Current Trials of Radiotherapy Timing Following RP
Resolving whether postoperative RT is optimally delivered in an adjuvant or salvage fashion requires the completion of large-scale Phase III trials. Fortunately, several such RCTs are now underway. The trial with the largest planned accrual, Radiotherapy and Androgen Deprivation In Combination After Local Surgery (RADICALS), is led by the Medical Research Council (UK) in collaboration with the National Cancer Institute of Canada Clinical Trials Group.[39] The trial includes two randomizations - one pertaining to RT timing and the other pertaining to the use of ADT with RT - and patients may enter one or both of them. The trial is unique in its use of the 'uncertainty principle' to assess patient eligibility. There are no specific pathologic eligibility criteria; instead, patients are eligible by virtue of uncertainty on the part of the treating physician regarding the need for adjuvant RT. Two other RCTs investigating the optimal timing of post-RP RT have been launched by cooperative groups: Groupe d'Étude des Tumeurs Uro-Génitales (GETUG) 17, a trial of the Genitourinary Tumour Study Group in France; and Radiotherapy Adjuvant Versus Early Salvage (RAVES), a trial of the Trans-Tasman Radiation Oncology Group. Further details concerning these studies are summarized in Table 1.

Androgen-deprivation Therapy
The use of androgen deprivation has been firmly entrenched in the management of metastatic prostate cancer since the seminal work of Huggins in the 1940s.[40,41] With the advent of synthetic luteinizing hormone-releasing hormone (LHRH) agonists in the 1980s, the use of ADT was prospectively evaluated in the primary management of prostate cancer in conjunction with definitive local therapy. Several randomized trials have been completed that now have mature results. Three of these trials demonstrate that, when used with primary external-beam RT, ADT significantly improves OS in a population of patients with predominantly high-risk features.[1,2,42] The success of ADT with RT stimulated interest in its application with radical RP. The published randomized data for adjuvant ADT given prior to and following RP are presented in turn.

Neoadjuvant ADT
The use of ADT prior to RP has been investigated in ten RCTs and their results have recently been pooled in a meta-analysis.[43] Seven of the trials compared RP alone with 3 months of neoadjuvant ADT,[44-50] one trial compared RP alone with 3 and 6 months of neoadjuvant ADT,[51] and the remaining trials compared 3 months of ADT with either 6[52] or 8 months[53] prior to RP. The type of ADT used - LHRH agonist alone, peripheral antiandrogen alone or combined androgen blockade - varied across the trials. There was also considerable heterogeneity across the trials in the stage, grade and pretreatment PSA of eligible patients. By contemporary definitions, a range of low-, intermediate- and high-risk patients were included.

Despite this heterogeneity, remarkably similar results were observed in the trial outcomes. Three trials reported data on OS. On meta-analysis, the pooled risk ratio (RR) for mortality was 1.00 (95% CI: 0.97-1.04; p = 0.95); neoadjuvant ADT, therefore, confers no benefit in survival beyond RP.[43] Five trials provided data on bPFS and in none of them was a significant benefit seen with neoadjuvant ADT. Similarly, on pooled analysis, no benefit was found (RR: 1.04; 95% CI: 0.93-1.16; p = 0.48). It should be noted that, at the time data were pooled, follow-up from included trials ranged from 6 months to 7 years. These data may, therefore, not be sufficiently mature to draw firm conclusions on outcomes such as bPFS and OS. Second, a significant proportion of the patients enrolled on the trials had low- or intermediate-risk disease, and it may be argued that a benefit for neoadjuvant ADT is unlikely to be demonstrated in this population. Interestingly, a small exploratory analysis (n = 33) of an RCT conducted by the Canadian Urologic Oncology Group and included in the meta-analysis did identify a benefit with respect to bPFS in a subgroup of enrolled patients with pretreatment PSA level greater than 20 ng/ml, raising the hypothesis that patients presenting with high-risk disease may derive benefit from ADT prior to RP.[49]

