Stage I Prostate Cancer Treatment
Standard Treatment Options for Stage I Prostate Cancer
Watchful waiting or active surveillance
External-beam radiation therapy (EBRT)
Interstitial implantation of radioisotopes
Treatment Options Under Clinical Evaluation for Stage I Prostate Cancer
Current Clinical Trials
Stage I prostate cancer is defined by the American Joint Committee on Cancer's TNM classification system:
- T1a–c, N0, M0, prostate-specific antigen (PSA) <10 ng/ml, Gleason ≤6.
- T2a, N0, M0, PSA <10 ng/ml, Gleason ≤6.
- T1–2a, N0, M0, PSA X, Gleason X.
The frequency of clinically silent, nonmetastatic prostate cancer that can be found at autopsy greatly increases with age and may be as high as 50% to 60% in men aged 90 years and older. Undoubtedly, the incidental discovery of these occult cancers at prostatic surgery performed for other reasons accounts for the similar survival of men with stage I prostate cancer, compared with the normal male population, adjusted for age.
Many stage I cancers are well differentiated and only focally involve the gland (T1a, N0, M0); most require no treatment other than careful follow-up.
In younger patients (aged 50–60 years) whose expected survival is long, treatment should be considered. Radical prostatectomy, external-beam radiation therapy (EBRT), interstitial implantation of radioisotopes, and watchful waiting and active surveillance yield apparently similar survival rates in noncontrolled, selected series. The decision to treat should be made in the context of the patient’s age, associated medical illnesses, and personal desires.Standard Treatment Options for Stage I Prostate Cancer
Standard treatment options for stage I prostate cancer include the following:
- Watchful waiting or active surveillance.
- Radical prostatectomy.
- External-beam radiation therapy (EBRT).
- Interstitial implantation of radioisotopes.
Asymptomatic patients of advanced age or with concomitant illness may warrant consideration of careful observation without immediate active treatment.[4-6] 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 Watchful Waiting or Active Surveillance section in 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 grade 1 or grade 2 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.
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.[7-9] 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.[10-12] Because duration of follow-up in available studies is still 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, and 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, the overall median survival was 14.7 years in the radiation therapy group versus 13.8 years in the observation group (P = .16).
- Although the overall 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%.
- 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]
- Another randomized trial came to a different conclusion with respect to the effect of postoperative radiation therapy on OS.[Level of evidence: 1iiA]. In the European Organization for Research and Treatment of Cancer (EORTC) trial (EORTC-22911 [NCT00002511]), 1,005 men aged 75 years and younger with clinical T0 to T3 prostate cancer were randomly assigned after prostatectomy to receive postoperative radiation (60 Gy) or observation, with subsequent therapy delayed until the occurrence of either biochemical or clinical relapse. The recommended treatment for local recurrence was radiation.
- With a median follow-up of 10.6 years (up to 16.6 years), the biochemical progression-free survival rates were higher in the observation study arm (60.6% vs. 41.1%; HR, 0.49; 95% CI, 0.41–0.59; P < .0001). Locoregional relapse rates were 8.4% versus 17.3% in favor of immediate radiation (HR, 0.45; 95% CI, 0.32–0.68; P < .0001).
- However, the large differences in biochemical relapse-free survival and local recurrence did not translate into an advantage in either distant metastasis (11.0% vs. 11.3%; HR, 0.99; 95% CI, 0.67–1.44; P = .94) or in OS (76.9% with immediate radiation vs. 80.7% with observation; HR, 1.18; 95% CI, 0.91–1.53; P = .2). Nor was there a difference in prostate cancer-specific mortality (3.9% vs. 5.2%; HR, 0.78; 95% CI, 0.46–1.33; P = .34)
- The 10-year cumulative risk of severe (grade 3) late toxicity in the immediate radiation study group was 5.3% versus 2.5% in the observation group (P = .052). Late adverse effects of any grade were also higher in the immediate radiation group (70.8% vs. 59.7%; P = .001).
Radical prostatectomy has been compared with watchful waiting or active surveillance. (Refer to the Radical prostatectomy compared with other treatment options section in the Treatment Option Overview for Prostate Cancer section of this summary for more information about radical prostatectomy compared with watchful waiting or active surveillance.)
Evidence (radical prostatectomy compared with watchful waiting):
- 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.[14,15][Levels of evidence 1iiA, 1iiB]
- About 50% of the men had nonpalpable, screen-detected disease.
- 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 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 ng/ml, 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 used with curative intent.[16-20] 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.[22,23]
Evidence (EBRT with or without adjuvant hormonal therapy):
- 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.; [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 agonist plus long-term flutamide (250 mg by mouth three 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 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.
- 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.
Interstitial implantation of radioisotopes (i.e., iodine 125 [125I], palladium, and iridium) done through a transperineal technique with either ultrasound or computed-tomography guidance, is being used in patients with T1 or T2a tumors. Short-term results in these patients are similar to those for radical prostatectomy or EBRT.[27,28]; [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%.[27,29] 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 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 I Prostate Cancer
Treatment options under clinical evaluation include the following:Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I 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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