Prostate Cancer Treatment (Professional) (cont.)
Stage III 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 III prostate cancer is defined by the American Joint Committee on Cancer's TNM classification system:
- T3a–b, N0, M0, any prostate-specific antigen (PSA), any Gleason.
Extraprostatic invasion with microscopic bladder neck invasion (T4) is included with T3a.
External-beam radiation therapy (EBRT), interstitial implantation of radioisotopes, and radical prostatectomy are used. The results of radical prostatectomy in stage III patients are greatly inferior compared with results in patients with stage II cancer. Interstitial implantation of radioisotopes is technically difficult in large tumors. EBRT using a linear accelerator is the most appropriate treatment for most patients with stage III prostate cancer, and large series support its success in achieving local disease control and disease-free survival (DFS).[3,4] Prognosis is greatly affected by whether regional lymph nodes are evaluated and proven not to be involved. The patient's symptoms related to cancer, age, and coexisting medical illnesses should be taken into account before deciding on a therapeutic plan. In a series of 372 patients treated with radiation therapy and followed for 20 years, 47% eventually died of prostate cancer, but 44% died of intercurrent illnesses without evidence of prostate cancer.
Hormonal therapy should be considered in conjunction with radiation therapy, especially in men who do not have underlying moderate or severe comorbidities.[5,6] Several studies have investigated its utility in patients with locally advanced disease. The Radiation Therapy Oncology Group (RTOG) performed a prospective, randomized trial (RTOG-8531) in patients with T3, N0, or any T, N1, M0 disease who received prostatic and pelvic radiation therapy and then were randomly assigned to receive immediate adjuvant goserelin or observation with administration of goserelin at time of relapse. In patients assigned to receive adjuvant goserelin, the drug was started during the last week of the radiation therapy course and was continued indefinitely or until signs of progression. The actuarial overall 10-year survival rate for the entire population of 945 analyzable patients was 49% on the adjuvant arm versus 39% on the observation arm P = .002. There was also an improved actuarial 10-year local failure rate (23% vs. 38%, P < .001).[Level of evidence: 1iiA]
A similar trial was performed by the European Organization for Research and Treatment of Cancer (EORTC). Patients with T1, T2 (World Health Organization grade 3), N0–NX or T3, T4, N0 disease were randomly assigned to receive either pelvic/prostate radiation therapy, or identical radiation therapy and adjuvant goserelin (with cyproterone acetate for 1 month) starting with radiation therapy and continuing for 3 years. The 401 patients available for analysis were followed for a median of 9.1 years. The Kaplan-Meier estimates of overall survival (OS) at 10 years were 58.1% on the adjuvant arm and 39.8% on the radiation alone arm (P = .0004). Similarly, 10-year DFS (47.7% vs. 22.7%, P < .0001) and local control (94.0% vs. 76.5%, P < .001) favored the adjuvant arm.[8,9][Levels of evidence: 1iiA,1iiDii] Two smaller studies, with 78 and 91 patients each, have also shown similar results.[10,11]
The role of adjuvant hormonal therapy in patients with locally advanced disease has been analyzed by the Agency for Health Care Policy and Research (AHCPR) (now the Agency for Healthcare Research and Quality). Most patients had more advanced disease, but patients with bulky T2b tumors were included in the study. Randomized clinical trial evidence comparing radiation therapy to radiation therapy with prolonged androgen suppression (with a luteinizing hormone-releasing hormone [LHRH] agonist or orchiectomy) was evaluated. The meta-analysis found a difference in 5-year OS in favor of radiation therapy plus continued androgen suppression compared with radiation therapy alone (hazard ratio [HR] = 0.631; 95% confidence interval [CI], 0.479–0.831).[Level of evidence: 1iiA]
Additionally, the RTOG did a study (RTOG-8610) in patients with bulky local disease (T2b, T2c, T3, or T4), with or without nodal involvement below the common iliac chain: 456 men were evaluable and were randomly assigned to receive either radiation therapy alone or radiation therapy with androgen ablation started 8 weeks before radiation therapy and continued for 16 weeks. At 10 years, OS was not statistically significantly different; however, disease-specific mortality (23% vs. 36%) and DFS (11% vs. 3%) favored the combined arm.[Level of evidence: 1iiA] This trial assessed only short-term hormonal therapy, not long-term therapy, as the studies analyzed by the AHCPR did. A subset analysis of this trial and the RTOG-8531 trial with 575 patients with T3, N0, M0 disease concluded that long-term hormones compared with short-term hormones resulted in improved biochemical DFS and cause-specific survival. This finding was confirmed by RTOG-9202, which reported that radiation therapy plus 28 months of androgen deprivation resulted in longer 10-year disease-specific survival (23% vs. 13%; P < .0001) but not OS (53.9% vs. 51.6%; P = 0.36). An unplanned post hoc–subgroup analysis reported increased OS with longer androgen deprivation (28 months vs. 4 months) (45% vs. 32%; P = .0061) in men with high-grade cancers and Gleason scores of 8 through 10.
