Neoadjuvant HT Before RP

Since the first reports of efficacy by Huggins and colleagues in 1941, androgen deprivation therapy (ADT) has gained widespread use in patients with metastatic prostate cancer. However, the question of which populations of patients with prostate cancer may benefit from neoadjuvant ADT continues to be poorly defined. Considering biochemical recurrence rates as a primary end point, patients with low-risk tumors (Gleason score ≤6, PSA level ≤10, stage <T2b) seem least likely to benefit from neoadjuvant ADT.

In intermediate- and high-risk patients, several randomized trials have attempted to quantify potential benefits. Most of these studies used a 3-month neoadjuvant treatment period before definitive therapy, and most of them used complete androgen blockade (CAB). A decrease in the postoperative positive surgical margins is consistently seen. However, a benefit in overall survival (OS) has not been observed in any trial. The largest study was conducted by the European Study Group on Neoadjuvant Treatment of Prostate Cancer. A total of 402 patients were randomized between CAB for 3 months followed by RP or RP alone. A significant difference in pathologic downstaging (15% vs 7%), percentage with positive margins (27% vs 46%), and local relapse rates for cT2 patients (3% vs 11%) were observed, favoring the neoadjuvant group. However, no significant difference was observed in biochemical recurrence or OS.

At least 2 studies have reported on the use of longer-term neoadjuvant therapy (>3 months). In the PROSIT (Protein S Italian Team) study, patients were randomized between neoadjuvant treatment with CAB for 3 or 6 months followed by RP or RP alone. The rates of positive surgical margins were significantly less in the neoadjuvant group, although not significantly different between the 2 neoadjuvant (3 and 6 months) groups (26% vs 19%, P = .295). However, a report by the Canadian Uro-Oncology Group (CUOG) randomized 547 patients to either 3 or 8 months of neoadjuvant therapy with CAB followed by RP; a significant decrease in the positive margin rate was observed favoring those patients receiving therapy for 8 months (5% vs 17%), and the organ-confined rates (91% vs 71%) ( P <.01). In the absence of a control group, no direct comparison could be made between neoadjuvant therapy and immediate RP.

A meta-analysis published in 2000 analyzed the routine use of neoadjuvant HT before RP. Six of the 7 studies reviewed noted a decrease in the positive surgical margin rate, but no significant improvement in survival was observed.

Although neoadjuvant ADT affects the rate of positive surgical margins, benefits in survival have not been shown. As such, the routine use of neoadjuvant HT before definitive RP is not recommended outside a clinical trial.

Adjuvant HT After RP

Several studies have attempted to address the issue of early HT in patients who have undergone definitive therapy with RP. The early use of HT in these patients was initially reported in the 1960s as having no effect on OS. However, newer hormonal agents have renewed interest in hormonal manipulation in the adjuvant setting for prostate cancer, and trials addressing this issue have subsequently been undertaken.

Several trials addressing the role of adjuvant HT for patients with positive lymph nodes after RP have been reported. Myers and colleagues reported the results of 62 patients with a long median follow-up (more than 10 years). The patients were divided according to DNA ploidy status and the use of adjuvant HT. Diploid (normal DNA) patients with cancer who received adjuvant HT had a statistically significant improvement in disease-free survival (DFS) and cancer-specific mortality. Although this was a small study, the benefit of early hormonal manipulation on a subset of patients was intriguing. However, further evaluation on the effect of DNA ploidy on prostate cancer has yet to be determined. A landmark study, conducted by Messing and colleagues, randomized 98 patients with node positive disease to either androgen deprivation (ie, surgical or biochemical) or observation following RP. After a follow-up of 11.9 years a significant increase in OS (64% vs 45%) was observed in favor of the ADT group. The benefit in favor of ADT was also observed for PSA recurrence-free survival (53% vs 14%), DFS (60% vs 25%), and prostate cancer–specific survival (85% vs 51%). Some limitations of this study must be acknowledged: (1) the accrual goal of 220 patients was not attained and the few patients who were accrued took many years to enrol; (2) the pathology review was not centralized, potentially contributing to an imbalance between the 2 arms (selection bias); and (3) the control group received ADT for metastatic progression, although many patients currently receive ADT for PSA progression. However, the strength of the effect and the underlying biologic hypothesis suggest that the benefit of ADT in node positive prostate cancer is compelling.

Regarding patients with pathologically negative lymph nodes, further investigation of the role of adjuvant ADT has been undertaken. Siddiqui and colleagues reported a retrospective series from the Mayo Clinic with patients who underwent RP and had negative lymph nodes. A total of 580 patients were treated with adjuvant ADT, and 1160 were observed only. A significant benefit in 10-year biochemical systemic progression-free survival (PFS) (95% vs 90%) and cancer-specific survival (98% vs 95%) was noted, favoring ADT therapy. However, no significant difference was observed in OS (83%, for ADT and observation groups), and this was not a randomized trial.

