Prostate Cancer Treatment (Professional) (cont.)
Stage II Prostate Cancer
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
Stage II prostate cancer is defined by the American Joint Committee on Cancer's TNM classification system:
- T1a–c, N0, M0, prostate-specific antigen (PSA) <20, Gleason 7.
- T1a–c, N0, M0, PSA =10 <20, Gleason =6.
- T2a, N0, M0, PSA =10 <20, Gleason =6.
- T2a, N0, M0, PSA <20, Gleason 7.
- T2b, N0, M0, PSA <20, Gleason =7.
- T2b, N0, M0, PSA X, Gleason X.
- T2c, N0, M0, any PSA, any Gleason.
- T1–2, N0, M0, PSA =20, any Gleason.
- T1–2, N0, M0, any PSA, Gleason =8.
Radical prostatectomy, external-beam radiation therapy (EBRT), and interstitial implantation of radioisotopes are each employed in the treatment of stage II prostate cancer with apparently similar therapeutic effects. Radical prostatectomy and radiation therapy yield apparently similar survival rates with as many as 10 years of follow-up. For well-selected patients, radical prostatectomy can achieve 15-year survival comparable to an age-matched population without prostate cancer. Unfortunately, randomized comparative trials of these treatment methods with prolonged follow-up are lacking. Patients with a small palpable cancer (T2a, N0, M0) fare better than patients in whom the disease involves both lobes of the gland (T2c, N0, M0). Patients proven free of node metastases by pelvic lymphadenectomy fare better than patients in whom this staging procedure is not performed; however, this is the result of selection of patients who have a more favorable prognosis. Side effects of the various forms of therapy—including impotence, incontinence, and bowel injury—should be considered in determining the type of treatment to employ. (For more information on impotence, refer to the Sexuality and Reproductive Issues summary.)
In a retrospective pooled analysis, 828 men with clinically localized prostate cancer were managed by initial conservative therapy with subsequent hormone therapy given at the time of symptomatic disease progression. This study showed that the patients with well or moderately well differentiated tumors experienced a disease-specific survival of 87% at 10 years and that their overall survival (OS) closely approximated the expected survival among men of similar ages in the general population. The decision to treat should be made in the context of the patient's age, associated medical illnesses, and personal desires.
Radical prostatectomy has been compared to watchful waiting in men with early-stage disease (clinical stages T1b, T1c, or T2) in a randomized clinical trial performed in Sweden in the pre-PSA screening era.[3,4] Only about 5% of the men in the trial had been diagnosed by PSA screening. The estimated overall mortality difference after 12 years between the radical prostatectomy and watchful waiting arms of the study was not statistically significant: 32.7% versus 39.8%; P = 0.09; see Figure 1.[Level of evidence: 1iiA]
Figure 1. Scandinavian Prostate Cancer Group-4 (SPCG-4) study. Trial flow diagram of the 695 men randomly assigned in the SPCG-4 study. RT equals radiation therapy; RP equals radical prostatectomy. Copyright A. Bill-Axelson 2008. Published by Oxford University Press. All rights reserved.
In a post hoc subset analysis, there was a statistically significant difference in overall mortality favoring prostatectomy for men aged 65 and younger: 21.9% versus 40.2%, P = .004 (relative risk of death = 0.59; 95% confidence interval [CI], 0.41–0.85). In contrast, for men aged 65 years or older, the overall mortality at 12 years for the prostatectomy and watchful waiting arms was 42% versus 39.3%, P = 0.81; (relative risk of death = 1.04; 95% CI, 0.77–1.40). Overall prostate cancer–specific mortality in the full trial at 12 years favored prostatectomy: 12.5% versus 17.9%, P = 0.03; relative risk = 0.65; 95% CI; 0.45–0.94; see Figure 2.[Level of evidence: 1iiB]
Figure 2. Cumulative incidence with 95% confidence intervals (CIs) at 4, 8, and 12 years of endpoints for all patients. A) Overall mortality: relative risk (RR) equals 0.82; 95% CI, 0.65–1.03; P equals .09. B) Prostate cancer (PC) death: RR equals 0.65; 95% CI, 0.45–0.94; P equals .03. C) Metastases: RR equals 0.65; 95% CI, 0.47–0.88; P equals .006. D) Local progression: RR equals 0.36; 95% CI, 0.27–0.47; P less than .001. E) Hormonal treatment: RR equals 0.54; 95% CI, 0.44–0.68; P less than .001. F) Other palliative treatment: RR equals 0.63; 95% CI, 0.41–0.97; P equals .04. P values (two-sided) were calculated using Gray's test. Copyright A. Bill-Axelson 2008. Published by Oxford University Press. All rights reserved.
