treatment and to instead provide treatment to relieve symptoms of local or metastatic progression if and when it occurs. In contrast to watchful waiting, a program of active surveillance is based on the premise that some, but not all, patients may benefit from treatment of their primary prostate cancer. A program of active surveillance is designed to provide definitive treatment for men with localized cancers that are likely to progress and to reduce the risk of treatment-related complications for men with cancers that are not likely to progress. Clinical studies suggest that individuals with lower risk cancers could be candidates for this treatment strategy because they have a low risk for clinical progression of their cancer within the first 10 to 15 years after the diagnosis. Thus this treatment strategy may be best suited for men with a shorter life expectancy.³, ⁶, ⁷

Treatment of the High-Risk stage I Prostate Cancer

Although active surveillance, brachytherapy, EBRT, and radical prostatectomy are options for the management of patients with high-risk stage I prostate cancer, recurrence rates are high. There are several areas of ongoing research where doctors are evaluating new treatment approaches to reduce the risk of cancer progression and improve survival of individuals with high-risk prostate cancer.

The current standard treatment for high-risk stage I prostate cancer is EBRT in conjunction with long-term androgen deprivation therapy (ADT). By combining ADT with a higher dose of EBRT delivered with 3D-CRT or IMRT radiation therapy the outcomes of high-risk patients can be improved. Generally, high-risk patients are usually not considered for treatment with brachytherapy; however, certain clinical scenarios may warrant the use of brachytherapy boost in combination with EBRT. Additionally, radical prostatectomy may be considered for selected high-risk-patients, although, it is a seemingly less popular approach due to the invasive nature in comparison to EBRT as well as the distinct set of complications which surgery poses; including perioperative mortality, long-term sexual dysfunction, and urinary incontinence. Additionally, the high likelihood that postoperative radiotherapy will be required potentially exposes patients to toxicities of both surgery and radiotherapy.¹, ³, ⁸

Radiation After Prostatectomy

A significant number of patients will still require postoperative radiation following radical prostatectomy because they are at an increased risk of cancer recurrence. Clinical studies have demonstrated that adjuvant radiation following radical prostatectomy may prolong the time until PSA recurrence, delay the use of hormonal therapy, and improve overall survival for certain patients.

Adjuvant radiation therapy is typically offered to high-risk patients following surgical prostatectomy. This includes individuals defined as high-risk and those found to have cancer involving the margins of the surgical specimen, seminal vesicle invasion, positive surgical margins, or extraprostatic extension following prostatectomy and individuals where the PSA remains persistently elevated.

The ideal time to deliver radiation therapy following radical prostatectomy is the subject of some debate. Radiation can be administered immediately after prostatectomy to high-risk individuals or in some cases delayed until there is evidence of PSA recurrence. The understanding of how best to use radiation following prostatectomy continues to evolve and patients should discuss the role and timing of radiation with their treating physician.⁹

Androgen Deprivation Therapy

In the management of high-risk prostate cancer ADT has been used before (neoadjuvant), during (concurrent), and after (adjuvant) local therapy. Hormone therapy deprives a man’s body of male hormones necessary for prostate cancer to grow. Clinical studies have demonstrated that ADT combined with EBRT delays cancer progression and improves survival in men with high-risk prostate cancer. The use of hormone therapy to shrink the prostate cancer prior to radical prostatectomy or radiation therapy can be used to 1) to reduce the prostate size prior to prostate brachytherapy and 2) to sensitize malignant cells to radiation during EBRT. Hormonal therapy prior to radiation therapy results in an average 20% shrinkage of prostate volume. This volume reduction may reduce the number of prostate cancer cells and diminish the volume irradiated decreasing the side effects. The understanding of how best to use ADT in men with high-risk prostate cancer continues to evolve and patients should discuss the role of ADT carefully with their treating physician.³, ⁵

Strategies to Improve Treatment

The progress that has been made in the treatment of prostate cancer has resulted from development of better treatments that were evaluated in clinical studies. Future progress in the treatment of stage I prostate cancer will result from continued participation in appropriate clinical trials. Currently, there are several areas of active exploration aimed at improving the treatment of localized prostate cancer.

Timing of Radiation: Although the use of radiation following prostatectomy improves outcomes in high-risk patients, some patients do not benefit and are exposed to its side effects unnecessarily. Clinical trials are ongoing to determine which patients benefit from radiation and whether radiation is best used immediately following prostatectomy or can be delayed in selected patients.

Newer Radiation Machines: Most EBRT uses high energy x-rays to kill cancer cells. Some radiation oncology centers use different types of radiation that require special machines to generate. These different types of radiation, such as protons or neutrons, appear to kill more cancer cells with the same dose. Combining protons or neutrons with conventional x-rays is one method of radiation therapy being evaluated in clinical trials.¹⁰, ¹¹

Combination Radiation Therapy: Some radiation oncologists are combining EBRT and interstitial seed brachytherapy for patients with stage I or III cancers. The purpose of the EBRT is to treat the tissues surrounding the prostate gland and lymph nodes where cancer cells may have spread. The interstitial seeds serve to deliver extra radiation dose to the prostate where the cancer cells are greatest. The combination of internal and external radiation is being evaluated to allow higher doses of radiation to the cancer while minimizing side effects to surrounding organs.⁸

Androgen Deprivation Therapy: Although Clinical studies have demonstrated that ADT combined with EBRT delays cancer progression and improves survival in men with high-risk prostate cancer, the optimal timing and duration of ADT is still being evaluated in clinical trials as is the role of ADT following prostatectomy in high risk patients.

