Stage II Prostate Cancer Treatment
Prostate-specific antigen (PSA) changes as markers of tumor progression
Bisphosphonates and risk of bone metastases
Standard Treatment Options for Stage II Prostate Cancer
Watchful waiting or active surveillance
External-beam radiation therapy (EBRT) with or without hormonal therapy
Interstitial implantation of radioisotopes
Treatment Options Under Clinical Evaluation for Stage II Prostate Cancer
Ultrasound-guided percutaneous cryosurgery
Proton-beam radiation therapy
Other clinical trials
Current Clinical Trials
Stage II prostate cancer is defined by the American Joint Committee on Cancer's TNM classification system:Stage IIA
- T1a–c, N0, M0, prostate-specific antigen (PSA) <20 ng/ml, Gleason 7.
- T1a–c, N0, M0, PSA ≥10 <20 ng/ml, Gleason ≤6.
- T2a, N0, M0, PSA ≥10 <20 ng/ml, Gleason ≤6.
- T2a, N0, M0, PSA <20 ng/ml, Gleason 7.
- T2b, N0, M0, PSA <20 ng/ml, Gleason ≤7.
- T2b, N0, M0, PSA X, Gleason X.
- T2c, N0, M0, any PSA, any Gleason.
- T1–2, N0, M0, PSA ≥20 ng/ml, 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 associated with a 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, and M0) fare better than patients in whom the disease involves both sides of the gland (T2c, N0, and 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. (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information on impotence.)Prostate-specific antigen (PSA) changes as markers of tumor progression
Often, changes in PSA 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 of very limited utility in making therapeutic decisions.
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 or active surveillance in the control arm of a randomized trial comparing radical prostatectomy to watchful waiting.[3,4] 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.Bisphosphonates and risk of bone metastases
Patients with locally advanced nonmetastatic disease (T2–T4, N0–N1, and M0) are at risk for developing bone metastases. Bisphosphonates are being studied as a strategy to decrease this risk.
Evidence (bisphosphonates and risk of bone metastases):
- 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 for stage II prostate cancer include the following:
- Watchful waiting or active surveillance.
- Radical prostatectomy.
- External-beam radiation therapy (EBRT) with or without hormonal therapy.
- Interstitial implantation of radioisotopes.
Asymptomatic patients of advanced age or with concomitant illness may warrant consideration of careful observation without immediate active treatment.[6-8] Watch and wait, observation, expectant management, and active surveillance are terms indicating a strategy that does not employ immediate therapy with curative intent. (Refer to the Treatment Option Overview for Prostate Cancer section of this summary for more information).
Evidence (observation with delayed hormonal therapy):
- In a retrospective pooled analysis, 828 men with clinically localized prostate cancer were managed by initial conservative therapy with subsequent hormonal therapy given at the time of symptomatic disease progression.
- This study showed that the patients with well-differentiated tumors 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, usually with pelvic lymphadenectomy (with or without the nerve-sparing technique designed to preserve potency) is the most commonly applied therapy with curative intent.[2,9,10] Radical prostatectomy may be difficult after a transurethral resection of the prostate (TURP).
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.
Consideration may also be given to postoperative radiation therapy (PORT) for patients who are found to have seminal vesicle invasion by tumor at the time of prostatectomy or who have a detectable level of PSA more than 3 weeks after surgery.[11-13] Because the duration of follow-up in available studies is relatively short, the value of PORT is yet to be determined; however, PORT does reduce local recurrence. Careful treatment planning is necessary to avoid morbidity.
Evidence (radical prostatectomy followed by radiation therapy):
- In a randomized trial of 425 men with pathologic T3, N0, M0 disease, postsurgical EBRT (60–64 Gy to the prostatic fossa over 30–32 fractions) was compared with observation.[Level of evidence: 1iiA]
- The primary endpoint, metastasis-free survival, 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 about 10.6 years, overall median survival was 14.7 years in the radiation therapy group versus 13.8 years in the observation group (P = .16).