Results from the Prostate Intervention Versus Observation Trial (PIVOT-1), a randomized trial in the United States that compared radical prostatectomy with watchful waiting, have not been reported. The PIVOT used overall mortality as its primary endpoint.
A quality-of-life substudy was conducted in 326 of the men in the randomized study. Men filled out questionnaires at a median of about 4 years after study entry. The principal differences in symptoms between the two groups were in sexual and urinary function. (For more information on sexual and urinary function, refer to the Sexuality and Reproductive Issues summary.) In the surgery and watchful waiting groups, 80% versus 45% of the men answering the questionnaire said they seldom or never had erections sufficient for sexual intercourse. Forty-nine percent of men in the prostatectomy arm had urinary leakage at least once a week, 43% used protective aids regularly, and 14% used diapers or urine bags compared to 21%, 10%, and 1%, respectively, in the watchful waiting arm; however, the men on the watchful waiting arm had more obstructive symptoms (e.g., severe symptoms on the American Urologic Symptom Index of 7% in the watchful waiting arm vs. 10% in the prostatectomy arm and moderate symptoms of 42% vs. 24%).[Level of evidence: 1iiC]
An older randomized study comparing radical prostatectomy at diagnosis to expectant therapy (careful observation with therapy as needed) in stage I and stage II cancers did not show a statistically significant difference in survival; however, the trial of 95 patients was not large enough to exclude a small but medically significant difference in OS, nor did it include information to measure time to progression, cancer-specific survival, or quality of life.
Often, baseline rates of PSA changes are thought to be markers of tumor progression. Even though a tumor marker or characteristic may be consistently associated with a high risk of prostate cancer progression or death, it may be a very poor predictor and therefore of very limited utility in making therapeutic decisions. For example, baseline PSA and rate of PSA change were associated with subsequent metastasis or prostate cancer death in a cohort of 267 men with clinically localized prostate cancer who were managed by watchful waiting in the control arm of a randomized trial comparing radical prostatectomy to watchful waiting.[8,9] Nevertheless, the accuracy of classifying men into groups whose cancer remained indolent versus those whose cancer progressed was poor at all examined cut points of PSA or PSA rate of change.
The role of adjuvant hormonal therapy in patients with locally advanced disease has been analyzed by the Agency for Health Care Policy and Research (now the Agency for Healthcare Research and Quality). Most patients have more advanced disease, but patients with bulky T2b to T2c tumors were included in the study groups that were re-evaluating the role of adjuvant hormonal therapy in patients with locally advanced disease. Randomized clinical trial evidence comparing radiation therapy to radiation therapy with prolonged androgen suppression has been published. The meta-analysis found a difference in 5-year OS in favor of radiation therapy plus continued androgen suppression (LHRH agonist or orchiectomy) compared to radiation therapy alone (HR = 0.631; 95% CI, 0.479–0.831).[Level of evidence: 1iiA]
Likewise, a meta-analysis of seven randomized controlled trials comparing early (adjuvant or neoadjuvant) to deferred hormonal treatment (LHRH agonists and/or antiandrogens) in patients with locally advanced prostate cancer, whether treated by prostatectomy, radiation therapy, or watchful waiting, showed improved overall mortality (RR = 0.86; 95% CI, 0.82–0.91).[Level of evidence: 1iiA]
Bicalutamide has not been shown to improve OS in patients with localized or locally advanced prostate cancer. The Early Prostate Cancer (EPC) program is a large, randomized, placebo-controlled, international trial that compared bicalutamide (150 mg orally per day) plus standard care (radical prostatectomy, radiation therapy, or watchful waiting, depending on local custom) with standard care alone for men with nonmetastatic localized or locally advanced prostate cancer (T1–2, N0, NX; T3–4, any N; or any T, N+). Less than 2% of the 8,113 men had known node disease. At a median follow-up of 7.4 years, there was no difference in OS between the bicalutamide and placebo groups (about 76% in both arms [HR = 0.99; 95% CI, 0.91–1.09; P = .89]).[Level of evidence: 1iA]