A putative advantage of a neoadjuvant approach to systemic therapy is its potential for downstaging and rendering tumors more amenable to surgical resection. All of the RCTs of neoadjuvant ADT considered earlier included pathologic outcomes. On meta-analysis, rates of surgical margin positivity (RR: 0.49; 95% CI: 0.42-0.56; p < 0.00001) and pelvic lymph-node involvement (RR: 0.66; 95% CI: 0.47-0.94; p = 0.02) were significantly reduced by neoadjuvant ADT, while the probability of finding organ-confined disease at RP was increased (RR: 1.63; 95% CI: 1.37-1.95; p < 0.0001).[43] In the absence of any coexisting bPFS or OS benefit, however, the clinical relevance of these pathologic end points is questionable. Furthermore, neoadjuvant ADT has been demonstrated to instigate cytoarchitectural changes in prostate epithelial cells that may obscure the tumor and confound the evaluation of surgical margin status and capsular integrity.[54] Patients erroneously reported to have R0 resections or pathologic T2 disease following neoadjuvant ADT may thereby be inappropriately denied additional postoperative treatment.

Adjuvant ADT
While immediate ADT following surgery has been demonstrated to prolong survival in men with pelvic lymph-node positive prostate cancer in a landmark RCT, conducted by the Eastern Cooperative Oncology Group,[55,56] its application in high-risk localized disease has been largely disappointing. The largest experience with adjuvant ADT following RP comes from the Early Prostate Cancer (EPC) program.[57-59] This trial - one of the largest randomized studies of a prostate cancer therapy ever mounted - investigated the adjuvant use of the nonsteroidal antiandrogen bicalutamide. The EPC program, in fact, comprised three trials that were conducted in parallel in North America, Europe and Scandinavia, and were powered for a combined analysis. Men with localized (T1-2 N0/NX) or locally advanced (T3-4 or N1) nonmetastatic prostate cancer to be treated with either primary RP, primary RT or a watchful waiting approach were eligible. As the trial was designed to reflect contemporary practice worldwide, the eligibility criteria varied across the three trials; for example, in North America, node-positive patients and those following a watchful waiting approach were ineligible. In total, 8113 men were enrolled and randomized to either bicalutamide 150 mg daily or placebo, administered for 2 years (North America) or until time of progression. Those treated with RP accounted for 55% (n = 4454) of this total.

Results have now been reported at a median follow-up of 7.4 years.[59] Considering the study population as a whole, adjuvant bicalutamide 150 mg daily conferred no benefit in the primary end point of OS (HR: 0.99; 95% CI: 0.91-1.09; p = 0.89) but a modest improvement in bPFS was observed (HR: 0.79; 95% CI: 0.73-0.85; p < 0.001). Similarly, in those patients treated with RP, bicalutamide improved bPFS but not OS (HRs not reported). Among those treated with RP, the significant benefit with respect to bPFS did extend to the subgroup of patients with locally advanced disease (HR: 0.75; 95% CI: 0.61-0.91; p = 0.004) but not to those with localized disease (HR not reported). Of note, in patients treated with primary RT, an OS benefit was seen in the subgroup with locally advanced disease (HR: 0.65; 95% CI: 0.44-0.95; p = 0.03).

Breast pain and gynecomastia were the most commonly observed toxicities of treatment with bicalutamide. Breast pain was reported in 73.6% of patients randomized to bicalutamide compared with 7.6% of those randomized to placebo. Gynecomastia occurred in 68.8% of patients receiving bicalutamide and 8.3% of patients receiving placebo. Other adverse events occurred with similar frequency across the two groups.

Wirth and colleagues have reported the results of a much smaller RCT (n = 309) of adjuvant therapy with another nonsteroidal antiandrogen, flutamide, in locally advanced node-negative prostate cancer following RP.[60] The results parallel those of the EPC trial. At a median follow-up of 6.1 years, adjuvant flutamide 250 mg three-times daily conferred a significant benefit with respect to bPFS (HR: 0.51; 95% CI: 0.32-0.81; p = 0.0041) but OS was unchanged (HR: 1.04; 95% CI: 0.53-2.02; p = 0.92). Considerable gastrointestinal and hepatic toxicity was reported in the flutamide arm, and 96 out of 152 patients randomized to it withdrew from treatment.