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]
In patients who are not candidates for or who are unwilling to undergo radical prostatectomy or radiation therapy, immediate hormonal therapy has been compared with deferred treatment (i.e., watchful waiting with hormonal therapy at progression). Initial results from a randomized study of immediate hormonal treatment (orchiectomy or LHRH analog) versus deferred treatment in men with locally advanced or asymptomatic metastatic prostate cancer showed better OS and prostate cancer–specific survival with the immediate treatment. This subsequently lost statistical significance as was recorded in abstract form. The incidence of pathologic fractures, spinal cord compression, and ureteric obstruction were also lower in the immediate treatment arm.[Level of evidence: 1iiA] In another trial, 197 men with stage III or stage IV prostate cancer were randomly assigned to receive bilateral orchiectomy at diagnosis or at the time of symptomatic progression (or at the time of new metastases that were deemed likely to cause symptoms). No statistically significant difference in OS was seen over a 12-year period of follow-up.[Level of evidence: 1iiA]
In the EORTC-30891 trial, 985 patients newly diagnosed with prostate cancer, stage T0–4, N0–2 M0, and a median age of 73 years were randomly assigned to receive androgen deprivation, either immediately or on symptomatic disease progression. The study was designed to demonstrate the noninferiority of deferred treatment compared with immediate treatment in relation to OS. At a median follow-up of 7.8 years, approximately 50% of the patients in the deferred treatment group had been started on androgen deprivation. The median OS in the immediate treatment group was 7.4 years and in the deferred treatment group was 6.5 years, corresponding to a mortality HR of 1.25 (95% CI, 1.05–1.48), which failed to meet the criteria for noninferiority.[Level of evidence: 1iiA]
Antiandrogen monotherapy has also been evaluated in men with locally advanced prostate cancer as an alternative to castration. In a randomized equivalence study involving 480 men with locally advanced (T3 and T4) disease, those who were treated with castration had a median OS of 70 months, while those treated with bicalutamide (150 mg/day) had a median OS of 63.5 months (HR = 1.05; 95% CI, 0.81–1.36); these results failed to meet the prespecified criteria for equivalence.[Level of evidence: 1iiA]
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:
- EBRT.[3,4,25,26,27] Hormonal therapy (LHRH agonist or orchiectomy) should be considered in addition to EBRT.[5,5,6,9,12,14,16,28,29] 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.[30,31][Level of evidence: 1iiDiii] Definitive radiation therapy should be delayed until 4 to 6 weeks after transurethral resection to reduce incidence of stricture. Radiation therapy designed to decrease exposure of normal tissues using methods such as computed tomography (CT)-based 3-D conformal treatment planning is under clinical evaluation.
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 three times per day) with or without EBRT. Nineteen percent of the men had tumor stage T2 and 78% had T3. At 10 years, both overall mortality (29.6% vs. 39.4%; 95% CI for the difference, 0.8%–8.8%) 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 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.
- Hormonal manipulations (orchiectomy or LHRH agonist).[Level of evidence: 1iiA]
- Radical prostatectomy, with or without pelvic lymphadenectomy (in highly selected patients). 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.[36,37] 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] Short-term 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. The role of preoperative (neoadjuvant) hormonal therapy is not established.[38,39] Also, the morphologic changes induced by neoadjuvant androgen ablation may even complicate assessment of surgical margins and capsular involvement.