Systemic Treatment of High Risk Patients: There is some evidence to suggest that the use of other systemic treatments like chemotherapy, which may be used alone or in combination with ADT may be beneficial in selected high-risk patients following local treatment with prostatectomy or EBRT. Clinical trials are ongoing to evaluate its potential benefits.

References

1 http://www.auanet.org/education/guidelines/prostate-cancer.cfm

2 Albertsen, P. C., Hanley, J. A., Barrows, G. H., Penson, D. F., Kowalczyk, P. D., Sanders, M. M. et al: Prostate cancer and the Will Rogers phenomenon. J Natl Cancer Inst, 97: 1248, 20053

3 Bill-Axelson, A., Holmberg, L., Ruutu, M., Haggman, M., Andersson, S. O., Bratell, S. et al: Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med, 352: 1977, 2005

4 Sylvester, J. E., Blasko, J. C., Grimm, P. D., Meier, R. and Malmgren, J. A.: Ten-year biochemical relapse-free survival after external beam radiation and brachytherapy for localized prostate cancer: the Seattle experience. Int J Radiat Oncol Biol Phys, 57: 944, 2003

5 D’Amico, A. V., Manola, J., Loffredo, M., Renshaw, A. A., DelaCroce, A. and Kantoff, P. W.: 6-Month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA, 292: 821, 2004

6 Klotz, L.: Active surveillance with selective delayed intervention for favorable risk prostate cancer. Urol Oncol, 24: 46, 2006

7 Adolfsson, J., Oksanen, H., Salo, J. O. and Steineck, G.: Localized prostate cancer and 30 years of follow-up in a population-based setting. Prostate Cancer Prostatic Dis, 3: 37, 2000

8 Bolla, M., Collette, L., Blank, L., Warde, P., Dubois, J. B., Mirimanoff, R. O. et al: Long- term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet, 360: 103, 2002

9 Wiegel T, Bottke K, Steiner U et al. Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with undetectable prostate-specific antigen: ARO 96-02/AUO AP 09/95. Journal of Clinical Oncology. 2009;27:2924-30.

10 Zietman AL, Bae K, Slater J, et al. Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: Long-term results from Proton Radiation Oncology Group/American College of Radiology 95-09. Journal of Clinical Oncology. 2010; 28: 1106-1111.

11 Yu JB, Soulos PR, Herrin J, et al. Proton versus intensity-modulated radiotherapy for prostate cancer: Patterns of care and early toxicity. Journal of the National Cancer Institute. Published early online December 14, 2012. doi: 10.1093/jnci/djs463

Stage II Prostate Cancer

Overview

Prostate cancer is referred to as stage II when the cancer can be detected by a digital rectal examination (DRE) or an elevated prostate-specific antigen (PSA), and there is no evidence that the cancer has spread outside the prostate to other organs. Stage II disease may also be further divided into the following depending on how much tissue is involved in the tumor (cancer):

T2a: The cancer involves half or less of a lobe (section) of the prostate.
T2b: The cancer involves half or more of a lobe of the prostate, but the other section isn’t involved at all.
T2c: The cancer involves both lobes of the prostate.

Should All Patients Receive Treatment of Stage II Prostate Cancer?

What is my life expectancy and risk of cancer progression without treatment?
How will my prognosis be improved with treatment?
What are the risks or side effects of the various treatment options?

Primary Treatment Options for Stage II Prostate Cancer

Patients with stage II prostate cancer are curable and have a number of treatment options, including surgical removal of the cancer with radical prostatectomy, radiation therapy with brachytherapy or External Beam Radiation (EBRT) or active surveillance without immediate treatment. It is important for patients to obtain as much information as possible about the results of each treatment modality and to obtain more than one opinion on the matter, especially when deciding on surgery versus radiation therapy.

Low risk: PSA <10 ng/mL, Gleason score < 6 and clinical stage T1c or T2a
Intermediate risk: PSA >10 to 20 ng/mL or Gleason score of 7 or clinical stage T2b
High risk: PSA >20 ng/mL or a Gleason score of 8 to 10 or clinical stage T2c

Radical Prostatectomy: Radical prostatectomy involves surgical removal of the prostate gland and a small amount of surrounding normal tissue. Surgical removal of the prostate is a very effective therapy if the cancer has not spread beyond the prostate and is a standard treatment for individuals with low, intermediate, and high-risk stage II cancer. Over 90% of patients with low-risk, and over 75% of those with intermediate risk prostate cancer treated with radical prostatectomy will survive greater than 10 years after surgery alone.¹, ³ Learn more about radical prostatectomy and its side effects.