ADT in Conjunction with Postoperative Radiotherapy
As noted earlier, across several trials, ADT has been demonstrated to improve survival when used in conjunction with RT in the primary treatment of prostate cancer.[1,2,42] When employed concurrently with RT, ADT is believed to exert a potentiating effect, probably by promoting RT-induced apopotic cell death. It is, therefore, reasonable to ask whether, if used adjunctively, ADT may enhance the efficacy of postoperative RT. The only randomized data pertaining to such a strategy are reported in a subgroup analysis of RTOG trial 85-31, a Phase III study investigating the use of adjuvant ADT in locally advanced and node-positive prostate cancer.[61] While most of the 977 patients enrolled received definitive RT, the trial also included 139 patients receiving postoperative RT after being found at RP to have pathologic T3 disease. These patients were randomized to either postoperative RT and immediate ADT (n = 68) or RT alone with ADT instituted at the time of relapse (n = 71). With a median follow-up of 5 years, immediate ADT was demonstrated to significantly prolong bPFS (65 vs 42% relapse free; p = 0.002) without affecting MFS or OS. One should be mindful of the fact that this analysis was post-hoc and based on only 139 patients and, therefore, lacked the power to identify differences in survival.

Several RCTs are currently investigating the use of ADT in addition to postoperative RT. Among them, RTOG 96-01 is nearest to reporting, having closed to accrual in 2003. It is a Phase III comparison of the addition of bicalutamide or placebo to salvage RT in patients with pathologic T3 or margin-positive disease that have progressed biochemically after RP. As noted previously, RADICALS also includes an ADT randomization; patients receiving postoperative RT may be randomized to receive 0, 6 or 24 months of ADT. The main features of these and other RCTs addressing the issue of ADT as an adjunct to postoperative RT are listed in Table 2.

Chemotherapy
Historically, prostate cancer was believed to be a chemoresistant disease. Multiple trials in the 1980s and 1990s failed to identify any substantial activity or survival benefit with agents from a variety of chemotherapeutic classes.[62] However, the publication of two large-scale RCTs in 2004 changed this paradigm. Both SWOG 9916 and TAX 327 investigated the use of docetaxel-based chemotherapy in metastatic castration-resistant prostate cancer.[63,64] In addition to considerable rates of objective and biochemical response, both demonstrated that docetaxel provided a modest survival advantage of 2-3 months. Thus, for the first time, chemotherapy was demonstrated to alter the natural history of the disease. While the magnitude of the survival benefit was small, the results of these trials have spurred interest in introducing docetaxel earlier in the disease course, before the development of overt metastatic disease. In this way, androgen-independent tumor cell subpopulations can be addressed at the time of initial treatment. Experience in other solid tumors - including breast, colorectal and lung cancer - has demonstrated that modest survival improvements from chemotherapy given for metastatic disease can translate into improvements of greater magnitude when used in the adjuvant setting in patients at high risk of relapse.

Neoadjuvant Chemotherapy
The use of chemotherapy before, rather than after, RP offers several theoretical advantages. First, it enables cytoreduction and downstaging prior to surgery and may thereby improve the resectability of locally advanced tumors. Second, it enables the immediate treatment of micrometastatic disease without the delay imposed by surgery and a postoperative convalescence period. As it occurs prior to any other therapy, patient compliance with treatment is also potentially higher. Finally, from the point of view of clinical research, as neoadjuvant therapy permits an in vivo evaluation of response to treatment, it enables the rapid identification of new agents with activity. The efficacy of a new regimen can be evaluated with fewer patients and shorter follow-up.