- Although the OS rates were not statistically different, complication rates were substantially higher in the radiation therapy group compared with the observation 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, however, OS was better in the radiation therapy arm; hazard ratio (HR)death of 0.72 (95% confidence interval [CI], 0.55–0.96; P = .023). The 10-year estimated survival rates were 74% in the radiation therapy arm and 66% in the control arm. The 10-year estimated metastasis-free survivals were 73% and 65% (P = .016).[Level of evidence: 1iiA]
Evidence (radical prostatectomy compared with watchful waiting):
- In a randomized clinical trial performed in Sweden in the pre-PSA screening era, 695 men with prostate cancer were randomly assigned to radical prostatectomy versus watchful waiting. Only about 5% of the men in the trial had been diagnosed by PSA screening. Therefore, the men had more extensive local disease than is typically the case in men diagnosed with prostate cancer in the United States.[14-16]
- The cumulative overall mortality at 18 years was 56.1% in the radical prostatectomy arm and 68.9% in the watchful waiting study arm (absolute difference, 12.7%; 95% CI, 5.1–20.3 percentage points; relative risk [RR]death of 0.71; 95% CI, 0.59–0.86.[Level of evidence: 1iiA]
- The cumulative incidence of prostate cancer deaths at 18 years was 17.7% versus 28.7% (absolute difference, 11.0%; 95% CI, 4.5–17.5 percentage points; RRdeath from prostate cancer, 0.56; 95% CI, 0.41–0.77).
- In a post-hoc–subset analysis, the improvement in overall and prostate cancer-specific mortality associated with radical prostatectomy was restricted to men younger than 65 years.
- The Prostate Intervention Versus Observation Trial (PIVOT-1 or VA-CSP-407 [NCT00002606]) is the only published randomized trial conducted in the PSA screening era that directly compared radical prostatectomy with watchful waiting. From November 1994 through January 2002, 731 men aged 75 years or younger with localized prostate cancer (stage T1–2, NX, M0, with a blood PSA <50 ng/ml) and a life expectancy of at least 10 years were randomly assigned to radical prostatectomy versus watchful waiting.[17,18][Levels of evidence: 1iiA, 1iiB]
- About 50% of the men had palpable tumors.
- After a median follow-up of 10 years (range up to about 15 years), the all-cause mortality was 47.0% versus 49.9% in the radical-prostatectomy and watchful-waiting study arms, respectively, a difference that was not statistically significant (HR, 0.88; 95% CI, 0.71–1.08; P = .22). Prostate cancer-specific mortality was 5.8% versus 8.4%, and it also was not statistically significant (HR, 0.63; 95% CI, 0.36–1.09; P = .09).
- Subgroup analyses showed a statistically significant reduction in overall mortality in the group of men with a baseline PSA greater than 10 ng/ml (61 of 126 men vs. 77 of 125 men; HR, 0.67) but no difference in men with a PSA of 10 ng/ml or less (110 of 238 men vs. 101 of 241 men; HR, 1.03; P for interaction = .04). Because the test for interaction was not adjusted for the numerous subgroup comparisons, it should be interpreted with caution.
- Although there was a trend favoring prostatectomy, for prostate cancer-specific mortality, in men with a PSA greater than 10, the numbers were very small (7 of 126 men vs. 16 of 125 men for a PSA >10 ng/ml; 14 of 238 men vs. 15 of 241 men with lower PSA levels), and the interaction with the PSA level was not statistically significant (P = .11). There were no statistically significant differences in efficacy associated with prostatectomy by age (< 65 years vs. ≥ 65 years), Gleason score, Charlson comorbidity status, race, or performance score.
EBRT is another treatment option often used with curative intent.[19-23] Definitive radiation therapy should be delayed 4 to 6 weeks after TURP to reduce the incidence of stricture. Adjuvant hormonal therapy should be considered for patients with bulky T2b to T2c tumors.
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 had more advanced disease, but patients with bulky T2b to T2c tumors were included in the studies that were re-evaluating the role of adjuvant hormonal therapy in patients with locally advanced disease.
Evidence (EBRT with or without adjuvant hormonal therapy):
- The Radiation Therapy Oncology Group's (RTOG) trial 7706 (RTOG-7706).[Level of evidence: 1iiA]
- Prophylactic radiation therapy to clinically or pathologically uninvolved pelvic lymph nodes does not appear to improve OS or prostate cancer-specific survival.