- Careful observation without further immediate treatment.[41,42]
Since many stage III patients have urinary symptoms, control of symptoms is an important consideration in treatment. This may often be accomplished by radiation therapy, radical surgery, transurethral resection of the prostate, or hormonal manipulation.
- Radiation therapy.[3,4,25,26] EBRT designed to decrease exposure of normal tissues using methods such as CT-based 3-D conformal treatment planning is under clinical evaluation.
- Hormonal manipulations effectively used as initial therapy for prostate cancer:
- Leuprolide or other LHRH agonists (goserelin) in daily or depot preparations. (These agents may be associated with tumor flare.)
- Estrogen (diethylstilbestrol [DES] is no longer available in the United States).
- Nonsteroidal antiandrogen (e.g., flutamide, nilutamide, and bicalutamide) or steroidal antiandrogen (cyproterone acetate).
A meta-analysis of randomized trials comparing various hormonal monotherapies in men with stage III or stage IV prostate cancer (predominantly stage IV) came to the following conclusions:[Level of evidence: 1iiA]
- OS at 2 years using any of the LHRH agonists is similar to treatment with orchiectomy or 3 mg per day of DES (HR = 1.26; 95% CI, 0.92–1.39).
- Survival rates at 2 years are similar or worse with nonsteroidal antiandrogens compared to orchiectomy (HR = 1.22; 95% CI, 0.99–1.50).
- Treatment withdrawals, used as a surrogate for adverse effects, occurred less with LHRH agonists (0%–4%) than with nonsteroidal antiandrogens (4%–10%).
When used as the primary therapy for patients with stage III or stage IV prostate cancer, androgen suppression with hormonal therapy is usually given continuously until there is disease progression. Some investigators have proposed intermittent androgen suppression as a strategy to attain maximal tumor cytoreduction followed by a period without therapy to allow tumor repopulation by hormone-sensitive cells. Theoretically, the strategy might provide tumor hormone responsiveness for a longer period of time. An animal model suggested that intermittent androgen deprivation (IAD) could prolong the duration of androgen dependence of hormone-sensitive tumors. A systematic review of all five randomized trials addressing this issue found no reliable data on the relative effectiveness of intermittent versus continuous androgen suppression for OS, prostate cancer–specific survival, disease progression, or quality of life.[Level of evidence: 1iiA] All five trials were small and had short follow-up. Intermittent therapy remains under evaluation. In a subsequent randomized trial, 626 men with clinically advanced prostate cancer (T3–T4, M0–M1, PSA =4) that responded to an initial 3-month induction course of cyproterone acetate plus an LHRH analogue were randomly assigned to either continue the regimen or cease treatment until there was evidence of progression. After 100 months of follow-up (median 51 months), there was no difference in OS (HR = 0.99; 95% CI, 0.80–1.23; P = 0.84) for continuous androgen deprivation versus IAD. Quality of life between the two treatment strategies was similar, but IAD was associated with lower rates of hot flushes and gynecomastia. Replication of these findings would be important, and there are ongoing trials such as SWOG-9346 to address this further.[Level of evidence: 1iiA]
- Palliative surgery (transurethral resection).
- Interstitial implantation combined with EBRT is being used in selected T3 patients, but little information is available.
- Clinical trials employing alternative forms of radiation therapy. A randomized trial from the RTOG reported improved local control and survival with mixed-beam (neutron/photon) radiation therapy compared with standard photon radiation therapy. A subsequent randomized study from the same group compared fast-neutron radiation therapy with standard photon radiation therapy. Local-regional control was improved with neutron treatment, but no difference in OS was seen, though follow-up was shorter in this trial. Fewer complications were seen with the use of a multileaf collimator. Proton-beam radiation therapy is also under investigation.
- Other clinical trials.
- Ultrasound-guided percutaneous cryosurgery is under clinical evaluation. Cryosurgery is a surgical technique under development that involves destruction of prostate cancer cells by intermittent freezing of the prostate tissue with cryoprobes, followed by thawing.[Level of evidence: 3iiiC];[52,53][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. The technique of cryosurgery is under development. Impotence is common. 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.[52,53]
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III 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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