Patients with locally advanced nonmetastatic disease (T2–T4, N0–N1, M0) are at risk for developing bone metastases, and bisphosphonates are being studied as a strategy to decrease this risk. However, a placebo-controlled randomized trial (MRC-PR04) of a 5-year regimen of the first-generation bisphosphonate clodronate in high oral doses (2,080 mg per day) had no favorable impact on either time to symptomatic bone metastasis or survival.[Level of evidence: 1iA]
Standard treatment options:
- Careful observation without further immediate treatment in selected patients.[2,7,14]
- Radical prostatectomy, with or without pelvic lymphadenectomy (with or without the nerve-sparing technique designed to preserve potency).[15,16,17] If allowed by the extent of tumor, anatomical dissection that preserves nerves necessary for erection may avoid impotence postoperatively in some patients.[17,18] Radical prostatectomy may be difficult after a transurethral resection of the prostate (TURP). Consideration may be given to postoperative radiation therapy for patients who are found to have capsular penetration or seminal vesicle invasion by tumor at the time of prostatectomy or who have a detectable level of PSA more than 3 weeks after surgery.[19,20,21,22,23,24,25] Because about 40% to 50% of men with clinically organ-confined disease are found to have pathologic extension beyond the prostate capsule or surgical margins, the role of postprostatectomy adjuvant radiation therapy has been studied.
In a randomized trial of 425 men with pathologic T3, N0, M0 disease, postsurgical EBRT (60 Gy–64 Gy to the prosthetic fossa over 30–32 fractions) was compared to observation. The primary endpoint, metastasis-free survival, was an endpoint that could be affected by serial PSA monitoring and resulting metastatic work-up for PSA increase. This could have biased the primary endpoint in favor of radiation therapy, which was associated with a lower rate of PSA rise. Nevertheless, metastasis-free survival was not statistically different between the two study arms (P = .06). After a median follow-up of 10.6 years, the median survival was 14.7 years in the radiation therapy group versus 13.8 years in the observation group (P = .16).[Level of evidence: 1iiA] Although the survival rates were not statistically different, complication rates were substantially higher in the radiation therapy group: overall complications were 23.8% versus 11.9%, rectal complications were 3.3% versus 0%, and urethral stricture was 17.8% versus 9.5%, respectively. After a median follow-up of about 12.5 years, OS was better in the radiation therapy arm; hazard ratio of death equaled 0.72 (95% CI, 0.55–0.96; P = .023). The 10-year estimated survival rates were 74% and 66% in the radiation therapy and control arms, respectively. The 10-year estimated metastasis-free survivals were 73% and 65% (P = .016).[Level of evidence: 1iiA] Careful treatment planning is necessary to avoid morbidity.[19,20,21,22,23,24]
- External-beam radiation therapy (EBRT).[27,28,29,30,31] Prophylactic radiation therapy to clinically or pathologically uninvolved pelvic lymph nodes does not appear to improve OS or prostate cancer–specific survival as seen in the Radiation Therapy Oncology Group (RTOG-7706) trial, for example.[Level of evidence: 1iiA] Although the RTOG-9413 trial showed an increased progression-free survival at 4 years for patients with a 15% estimated risk of lymph node involvement who received whole-pelvic radiation therapy as compared with prostate-only radiation therapy, OS and PSA failure rates were not significantly different.[33,34][Level of evidence: 1iiDiii] Definitive radiation therapy should be delayed 4 to 6 weeks after TURP to reduce incidence of stricture. For patients with bulky T2b to T2c tumors, adjuvant hormonal therapy should be considered.
In a randomized trial, 875 men with locally advanced nonmetastatic prostate cancer (T1b–T2 moderately or poorly differentiated tumors; T3 tumors of any grade) were randomly assigned to receive 3 months of an LHRH-agonist plus long-term flutamide (250 mg orally 3 times per day) with or without EBRT. Nineteen percent of the men had tumor stage T2, and 78% of the men had T3. At 10 years, both overall mortality (29.6% vs. 39.4%; 95% CI for the difference, 0.8%–18.8%) and the prostate cancer–specific mortality (11.9% vs. 23.9%; 95% CI for the difference, 4.9%–19.1%) favored combined hormonal and radiation therapy.[Level of evidence: 1iiA]
While flutamide might not be considered a standard hormonal monotherapy in the setting of T2 or T3, nonetheless, it is interesting to see that radiation therapy provided a disease-free survival (DFS) or tumor-specific survival advantage even though this monotherapy was applied. This analysis rests on the assumption that flutamide does not shorten life expectancy and cancer-specific survival. Radiation therapy was not delivered by current standards of dose and technique.
