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.
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
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.
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 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.
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.1, 6, 7
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.
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
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.
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
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
3Bill-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 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.