Because radiation implants focus the radiation closely around the prostate, this form of radiation works best in patients with low or intermediate risk stage II prostate cancer. For high-risk patients another form of treatment may be better suited for the patient. In addition, patients with a large prostate gland, prior history of prostate infections or recent transurethral resection of the prostate (TURP) may not be able to undergo the implantation procedure for brachytherapy.¹, ⁴, ⁵ Learn more about the risks and benefits of EBRT and brachytherapy.

Treatment of the High-Risk Stage II Prostate Cancer

Although active surveillance, brachytherapy, EBRT, and radical prostatectomy are options for the management of patients with high-risk stage II prostate cancer, recurrence rates are high. There are several areas of ongoing research where doctors are evaluating new treatment approaches to reduce the risk of cancer progression and improve survival of individuals with high-risk prostate cancer.

The current standard treatment for high-risk stage II prostate cancer is EBRT in conjunction with long-term androgen deprivation therapy (ADT). By combining ADT with a higher dose of EBRT delivered with 3D-CRT or IMRT radiation therapy the outcomes of high-risk patients can be improved. Generally, high-risk patients are usually not considered for treatment with brachytherapy; however, certain clinical scenarios may warrant the use of brachytherapy boost in combination with EBRT. Additionally, radical prostatectomy may be considered for selected high-risk-patients, although, it is a seemingly less popular approach due to the invasive nature in comparison to EBRT as well as the distinct set of complications which surgery poses; including perioperative mortality, long-term sexual dysfunction, and urinary incontinence. Additionally, the high likelihood that postoperative radiotherapy will be required potentially exposes patients to toxicities of both surgery and radiotherapy.¹, ³, ⁸

Radiation After Prostatectomy

Androgen Deprivation Therapy

Strategies to Improve Treatment

The progress that has been made in the treatment of prostate cancer has resulted from development of better treatments that were evaluated in clinical studies. Future progress in the treatment of stage II prostate cancer will result from continued participation in appropriate clinical trials. Currently, there are several areas of active exploration aimed at improving the treatment of localized prostate cancer.

Combination Radiation Therapy: Some radiation oncologists are combining EBRT and interstitial seed brachytherapy for patients with stage II or III cancers. The purpose of the EBRT is to treat the tissues surrounding the prostate gland and lymph nodes where cancer cells may have spread. The interstitial seeds serve to deliver extra radiation dose to the prostate where the cancer cells are greatest. The combination of internal and external radiation is being evaluated to allow higher doses of radiation to the cancer while minimizing side effects to surrounding organs.⁸

References

1 http://www.auanet.org/education/guidelines/prostate-cancer.cfm

2 Albertsen, P. C., Hanley, J. A., Barrows, G. H., Penson, D. F., Kowalczyk, P. D., Sanders, M. M. et al: Prostate cancer and the Will Rogers phenomenon. J Natl Cancer Inst, 97: 1248, 20053

3 Bill-Axelson, A., Holmberg, L., Ruutu, M., Haggman, M., Andersson, S. O., Bratell, S. et al: Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med, 352: 1977, 2005

6 Klotz, L.: Active surveillance with selective delayed intervention for favorable risk prostate cancer. Urol Oncol, 24: 46, 2006

7 Adolfsson, J., Oksanen, H., Salo, J. O. and Steineck, G.: Localized prostate cancer and 30 years of follow-up in a population-based setting. Prostate Cancer Prostatic Dis, 3: 37, 2000

Stage III (C) Prostate Cancer

Overview

Prostate cancer is referred to as stage III if the cancer has extended through the capsule that encloses the prostate gland and may involve nearby tissues. Stage III prostate cancer is further divided into the following categories, depending on how extensive the cancer is:

T3a: The tumor has extended outside of the prostate on one side.
T3b: The tumor has extended outside of the prostate on both sides.
T3c: The tumor has invaded one or both of the seminal vesicles, which are small bag-like organs near the bladder.

Prostate cancer is typically a disease of aging. It may persist undetected for many years without causing symptoms. Patients with stage III prostate cancer are curable and have a number of treatment options, including external beam radiation therapy (EBRT) with or without hormone therapy, surgical removal of the cancer with radical prostatectomy, or active surveillance without immediate treatment. It is important for patients to obtain as much information as possible about the results of each treatment modality and to obtain more than one opinion on the matter, especially when deciding on surgery versus radiation therapy.

Despite the prostate cancer being treated locally with radiation or surgery, over half of patients will experience recurrence of their cancer. Given the poor results of treatment with radiation or surgery alone, it is increasingly common to use one or more treatment strategies in combination. The current standard treatment for stage III prostate cancer is external beam radiation therapy (EBRT) in conjunction with long-term androgen deprivation therapy (ADT). By combining ADT with a higher dose of EBRT delivered with 3D-CRT or IMRT radiation therapy the outcomes of stage III patients have been improved.¹, ²

Local Treatment Options for Stage III Prostate Cancer

Treatment with surgery or radiation is referred to as local therapy because they treat prostate cancer in or near the prostate only. Despite effective local treatment over half of patients will experience recurrence of their cancer. This is because the majority of patients with stage III disease already have small amounts of cancer that have spread outside the prostate and were not effectively treated. Undetectable areas of cancer outside the prostate gland are referred to as micrometastases. The presence of micrometastases may cause the relapses that follow local treatment. An effective treatment is needed to cleanse the body of micrometastases in individuals at high risk of recurrence after local therapy.