- RTOG-9413 (RTOG-9413 [NCT00769548]) trial.[27,28][Level of evidence: 1iiDiii]
- Although RTOG-9413 showed increased progression-free survival at 4 years for patients who had a 15% estimated risk of lymph node involvement and received whole-pelvic radiation therapy compared with prostate-only radiation therapy, OS and PSA failure rates were not significantly different.
- 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 a luteinizing hormone-releasing hormone (LH-RH) agonist plus long-term flutamide (250 mg orally 3 times a day) with or without EBRT.[Level of evidence 1iiA]
- Nineteen percent of the men had tumor stage T2, and 78% of the men had tumor stage T3. At 10 years, both overall mortality (29.6% vs. 39.4%; 95% CI for the difference, 0.8%–18.8%) and prostate cancer-specific mortality (11.9% vs. 23.9%; 95% CI for the difference, 4.9%–19.1%) favored combined hormonal and radiation therapy.
- Although flutamide might not be considered a standard hormonal monotherapy in the setting of T2 or T3 tumors, it is interesting to see that radiation therapy provided a disease-free survival 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.
- Another trial compared androgen deprivation therapy (ADT: an LH-RH agonist or orchiectomy) to ADT plus radiation therapy (65–69 Gy to the prostate by 4-field box technique, including 45 Gy to the whole pelvis, seminal vesicles, and external/internal iliac nodes unless the lymph nodes were known to be histologically negative). This trial, NCIC CGT PR.3/MRC UKPRO7 [NCT00002633], from the National Cancer Institute of Canada randomly assigned 1,205 patients with high-risk (PSA >40 ng/ml or PSA >20 ng/ml and Gleason score ≥8), T2 (12%–13% of the patients), T3 (83% of the patients), and T4 (4%–5% of the patients) with clinical or pathologically staged N0, M0 disease.[Level of evidence; 1iiA]
- At a median follow-up of 6 years (maximum = 13 years), OS was superior in the ADT plus radiation therapy group (HR death of 0.77; 95% CI, 0.61–0.98, P = .03). OS at 7 years was 74% for the ADT plus radiation therapy group versus 66% for the ADT alone group.
- Although radiation therapy had the expected bowel and urinary side effects, quality of life was the same in each study group by 24 months and beyond.
- A meta-analysis of randomized clinical trial evidence comparing radiation therapy with radiation therapy plus 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 (LH-RH agonist or orchiectomy) as compared with radiation therapy alone (HR, 0.631; 95% CI, 0.479–0.831).[Level of evidence: 1iiA]
- A meta-analysis of seven randomized controlled trials comparing early hormonal treatment (adjuvant or neoadjuvant) to deferred hormonal treatment (LH-RH agonists and/or antiandrogens) in patients with locally advanced prostate cancer, whether treated with prostatectomy, radiation therapy, or watchful waiting or active surveillance, showed improved overall mortality for patients receiving early treatment (RR, 0.86; 95% CI, 0.82–0.91).[Level of evidence: 1iiA]
- Short-term neoadjuvant-androgen therapy administered before and during radiation therapy has shown benefit in at least some patients with clinically localized prostate cancer. In an open-label, randomized trial (RTOG-9408 [NCT00002597]), 1,979 men with nonmetastatic stage T1b–c, T2a, or T2b tumors and a PSA level of 20 ng/ml or less were randomly assigned to receive radiation therapy (66.6 Gy prostate dose in 1.8 Gy daily fractions) with or without 4 months of ADT (flutamide 250 mg by mouth 3 times per day plus either monthly goserelin 3.6 mg subcutaneously or leuprolide 7.5 mg intramuscularly), beginning 2 months prior to radiation therapy. Median follow-up was about 9 years.[Level of evidence: 1iiA]
- The 10-year OS rate was 57% in the radiation only group versus 62% in the combined therapy group (HRdeath of 1.17; 95% CI, 1.01–1.35; P = .03).