- EBRT plus androgen-suppression therapy (RTOG-9202).[36,37,38,39] Three-dimensional–conformal radiation therapy (3D–CRT) (70 Gy) with versus without a total of 6 months of androgen-suppression therapy ([AST]: combined luteinizing hormone–release hormone [LHRH] plus flutamide) have been compared in a randomized trial of men with clinical stage I or stage II cancer who are at elevated risk for disease progression (i.e., PSA =10 mg/mL or Gleason score =7). In the trial, 206 patients were randomly assigned and followed for a median of 4.5 years. The estimated 5-year OS rate in the radiation-only arm was 78% (95% CI, 68%–88%) versus 88% (95% CI, 80%–95%) in the radiation-plus AST arm (P = .04).[Level of evidence: 1iiA]
A multi-institutional Canadian trial randomly assigned 378 men to 3 months versus 8 months of neoadjuvant androgen deprivation therapy prior to EBRT to a dose of 66 Gy. With 6 years' median follow-up, there was no difference in OS or DFS.
Bicalutamide has not been shown to improve OS in patients with localized or locally advanced prostate cancer. The EPC program is a large, randomized, placebo-controlled, international trial that compared bicalutamide (150 mg orally per day) plus standard care (radical prostatectomy, radiation therapy, or watchful waiting, depending on local custom) with standard care alone for men with nonmetastatic localized or locally advanced prostate cancer (T1–2, N0, NX; T3–4, any N; or any T, N+). Less than 2% of the 8,113 men had known node disease. At a median follow-up of 7.4 years, there was no difference in OS between the bicalutamide and placebo groups (about 76% in both arms [hazard ratio (HR) = 0.99; 95% CI, 0.91–1.09; P = .89]).[Level of evidence: 1iA]
- Interstitial implantation of radioisotopes (i.e., iodine I 125, palladium, and iridium) done through a transperineal technique with either ultrasound or computed tomography (CT) guidance is being done in carefully selected patients with T1 or T2a tumors. Short-term results in these patients are similar to those for radical prostatectomy or EBRT.[42,43,44][Level of evidence: 3iiiDiv] One advantage is that the implant is performed as outpatient surgery. The rate of maintenance of sexual potency with interstitial implants has been reported to be 86% to 92%,[42,44] which compares with rates of 10% to 40% with radical prostatectomy and 40% to 60% with EBRT; however, urinary tract frequency, urgency, and less commonly, urinary retention are seen in most patients but subside with time. Rectal ulceration may also be seen. In one series, a 10% 2-year actuarial genitourinary grade 2 complication rate and a 12% risk of rectal ulceration was seen. This risk decreased with increased operator experience and modification of implant technique. Long-term follow-up of these patients is necessary to assess treatment efficacy and side effects.
Retropubic freehand implantation with iodine I 125 has been associated with an increased local failure and complication rate [45,46] and is now rarely done.
- EBRT designed to decrease exposure of normal tissues using methods such as CT-based 3-D conformal treatment planning is under clinical evaluation.
Treatment options under clinical evaluation:
- Ultrasound-guided percutaneous cryosurgery.
Cryosurgery is a surgical technique that involves destruction of prostate cancer cells by intermittent freezing of the prostate tissue with cryoprobes and is followed by thawing.[Level of evidence: 3iiiC][49,50][Level of evidence: 3iiiDiv] Cryosurgery is less well established than standard prostatectomy, and long-term outcomes are not as well established as with prostatectomy or radiation therapy. Serious toxic effects include bladder outlet injury, urinary incontinence, sexual impotence, and rectal injury. (For more information on impotence, refer to the Sexuality and Reproductive Issues summary.) The frequency of other side effects and the probability of cancer control at 5 years' follow-up have varied among reporting centers, and series are small compared with surgery and radiation therapy.[49,50]
- High-intensity–focused ultrasound.[51,52,53]
- Proton-beam radiation therapy. Outcome data is awaited.
- Other clinical trials, including trials of neoadjuvant hormonal therapy followed by radical prostatectomy.[54,55]
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II prostate cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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