Low risk: PSA <10 ng/mL, Gleason score < 6 and clinical stage T1c or T2a
Intermediate risk: PSA >10 to 20 ng/mL or Gleason score of 7 or clinical stage T2b
High risk: PSA >20 ng/mL or a Gleason score of 8 to 10 or clinical stage T2c

Radical Prostatectomy: Radical prostatectomy involves surgical removal of the prostate gland and a small amount of surrounding normal tissue. The majority of men with stage III prostate cancer are not candidates for surgery because the cancer is likely to have spread beyond the prostate. This is especially true for men with high Gleason scores or PSA levels. Before a prostatectomy is performed, patients may want to have pelvic lymph nodes removed to see if they contain cancer. This is called a pelvic lymph node dissection. If the lymph nodes contain cancer, usually the surgeon will not proceed with a radical prostatectomy. Another form of treatment, usually hormone therapy, radiation therapy or participation in a clinical study is generally recommended.

Patients without evidence of lymph node invasion may want to proceed to radical prostatectomy. Approximately 80% of patients with surgically confined stage III prostate cancer (cancer confined to the prostate that can be surgically removed) will be alive 5 years after surgery, and most patients who die do so of causes other than prostate cancer.

Radical prostatectomy may be considered for selected patients, although, it is a seemingly less popular approach due to the invasive nature in comparison to EBRT as well as the distinct set of complications which surgery poses; including perioperative mortality, long-term sexual dysfunction, and urinary incontinence. Additionally, the high likelihood that postoperative radiotherapy will be required potentially exposes patients to toxicities of both surgery and radiotherapy.¹, ³ Learn more about radical prostatectomy and its side effects.

Because brachytherapy focus the radiation closely around the prostate, this form of radiation does not work as well in patients with stage III prostate cancer unless combined with EBRT. The purpose of the EBRT is to treat the surrounding tissues and lymph nodes where cancer cells may have spread. The radioactive implant seeds deliver an increased radiation dose to the prostate where the cancer cells are greatest. The combination of internal and external radiation may permit high doses of radiation to be delivered to the cancer while minimizing side effects to surrounding organs.¹, ⁴, ⁵ Learn more about the risks and benefits of EBRT and brachytherapy.

Radiation After Prostatectomy

A significant number of patients electing treatment with surgery will still require postoperative EBRT because they are at an increased risk of cancer recurrence. Clinical studies have demonstrated that EBRT following radical prostatectomy may prolong the time until PSA recurrence, delay the use of hormonal therapy, and improve overall survival for certain patients.

EBRT is typically offered to high-risk patients electing treatment with surgical prostatectomy. This includes individuals defined as high-risk and those found to have cancer involving the margins of the surgical specimen, seminal vesicle invasion, positive surgical margins, or extraprostatic extension following prostatectomy and individuals where the PSA remains persistently elevated.

Combined Modality Therapy

Despite the prostate cancer being treated with radiation, many patients with stage III prostate cancer will experience recurrence of their cancer. Research indicates that multi-modality treatment, which uses combinations of chemotherapy, surgery, radiation, and hormone therapy into a single overall treatment strategy improves cure and survival rates.

Several clinical studies have directly compared radiation therapy alone to a combination of radiation therapy and hormone therapy for locally advanced prostate cancer. The results suggest that the combination of radiation therapy and hormone therapy reduces the time to cancer recurrence, and development of metastatic disease, and may improve a patient’s quality of life and increase overall survival. Clinical studies are ongoing to determine the optimal timing and duration of hormone therapy when utilized in combination with EBRT or radical prostatectomy.¹, ⁸, ⁹

Androgen Deprivation Therapy (ADT)

Hormone therapy deprives a man’s body of male hormones necessary for prostate cancer to grow and is known as androgen-deprivation therapy or (ADT). It is designed to stop testosterone from being released or to prevent it from acting on the prostate cells and prevent the growth of cancer. Hormone therapy is a systemic treatment; it can affect the growth of prostate cancer everywhere in the body, whether the cancer cells are in the prostate itself or elsewhere in the body.

Clinical studies have demonstrated that ADT combined with EBRT delays cancer progression and improves survival in men with high-risk prostate cancer. In the management of stage III prostate cancer ADT has been used before (neoadjuvant), during (concurrent), and after (adjuvant) local therapy. The use of hormone therapy to shrink the prostate cancer prior to radical prostatectomy or radiation therapy can be used to 1) to reduce the prostate size prior to prostate brachytherapy and 2) to sensitize malignant cells to radiation during EBRT. Hormonal therapy prior to radiation therapy results in an average 20% shrinkage of prostate volume. This volume reduction may reduce the number of prostate cancer cells and diminish the volume irradiated decreasing the side effects. The understanding of how best to use ADT in men with high-risk prostate cancer continues to evolve and patients should discuss the role of ADT carefully with their doctor.⁹, ¹⁰, ¹¹ Learn more about ADT options.

