Stage III Prostate Cancer Treatment
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 extension with microscopic bladder neck invasion (T4) is included with T3a.
External-beam radiation therapy (EBRT), interstitial implantation of radioisotopes, and radical prostatectomy are used to treat stage III prostate cancer. Prognosis is greatly affected by whether regional lymph nodes are evaluated and proven not to be involved.
EBRT using a linear accelerator is the most common treatment for patients with stage III prostate cancer, and large series support its success in achieving local disease control and disease-free survival (DFS).[3,4] 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.
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.
Standard Treatment Options for Stage III Prostate Cancer
Standard treatment options for stage III prostate cancer include the following:
External-beam radiation therapy (EBRT) with or without hormonal therapy
EBRT alone [3-7] or hormonal therapy luteinizing hormone-releasing hormone (LH-RH) agonist or orchiectomy) in addition to EBRT should be considered.[8-16] Definitive radiation therapy should be delayed until 4 to 6 weeks after transurethral resection to reduce the incidence of stricture.
Hormonal therapy should be considered in conjunction with radiation therapy especially in men who do not have underlying moderate or severe comorbidities.[8,9] Several studies have investigated its utility in patients with locally advanced disease.
Evidence (EBRT with or without hormonal therapy):
- Although patients in the RTOG-9413 (NCT00769548) trial showed a 15% estimated risk of lymph node involvement and received whole-pelvic radiation therapy compared with prostate-only radiation therapy, overall survival (OS) and PSA failure rates were not significantly different.; [Level of evidence: 1iiDiii]
- 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 LH-RH agonist plus long-term flutamide (250 mg orally 3 times a day) with or without EBRT. Nineteen percent of the men had tumor stage T2, and 78% of the men had stage T3.[Level of evidence; 1iiA]
- At 10 years, both overall mortality (29.6% vs. 39.4%; 95% confidence intervaI [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.
- 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 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.
- 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 (hazard ratio [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.
- 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.[Level of evidence: 1iiA]
- The actuarial 10-year OS 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).
- 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.[10,23][Levels of evidence: 1iiA, 1iiDii]
- The Kaplan-Meier estimates of OS at 10 years were 58.1% in the adjuvant goserelin arm and 39.8% in 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.[10,23]
- Two smaller studies, with 78 and 91 patients each, have shown similar results.[24,25]
- 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). Randomized clinical trial evidence comparing radiation therapy to radiation therapy with prolonged androgen suppression (with an LH-RH agonist or orchiectomy) was evaluated in a meta-analysis. Most patients had more advanced disease, but patients with bulky T2b tumors were included in the study.[Level of evidence: 1iiA]
- 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% CI, 0.479–0.831).
- 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 randomly assigned to receive either radiation therapy alone or radiation therapy with androgen ablation, which was started 8 weeks before radiation therapy and continued for 16 weeks. This trial assessed only short-term hormonal therapy, not long-term therapy, as the studies analyzed by the AHCPR did.[12,26]
- A subset analysis of the RTOG-8610 trial and the RTOG-8531 trial that involved 575 patients with T3, N0, M0 disease indicated 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 (NCT00767286), 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 found 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 hormonal treatment (adjuvant or neoadjuvant) to deferred hormonal treatment (LH-RH agonists and/or antiandrogens) in patients with locally advanced prostate cancer, whether treated by prostatectomy, radiation therapy, or watchful waiting or active surveillance, showed improved overall mortality for patients receiving early treatment (relative risk, 0.86; 95% CI, 0.82–0.91).[Level of evidence: 1iiA]
- 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).
Hormonal manipulations (orchiectomy or luteinizing hormone-releasing hormone [LH-RH] agonist)
Antiandrogen monotherapy has also been evaluated in men with locally advanced prostate cancer as an alternative to castration.
Evidence (orchiectomy vs. LH-RH agonist):
- 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, whereas 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]
Immediate versus deferred hormonal therapy
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 or active surveillance with hormonal therapy at progression).
Evidence (immediate vs. deferred hormonal therapy):
- A randomized trial looked at immediate hormonal treatment (orchiectomy or LH-RH agonist) versus deferred treatment in men with locally advanced or asymptomatic metastatic prostate cancer.[Level of evidence: 1iiA]
- Initial results 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.
- 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).[Level of evidence: 1iiA]
- No statistically significant difference in OS was seen over a 12-year period of follow-up.
- 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 as compared with immediate treatment in relation to OS.[Level of evidence: 1iiA]
- At a median follow-up of 7.8 years, approximately 50% of the patients in the deferred treatment group had initiated androgen deprivation.
- The median OS in the immediate treatment group was 7.4 years, and, in the deferred treatment group, it 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.
Intermittent versus continuous androgen suppression
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, this 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.
Evidence (intermittent vs. continuous androgen suppression):
- 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 on 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 LH-RH agonist were randomly assigned to either continue the regimen or cease treatment until there was evidence of progression.[Level of evidence: 1iiA]
- 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 = .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 flashes and gynecomastia.
- Replication of these findings is important, and there are ongoing trials such as SWOG-9346 to address this further.
Radical prostatectomy with or without EBRT
Radical prostatectomy may be used with or without EBRT (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.
Evidence (radical prostatectomy with or without EBRT):
- 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.[38,39]
- After a median follow-up of about 12.5 years, OS was better in the radiation therapy arm; HRdeath of 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%.
- The role of preoperative (neoadjuvant) hormonal therapy is not established.[40,41] Also, the morphologic changes induced by neoadjuvant androgen ablation may even complicate assessment of surgical margins and capsular involvement.
Watchful waiting or active surveillance
Asymptomatic patients of advanced age or with concomitant illness may warrant consideration of careful observation without immediate active treatment.[45-47] 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.)
Treatment of Symptoms
Since many stage III patients have urinary symptoms, control of symptoms is an important consideration in treatment. The following modalities may be used to improve local control of disease and subsequent symptoms:
- Radiation therapy.
- Hormonal manipulation.
- Palliative surgery (transurethral resection of the prostate [TURP]).
- Interstitial implantation combined with EBRT.
- Alternative forms of radiation therapy (under clinical evaluation).
- Ultrasound-guided percutaneous cryosurgery (under clinical evaluation).
- Radiation therapy.[3-6] EBRT designed to decrease exposure of normal tissues using methods such as CT-based 3D-CRT treatment planning is under clinical evaluation.
- Hormonal manipulations effectively used as initial therapy for prostate cancer include the following:
- Leuprolide or other LH-RH agonists (e.g., goserelin) in daily or depot preparations. These agents may be associated with tumor flare.
- Estrogens (diethylstilbestrol [DES] is no longer available in the United States).
- Nonsteroidal antiandrogens (e.g., flutamide, nilutamide, and bicalutamide) or steroidal antiandrogen (e.g., 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 LH-RH 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 with orchiectomy (HR, 1.22; 95% CI, 0.99–1.50).
- Treatment withdrawals, used as a surrogate for adverse effects, occurred less with LH-RH agonists (0%–4%) than with nonsteroidal antiandrogens (4%–10%).
- Palliative surgery (TURP).
- Interstitial implantation combined with EBRT is being used in selected T3 patients, but little information is available.
- Alternative forms of radiation therapy are being employed in clinical trials. 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, although 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.
- 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 with cryoprobes, followed by thawing.[Level of evidence: 3iiiC]; ; [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.[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 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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