Stage II Prostate Cancer
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.