Active Surveillance

Some physicians and patients choose a strategy of delaying any treatment of prostate cancer until symptoms from the cancer appear. Because treatment with radiation or surgery may be associated with side effects, in addition to inconvenience, electing not to receive immediate treatment may be appropriate for selected patients. This strategy may be described as “watchful waiting” or “active surveillance”

Watchful waiting is based on the premise that some patients will not benefit from definitive treatment of the primary prostate cancer. The decision is to forgo definitive treatment and to instead provide treatment to relieve symptoms of local or metastatic progression if and when it occurs. In contrast to watchful waiting, a program of active surveillance is based on the premise that some, but not all, patients may benefit from treatment of their primary prostate cancer. A program of active surveillance is designed to provide definitive treatment for men with localized cancers that are likely to progress and to reduce the risk of treatment-related complications for men with cancers that are not likely to progress. Clinical studies suggest that individuals with lower risk cancers could be candidates for this treatment strategy because they have a low risk for clinical progression of their cancer within the first 10 to 15 years after the diagnosis. This treatment strategy may be best suited for men with a shorter life expectancy or those with other significant medical problems.

Strategies to Improve Treatment

The progress that has been made in the treatment of prostate cancer has resulted from development of better treatments that were evaluated in clinical studies. Future progress in the treatment of stage III prostate cancer will result from continued participation in appropriate clinical trials. Currently, there are several areas of active exploration aimed at improving the treatment of localized prostate cancer.

Strategies to Improve Systemic Therapy

Surgery and radiation are local therapies directed at treating cancer in and around the prostate gland. Over the past several years, many new anti-cancer drugs have been discovered that are more active at destroying cancer cells. Administration of these newer anti-cancer agents in addition to radiation or surgical removal of prostate cancer may improve the treatment of locally advanced prostate cancer.¹⁴, ¹⁵

Systemic Treatment of High Risk Patients: There is some evidence to suggest that the use of systemic treatments like chemotherapy alone or in combination with ADT may be beneficial in selected high-risk patients following local treatment with prostatectomy or EBRT.

Androgen Deprivation Therapy: Although Clinical studies have demonstrated that ADT combined with EBRT delays cancer progression and improves survival in men with stage III prostate cancer, the optimal timing and duration of ADT is still being evaluated in clinical trials as is the role of ADT following prostatectomy in high risk patients.¹, ⁹

Neoadjuvant therapy: Treatment administered before local therapy is called neoadjuvant therapy. Administering systemic therapies, such as hormonal therapy and chemotherapy, before local therapy is a strategy that is being actively investigated. This technique can shrink the cancer so that it is more treatable with local therapies. Hormonal therapy prior to local treatment appears to decrease the size of the prostate cancer by approximately 20-50%. The impact of neoadjuvant hormone therapy prior on cancer progression and survival is being evaluated in clinical studies.¹⁴

Chemotherapy can also be administered before surgery or radiation, to shrink the cancer so that it is more treatable with local therapies. Chemotherapy also provides the benefit of killing cancer cells that have already spread away from the prostate and are not treated with local therapy.

Studies suggest that neoadjuvant chemotherapy can significantly reduce the amount of detectable prostate cancer. Research also indicates that combination chemotherapy and hormone therapy may improve survival in patients with locally advanced prostate cancer. Clinical trials evaluating neoadjuvant chemotherapy and hormone therapy alone or in combination are ongoing and should be considered especially in individuals at high risk of recurrence.

Strategies to Improve Local Therapy

Researchers recently evaluated the effectiveness of brachytherapy plus EBRT versus EBRT alone in the treatment of over 300 patients with advanced localized prostate cancer. Half of the patients received treatment consisting of both brachytherapy and EBRT and the other half received EBRT alone. Five years following treatment, high PSA levels existed in only 33% of patients that had received the combination of brachytherapy plus EBRT compared to 56% of patients that received EBRT alone. Since high PSA levels are an indication of the presence of cancer, these results suggest that brachytherapy plus EBRT may be more effective than EBRT alone in the treatment of advanced localized prostate cancer.¹

Whole pelvic radiation therapy: Because certain patients are at higher risk of cancer involving the pelvic lymph nodes, some doctors have advocated expanding the radiation field to include the pelvic lymph nodes. This is referred to as whole pelvic radiation therapy (WPRT). Some, but not all, comparisons of WPRT to prostate only radiation therapy have demonstrated that WPRT may improve survival and is not more toxic than radiation to the prostate only. Many doctors believe, however, that if cancer has spread to the pelvic lymph nodes, it has probably spread elsewhere in the body and expanding the radiation field will be of little benefit. Efforts to improve treatment might be better focused on systemic treatment approaches versus local treatment with radiation. Doctors in the United States are currently conducting a clinical study comparing WPRT to prostate only radiation.¹

References

1 http://www.auanet.org/education/guidelines/prostate-cancer.cfm

2 Albertsen, P. C., Hanley, J. A., Barrows, G. H., Penson, D. F., Kowalczyk, P. D., Sanders, M. M. et al: Prostate cancer and the Will Rogers phenomenon. J Natl Cancer Inst, 97: 1248, 20053

3 Bill-Axelson, A., Holmberg, L., Ruutu, M., Haggman, M., Andersson, S. O., Bratell, S. et al: Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med, 352: 1977, 2005

5 Wiegel T, Bottke K, Steiner U et al. Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with undetectable prostate-specific antigen: ARO 96-02/AUO AP 09/95. Journal of Clinical Oncology. 2009;27:2924-30.