- In a post-hoc analysis, there was no statistically significant interaction between the treatment effect and baseline-risk category of the patients. However, there appeared to be little, if any, benefit associated with combined therapy in the lowest-risk category of patients (Gleason score ≤6; PSA ≤10 ng/ml; and clinical stage ≤T2a).
- The OS benefit was most apparent in men with intermediate-risk tumors (Gleason score 7; or Gleason score ≤6 and PSA >10 ng/ml; or clinical stage T2b).
- The duration of neoadjuvant hormonal therapy has been tested in a randomized trial (TROG 96.01 [ACTRN12607000237482]) involving 818 men with locally advanced (T2b, T2c, T3, and T4) nonmetastatic cancer treated with radiation therapy (i.e., 66 Gy in 2 Gy daily fractions to the prostate and seminal vesicles but not including regional lymph nodes). In an open-label design, patients were randomly assigned to radiation therapy alone, 3 months of neoadjuvant androgen deprivation therapy (NADT) (goserelin 3.6 mg subcutaneously each month plus flutamide 250 mg by mouth 3 times per day) for 2 months prior to and during radiation, or 6 months of NADT for 5 months prior to and during radiation.[Level of evidence: 1iiA]
- After a median follow-up of 10.6 years, there were no statistically significant differences between the radiation alone group and the radiation plus 3 months of NADT group.
- However, the 6-month NADT arm showed better prostate cancer-specific mortality and overall mortality than radiation alone; 10-year all-cause mortality 29.2% versus 42.5% (HR, 0.63; 95% CI, 0.48–0.83, P = .0008).
- Addition of androgen suppression therapy to EBRT may benefit men who are at an elevated risk of disease recurrence and death from prostate cancer (RTOG-9202 [NCT00767286]).
EBRT designed to decrease exposure of normal tissues using methods such as CT-based 3-D conformal treatment planning is under clinical evaluation.Interstitial implantation of radioisotopes
Interstitial implantation of radioisotopes (i.e., iodine-125 [125I], palladium, and iridium), using a transperineal technique with either ultrasound or computed-tomography (CT) guidance, is being done in patients with T1 or T2a tumors. Short-term results in these patients are similar to those for radical prostatectomy or EBRT.[35,36]; [Level of evidence: 3iiiDiv]
Factors for consideration in the use of interstitial implants include the following:
- 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%.[35,37] In contrast, rates of maintenance of sexual potency with radical prostatectomy were 10% to 40% and 40% to 60% with EBRT.
- Typical side effects from interstitial implants that are seen in most patients but subside with time include urinary tract frequency, urgency, and less commonly, urinary retention.
- 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 were seen. This risk decreased with increased operator experience and modification of the implant technique.
Long-term follow-up of these patients is necessary to assess treatment efficacy and side effects.Treatment Options Under Clinical Evaluation for Stage II Prostate Cancer
Treatment options under clinical evaluation include the following:
- Ultrasound-guided percutaneous cryosurgery.
- High-intensity–focused ultrasound.
- Proton-beam radiation therapy.
- Other clinical trials.
Cryosurgery is a surgical technique that involves destruction of prostate cancer cells by intermittent freezing of the prostate with cryoprobes followed by thawing.[Level of evidence: 3iiiC]; [41,42][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.
- Rectal injury.
(Refer to the PDQ summary on Sexuality and Reproductive Issues for more information on impotence.)
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.[41,42]High-intensity–focused ultrasound
High-intensity–focused ultrasound has been reported in case series to produce good local disease control. However, it has not been directly compared with more standard therapies, and experience with it is more limited.[43-45]Proton-beam radiation therapy
There is growing interest in the use of proton-beam radiation therapy for the treatment of prostate cancer. Although the dose distribution of this form of charged-particle radiation has the potential to improve the therapeutic ratio of prostate radiation, allowing for an increase in dose to the tumor without a substantial increase in side effects, no randomized controlled trials have been that compare its efficacy and toxicity with those of other forms of radiation therapy.Other clinical trials
Other clinical trials, including trials of neoadjuvant hormonal therapy followed by radical prostatectomy, are ongoing.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.References
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