Several Phase I and II trials of neoadjuvant docetaxel, administered either alone or in combination with ADT or other chemotherapeutic agents, have been completed.[65-70] Taken together, these studies demonstrate the safety and feasibility of administering neoadjuvant chemotherapy prior to RP without complicating the surgical procedure itself. Observed toxicity has generally been reversible. In the absence of nonchemotherapy control arms, definitive statements cannot be made regarding efficacy. It should be noted from these studies, however, that pathologic complete responses to neoadjuvant docetaxel-based regimens are rare.

No RCTs of neoadjuvant docetaxel-based chemotherapy have been completed to date. Two cooperative group trials are currently in progress. Cancer and Leukemia Group B (CALGB) 90203, the larger of the two, is enrolling patients with high-risk localized prostate cancer determined to have a more than 40% probability of relapse at 5 years on a pretreatment nomogram.[71] Patients are randomized to either RP alone or docetaxel and ADT administered concurrently prior to RP. The primary end point is 5-year bPFS. Additional details pertaining to this trial and GETUG 12, a similarly designed trial, are provided in Table 3.

Adjuvant Chemotherapy
Notwithstanding the aforementioned potential benefits of a neoadjuvant policy to chemotherapy, a significant drawback of this approach is the possibility of overtreatment. Adjuvant approaches, by contrast, enable complete pathologic evaluation of the RP specimen and more precise definition of the high-risk population. The toxicity of any additional therapy can be, therefore, limited to those patients who are truly at highest risk of relapse.

Two small RCTs of chemotherapy in the initial treatment of high-risk prostate cancer have been completed.[72,73] Neither included docetaxel as part of the treatment regimen and both were inadequately powered to address survival end points. Interestingly, the more recent of the two, conducted in the 1990s by Wang and colleagues at the Hammersmith Hospital in London (UK), identified a survival advantage for mitoxantrone and ADT when compared with ADT alone in a subgroup (n = 38) of patients with locally advanced (T3-4) prostate cancer (median survival 80 vs 36 months; p = 0.04). No such benefit was seen in the subgroup of patients with metastatic disease (n = 57) also included in the trial. The small size of this study and the fact that no definitive local therapies were employed limits the strength and applicability of its findings.

Several large multicenter RCTs of adjuvant chemotherapy, at various stages of completion, have been undertaken for patients with high-risk localized prostate cancer treated with RP. SWOG 9921 was a randomized, Phase III trial comparing adjuvant mitoxantrone and ADT with ADT alone in patients with high-risk features after RP.[74] This trial was designed to have adequate power to address OS as primary end point. After accrual of 983 patients, the trial was closed prematurely in January 2007 after the identification of three cases of acute myelogenous leukemia in the mitoxantrone arm. At least two of the cases were felt to be induced by mitoxantrone. The decision to close the trial was also influenced by a lower than expected death rate for the overall patient population, such that treatment-related deaths early in follow-up would carry potentially greater significance. Despite the trial closure, all enrolled patients will continue to be observed and efficacy results will be reported as the data mature.

TAX 3501 was a pharmaceutical industry-sponsored Phase III trial with a 2 x 2 factorial design in which patients with adverse pathologic features at RP were randomized to either immediate adjuvant therapy or active surveillance with therapy held in reserve for salvage at the time of biochemical progression. Whether therapy was given on an adjuvant or salvage basis, it consisted of random assignment to either ADT alone or ADT with concurrent docetaxel. The study was closed owing to poor accrual in September 2007 after 216 patients had been enrolled. Additional details of SWOG 9901, TAX 3501 and two other active cooperative group RCTs of adjuvant chemotherapy are shown in Table 3.

Compared with other solid tumors, attempts to integrate chemotherapy into the initial management of high-risk localized prostate cancer remain in their infancy. None of the Phase III trials described, investigating the use of docetaxel-based chemotherapy before or after RP, have reported mature results and several years of additional follow-up will probably be required. Until the results of these trials are at hand, adjuvant chemotherapy should not be used outside of a well-designed protocol.

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