6 Adolfsson, J., Oksanen, H., Salo, J. O. and Steineck, G.: Localized prostate cancer and 30 years of follow-up in a population-based setting. Prostate Cancer Prostatic Dis, 3: 37, 2000

7 Thompson IM, Valicenti R, Albertsen PC, et al. Adjuvant and Salvage Radiotherapy after Prostatectomy: ASTRO/AUA Guideline. Available at: http://www.auanet.org/education/guidelines/radiation-after-prostatectomy.cfm

8 D’Amico, A. V., Manola, J., Loffredo, M., Renshaw, A. A., DelaCroce, A. and Kantoff, P. W.: 6-Month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA, 292: 821, 2004

9 Bolla, M., Collette, L., Blank, L., Warde, P., Dubois, J. B., Mirimanoff, R. O. et al: Long- term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet, 360: 103, 2002

10 Warde P, Manson M, Ding K et al. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet. Early online publication November 3, 2011.

11 Cook JM, O’Callaghan CJ, Duncan G, et al. Intermittent androgen suppression for rising PSA level after radiotherapy. New England Journal of Medicine. 2012; 367: 895-903.

12 Klotz, L.: Active surveillance with selective delayed intervention for favorable risk prostate cancer. Urol Oncol, 24: 46, 2006

13 Adolfsson, J., Oksanen, H., Salo, J. O. and Steineck, G.: Localized prostate cancer and 30 years of follow-up in a population-based setting. Prostate Cancer Prostatic Dis, 3: 37, 2000

14 Fizazi K, Lesaunier F, Delva R, et al. A phase III trial of docetaxel-estramustine in high-risk localized prostate cancer (GETUG 12 trial): Design, tolerance, response, and quality of life (QOL). Presented at the 2010 Genitourinary Cancers Symposium in San Francisco. March 5-7, 2010. Abstract #7.

15 Sweeney C., et al. Impact on overall survival with chemohormonal therapy versus hormonal therapy for home-sensitivity newly metastatic prostate cancer: An ECOG-led phase III randomized trial. ASCO 2014; Abstract LBA2.

Stage IV (D) Prostate Cancer

Overview

A stage IV prostate cancer is said to exist if the final evaluation shows that the cancer has spread to distant locations in the body, which usually includes bones. Stage IV disease may be further classified as the following depending on the extent of the cancer (tumor):

The tumor has spread to pelvic lymph nodes or is obstructing the ureters (the tubes from the kidneys to the bladder), or both.
Cancer spread (metastasis) to lymph nodes outside the pelvic area, bone involvement, or spread to other distant parts of the body.

Patients diagnosed with stage IV prostate cancer can be broadly divided into two groups. Patients with cancer locally confined to the pelvis, but involving adjacent organs or lymph nodes have localized stage IV or D1 prostate cancer. Patients with disease that has spread to distant organs, most commonly the spine, ribs, pelvis and other bones have metastatic stage IV or D2 prostate cancer.

Prostate cancer diagnosed in this stage is often difficult to cure, although patients may live for several years with effective treatment. Recent advances in treatment have resulted in new treatment options that reduce symptoms and improve survival. Each person with prostate cancer is different, and the specific characteristics of your condition will determine how it is managed. The following general overview of the treatment of stage IV prostate cancer is intended to help educate you about treatment options and to facilitate a shared decision-making process with your treating physician.

Treatment of Metastatic Stage IV or D2 Prostate Cancer

Prostate cancer that has spread to distant organs and bones is treatable, but not curable with current standard therapies. Hormone therapy has been the standard treatment of metastatic prostate cancer for many years. Metastatic prostate cancer usually can be controlled with hormone therapy for a period of time, often several years. Advances in chemotherapy, immunotherapy, and hormone therapy have expanded the treatment options available for patients with advanced prostate cancer in recent years.¹

Hormone Therapy

Hormone therapy deprives a man’s body of male hormones necessary for prostate cancer to grow. Initial hormone therapy for prostate cancer can be achieved with orchiectomy or luteinizing hormone-releasing hormone (LHRH) analogues, alone or in combination with an anti-androgen.