The use of adjuvant antiandrogen therapy has also been studied. The Early Prostate Cancer (EPC) study enrolled patients with T1-4NxM0 prostate cancer in a multicenter, international, randomized clinical trial. Patients were treated with the standard of care, which was RP, radiotherapy, or watchful waiting, followed by either adjuvant high-dose bicalutamide (150 mg daily) for 2 years or placebo. There have been different reports with different populations depending on the site of the trial, but a significant improvement was noted in the PFS of patients with locally advanced prostate cancer who received bicalutamide (high risk). However, only patients treated with radiotherapy and watchful waiting had an improvement in OS. The North American EPC trial (0023) did not enrol patients on watchful waiting, making the comparison between different sites and arms difficult. In the US trial, eligible patients (3292 patients, with ∼80% post-RP and ∼20% post-RT) after a median follow-up of 7.7 years showed a significant benefit in the treatment group for time to PSA progression (hazard ratio [HR] 0.80, P <.001), but no significant differences in mortality (12.9% vs 12.3%, respectively) or in objective progression rates (15.4% vs 15.3%, respectively) were observed.

Although the treatment is still controversial, most specialists in genitourinary cancers advocate the use of adjuvant ADT in patients with lymph node positive disease who have undergone RP. The exact duration of therapy is debated although patients in Messing and colleagues’ study underwent lifelong androgen deprivation. In patients without lymph node positive disease, there remains no conclusive evidence for the use of adjuvant HT after definitive therapy with RP.

Adjuvant HT After Radiation Therapy

The use of adjuvant HT for locally advanced prostate cancer or high-risk patients after RT is well established. The RTOG (Radiation Therapy Oncology Group) 85-31 trial randomized 977 patients with locally advanced prostate cancer (lymph node positive or clinical T3 disease) to receive adjuvant ADT indefinitely after definitive RT. After a follow-up of 7.6 years, a significant increase in the 10-year OS (49% vs 39%, P = .002), and significant decreases in local failure rate (23% vs 38%), incidence of distant metastases (24% vs 39%), and disease-specific mortality (16% vs 22%) were observed, favoring the adjuvant group. This study had some limitations because 139 patients received prior RP and, in addition, the trial was conducted in the pre-PSA era, making it difficult to translate it to current practice.

A subsequent landmark trial, EORTC (European Organization for Research and Treatment of Cancer) trial 22863, reported by Bolla and colleagues, enrolled 415 node negative patients with T3 or T4 tumors or high-grade (grade 3) T1 or T2 tumors, and randomized them to either adjuvant HT with goserelin for a total of 3 years or observation after definitive RT. At a median follow-up of 66 months, a significant benefit was observed for the adjuvant group in 5-year OS (78% vs 62%, P = .0002), cancer-specific survival (94% vs 79%), and clinical DFS (74% vs 40%).

Another trial evaluated the use of a shorter course of adjuvant HT. D’Amico and colleagues randomized 206 patients with intermediate- or high-risk features (T1b–T2b tumors with PSA level 10–40 or Gleason score ≥7) to receive or not ADT (leuprolide or goserelin combined with a nonsteroidal antiandrogen flutamide) for 6 months beginning 2 months prior to definitive RT. After a median follow-up of 4.5 years, a significant advantage favoring the combination treatment group was noted in freedom from salvage ADT therapy (82 vs 57%), cancer-specific mortality (0% vs 5%), and 5-year OS (88 vs 78%, P = .04).

The optimal duration of the HT has been addressed specifically in 2 trials. The RTOG 92-02 trial enrolled 1554 patients with locally advanced prostate cancer (T2c–T4 with no extrapelvic lymph node involvement and PSA level ≤150). Patients were treated with 4 months of ADT (goserelin and flutamide) before and during RT, and were randomized to no further ADT or 24 months of ADT. The patients who received the long-term ADT, compared with short-term, had a significant benefit in DFS (23% vs 13%, respectively), local progression (12% vs 22%, respectively), distant metastasis (15% vs 23%, respectively), and PSA failure (52% vs 68%, respectively), but failed to show a significant increase in OS (54% vs 52%, respectively). However, the EORTC trial 22961 did show a significant increase in OS for patients treated with long-term ADT. A total of 970 patients with locally advanced prostate cancer (T1c–2b pN1–2 M0 or cT2–4 cN0–2, and PSA level less than 40 times the upper limit) were randomized to short-term (6 months) or long-term (36 months) ADT. At a median follow-up of 6.4 years, the 5-year overall mortality was decreased for patients on long-term ADT compared with short-term ADT (15% vs 19%, respectively) (HR 1.42, 95.71% confidence interval [CI] 1.09–1.85). Moreover, a secondary analysis from the RTOG 85-31 trial showed an association between increased survival and the length of HT. In this analysis, only 189 from 977 patients were included and they were divided into 3 groups: HT for 1 year or longer; HT for between 1 and 5 years; and HT for more than 5 years. At a median follow-up time of 9.6 years, the median duration of HT was 2.2 years, and a significant increase was observed in the 5-year (100% vs 72% and 67%) and 11-year (64% vs 42% and 33%) survivals for the group who received HT for more than 5 years, compared with those who received HT for less than 1 year, and HT for between 1 and 5 years, respectively.