Newer hormonal medications that inhibit the synthesis of androgen (abiraterone) and block androgen receptor signaling (enzalutamide) are now FDA-approved for the treatment of metastatic prostate cancer after treatment with chemotherapy, and are being evaluated for earlier use in the disease.²,³,⁴,⁵,⁶

Abiraterone (Zytiga^®) Abiraterone is an oral targeted agent that blocks the production of androgens not only by the testes, but also by the adrenal glands and the tumor itself. Abiraterone when administered with prednisone has been shown to improve quality of live and delay patient-reported pain progression in HRPC patients. Although this medication is generally well-tolerated, side effects may include fatigue, high blood pressure, and electrolyte or liver abnormalities and patients need to be monitored regularly.²,³,⁶

Enzalutamide (Xtandi^®) Enzalutamide targets multiple steps in the androgen-receptor–signaling pathway, interfering with molecular pathways that help the prostate cancer grow. What’s more, the drug does not cause side effects commonly associated with chemotherapy, such as nausea and hair loss. Enzalutamide has been shown to improve survival, reduce the risk of cancer progression, and delay the need for additional chemotherapy in men with HRPC.³,⁵

Chemotherapy

Chemotherapy, like hormone therapy is a systemic therapy in that the cancer-fighting drugs circulate in the blood to parts of the body where the cancer may have spread and can kill or eliminate cancers cells at sites great distances from the original cancer. Several chemotherapeutic drugs have demonstrated the ability to kill prostate cancer cells in patients with advanced prostate cancer. In particular, the chemotherapy drugs mitoxantrone (Novantrone^®), docetaxel (Taxotere^®), paclitaxel and estramustine have all been demonstrated to have some effectiveness in treating prostate cancer.⁷,⁸

Docetaxel chemotherapy was demonstrated to improve survival of men with advanced HRPC in 2004 and has remained the mainstay of chemotherapy often utilized in combination with prednisone or estramustine. The results of a more recent study conducted by researchers at the Dana-Farber Cancer Institute recently confirmed the role of docetaxel chemotherapy. Docetaxel when administered with androgen-deprivation therapy (ADT) to metastatic prostate cancer patients was found to extend overall survival by more than 13 months.⁹ These results were reported at the 2014 American Society of Clinical Oncology meeting held in Chicago. The study included 790 men with hormone-sensitive metastatic prostate cancer. Patients were treated with standard ADT and compared with those treated with ADT plus docetaxel. Men treated with ADT/docetaxel had a median overall survival rate of 57.4 months compared to only 44 months for those treated with ADT alone. Importantly, for men with a high disease burden at the beginning of the study, the survival difference was even greater: a median overall survival of 49.2 months versus 32.2 months.

More recently, several new chemotherapy and targeted therapy drugs have been approved for the treatment of advanced prostate cancer. A Targeted therapy is one that is designed to treat only the cancer cells and minimize damage to normal, healthy cells. Treatments that “target” cancer cells may offer the advantage of reduced treatment-related side effects and improved outcomes. Doctors are working to determine the best sequence, combinations, and timing of utilization of newer chemotherapy and targeted therapy drugs.

Cabazitaxel (Jevtana^®): Cabazitaxel is administered intravenously and has been demonstrated to improve time to cancer progression and overall survival in men with HRPC previously treated with docetaxel. Cabazitaxel’s primary side effect is neutropenia, and it is recommended that patients receive a white blood cell growth factor if they are at high risk of this complication.¹⁰

Immunotherapy

Biological therapy is referred to by many terms, including immunologic therapy, immunotherapy, or biotherapy. Biological therapy is a type of treatment that uses the body’s immune system to facilitate the killing of cancer cells. Types of biological therapy include interferon, interleukin, monoclonal antibodies, colony stimulating factors (cytokines), and vaccines. Biologic therapies are being developed for the treatment of prostate cancer.

Sipuleucel-T( Provenge^®): Sipuleucel-T is an immunotherapy that prompts the body’s immune system to respond against the cancer. A Phase III clinical trial that contributed to the FDA approval of sipuleucel-T was a study known as IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) which demonstrated an improvement in overall survival for men treated with sipuleucel-T. The main side effects reported were chills, fever, and headache.¹¹

Treatment of Bone Complications

Patients with advanced prostate cancer can have cancer cells that have spread to their bones, called bone metastases. Bone metastases commonly cause pain, increase the risk of fractures, and can lead to a life-threatening condition characterized by an increased amount of calcium in the blood called hypercalcemia. Treatments for bone complications may include drug therapy or radiation therapy.¹²

Zoledronic acid (Zometa^®): Zoledronic acid is a bisphosphonate drug that can effectively prevent loss of bone that occurs from cancer that has spread to the bones thereby reducing the risk of fractures, and decreasing pain. Bisphosphonate drugs work by inhibiting bone resorption, or breakdown. Zoledronic acid may be used to reduce the risk of complications from bone metastases or to treat cancer-related hypercalcemia.¹³,¹⁴

Denosumab (Xgeva): Denosumab targets a protein known as the RANK ligand. This protein regulates the activity of osteoclasts (cells that break down bone). Studies have suggested that Denosumab may be more effective than Zoledronic acid at delaying bone complications in prostate cancer patients with bone metastases. Denosumab is associated with side effects including hypocalcemia (low levels of calcium in the blood) and osteonecrosis of the jaw (death of bone in the jaw).¹⁵

Xofigo^® (radium Ra 223 dichloride): Radium 223 is a targeted radiopharmaceutical agent that binds with minerals in the bone to deliver radiation directly to bone tumors, thereby limiting the damage to the surrounding normal tissues. The U.S. Food and Drug Administration (FDA) approved the drug in May 2013 after a trial known as Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) was stopped early after an interim analysis showed that treatment with significantly improved survival.¹⁶

Radiation therapy: Pain from bone metastases may also be relieved with radiation therapy directed to the affected bones.