Adjuvant HT has become an accepted standard of care for high-risk localized prostate cancer treated with radiation therapy. In intermediate- and high-risk patients, as shown by D’Amico and colleagues, at least 6 months of total ADT before, during, and after definitive radiation therapy seems appropriate. In the high-risk patients the data regarding duration of therapy remain controversial, although it seems that a longer duration of ADT is important in improving survival.

Neoadjuvant Chemotherapy

Several phase II trials proved the safety and feasibility of neoadjuvant chemotherapy with different agents and combinations, and docetaxel-based chemotherapy has been studied in this setting. Two trials in particular reported the results of single-agent use of docetaxel (without HT). Although the studies were similar in design, Dreicer and colleagues studied a high-dose docetaxel for a short course (40 mg/m ² /wk, for 6 weeks), whereas Febbo and colleagues studied a standard dose of docetaxel for a prolonged period (36 mg/m ² /wk, for 6 months). Both studies showed significant PSA reductions after chemotherapy of at least 50% in 24% and 58% of treated patients, respectively. No pathologic complete responses were observed. However, when neoadjuvant HT is combined with chemotherapy, some pathologic responses have been reported.

Another area of study is the use of targeted agents. Bevacizumab is a monoclonal antibody directed against the vascular endothelial growth factor. Oh and colleagues reported a phase II trial with high-risk patients with prostate cancer treated with docetaxel (70 mg/m ² ), every 3 weeks for 6 cycles, and bevacizumab 15 mg/kg, every 3 weeks for 5 cycles, followed by RP. Almost all patients, except 1, presented a decline in tumor volume measured by endorectal magnetic resonance imaging, with 36% patients presenting with a decline of more than 50%.

No phase III randomized controlled trials have been completed to address outcomes when using neoadjuvant chemotherapy. Currently, the CALGB 90203 study is planning to enrol 700 high-risk patients and to compare docetaxel plus ADT followed by RP with RP alone.

Another multi-institutional phase III trial is being conducted by D’Amico and colleagues. Intermediate- and high-risk patients are being treated with standard RT and concurrent ADT for 6 months, and randomized to receive docetaxel (60 mg/m ² every 3 weeks) for 3 cycles at the start of treatment followed by weekly docetaxel (20 mg/m ² ) beginning at week 1 of RT and continuing for 7 weeks.

Adjuvant Chemotherapy

Early adjuvant chemotherapy studies have reported inconclusive results. An early trial, published by the National Prostate Cancer Project (NPCP), randomized a total of 437 patients to either estramustine phosphate (600 mg/m ² orally daily), cyclophosphamide (1 g/m ² intravenously every 3 weeks), or observation for 2 years following definitive RT (Protocol 900) or RP (Protocol 1000). At more than 10 years’ median follow-up, patients receiving estramustine had a significant improvement in PFS. A second underpowered study by Wang and colleagues compared HT with or without chemotherapy with mitoxantrone and prednisone in 96 patients with pT3 or T4 disease. The results significantly favored OS in the chemotherapy arm (median OS 84 months vs 41 months).

These studies led to the development of larger randomized trials. SWOG study 9921 is a phase III trial that randomized high-risk patients with prostate cancer to receive ADT for 2 years, with or without 6 cycles of mitoxantrone (12 mg/m ² every 4 weeks) plus prednisone. A total of 983 patients were enrolled of the planned 1360, before early closure of the trial secondary to excessive numbers of acute myeloid leukemias in the mitoxantrone chemotherapy arm. Results of survival have not been reported yet, and it is unknown if there will be enough power to detect a difference in survival between the 2 arms.

Another trial, TAX 3501, was designed to assess the efficacy of adjuvant docetaxel in improving survival. High-risk patients were treated with adjuvant ADT and randomized to receive immediately 6 cycles of adjuvant docetaxel (75 mg/m ² ) or as a salvage treatment. However, because of poor accrual, this trial was also closed prematurely. A more recent, ongoing trial, TAX 3503, was initiated with a similar design, but is enrolling patients with increasing PSA levels (biochemical failure) after RP, and randomizing them to ADT alone followed by docetaxel when they have CRPC or ADT plus early docetaxel.

Docetaxel is also being investigated in the adjuvant setting after definitive RT. RTOG study 0521 is a phase III trial that plans to enrol 600 high-risk patients. Patients are treated with RT and ADT (LHRH agonist and oral antiandrogen) for a total of 2 years, beginning 2 months before RT, and randomized to receive adjuvant docetaxel (75 mg/m ² every 3 weeks) for 6 cycles, beginning 1 month after the completion of RT.

The use of chemotherapy, in particular docetaxel, in the neoadjuvant and adjuvant settings is promising. It is to be hoped that the current phase III trials will answer the question regarding the potential benefit of chemotherapy in improving the survival rates for high-risk patients with prostate cancer.