Treatment of Localized Stage IV or D1 Prostate Cancer Prostate cancer may not be diagnosed until it has invaded adjacent organs, such as the rectum or bladder, or spread to lymph nodes in the pelvis. When this occurs, surgery (radical prostatectomy) is seldom an effective treatment. Current treatment involves a combination of external beam radiation therapy (EBRT) and hormone therapy. In localized stage IV prostate cancer, hormone therapy and radiation therapy are often given together and studies have demonstrated that patients treated with radiation therapy and immediate hormonal therapy are more likely to be alive 5 years from initiation of treatment without evidence of cancer progression or development of distant metastatic disease than patients treated with radiation and delayed hormonal therapy. The combination of radiation and immediate hormonal therapy appear to increase the survival of some patients.¹

Strategies to Improve Treatment

The progress that has been made in the treatment of prostate cancer has resulted from development of better treatments that were evaluated in clinical studies. Future progress in the treatment of prostate cancer will result from patients continued participation in appropriate clinical trials. Developing novel immunotherapy and single or multi-agent chemotherapy treatments for patients with advanced prostate cancer is the main area of active investigation.

Immunotherapy: Novel vaccine strategies to harness the immune system are being tested, such as PROSTVAC in asymptomatic, chemotherapy-naïve men prostate cancer Other immune based strategies include inhibition of immune check points using Ipilimumab, which is a monoclonal anti-CTLA4 antibody that binds to a receptor on T cells, blocking CTLA4 and, in turn, activating T-cell anti-tumor activity.

Chemotherapy: Because hormone therapy is not curative and only controls metastatic prostate cancer for a certain amount of time, efforts are underway to discover more effective systemic therapy. Combining agents with novel or different mechanisms of killing prostate cancer cells with docetaxel remains an area of significant interest.

Custirsen is a novel chemotherapy drug that inhibits the production of clusterin, a protein associated with treatment resistance in a number of cancers, including prostate cancer.

Orteronel is a CYP17A inhibitor but is more specifically a 17,20-lyase inhibitor. It is currently being tested in a phase III trial comparing orteronel and prednisone to placebo and prednisone.

Tasquinomod is an orally active quinoline-3-carboxamide that has anti-angiogenic and anti-tumor properties.

References

1 http://www.auanet.org/education/guidelines/prostate-cancer.cfm

2 Basch E, Autio K, Ryan CJ, et al: Abiraterone acetate plus prednisone versus prednisone alone in chemotherapy-naive men with metastatic castration-resistant prostate cancer: patient-reported outcome results of a randomised phase 3 trial. The Lancet Oncology. 2013; 14(12):1193-1199.

3 Beer TM, Armstrong AJ, Sternberg CN, et al: Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): Results of phase III PREVAIL study. Presented at the 2014 Genitourinary Cancers Symposium. Journal of Clinical Oncology. 2014; 32 (supplement 4; abstract LBA1).

4 Nelson J, Banato A, Battistini B, Nisen P. The endothelin axis: emerging role in cancer. Nat Rev Cancer2003;3(2):110-116.

5 Scher HI, Fizazi K, Saad F et al: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Eng J Med 2012; 367: 1187.

6 de Bono JS, Logothetis CJ, Molina A et al: Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364: 1995.

7 Tannock I, de Wit R, Berry W, et al.Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer. New England Journal of Medicine. 2004; 351:1502-1512.

8 Petrylak D, Tangen C, Hussain M, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. New England Journal of Medicine. 2004; 351:1513-1520.

9 Sweeney C., et al. Impact on overall survival with chemohormonal therapy versus hormonal therapy for home-sensitivity newly metastatic prostate cancer: An ECOG-led phase III randomized trial. ASCO 2014; Abstract LBA2.

10 de Bono JS, Oudard S, Ozguroglu M et al: Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomized open-label trial. Lancet 2010; 376: 1147.

11 Kantoff PW, Higano CS, Shore ND et al: Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: 411.

12 Higano C, Shields A, Wood N, et al. Bone mineral density in patients with prostate cancer without bone metastases treated with intermittent androgen suppression. Urology 2004;64(6):1182-6.

13 Saad F, Gleason D, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. Journal of the National Cancer Institute 2002; 94:1458-1468.

14 Smith MR, Eastham J, Gleason DM, et al. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. Journal of Urology 2003; 169:2008-2012.

15 Smith MR, Saad F, Coleman R et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. Early online publication November 16, 2011.

16 Michalski J, Sartor O, Parker C, et al. Radium-223 dichloride (Ra-223) impact on skeletal-related events, external-beam radiotherapy (EBRT), and pain in patients with castration-resistant prostate cancer (CRPC) with bone metastases: Updated results from the phase III ALSYMPCA trial. Proceedings of the 55^th Annual Meeting of the American Society of Radiation Oncology. International Journal of Radiation Oncology Biology Physics. 2013; 87(2): S108-S109. Abstract 265.