Addition of radiotherapy to long-term androgen deprivation in locally advanced prostate cancer: an open randomised phase 3 trial.

BACKGROUND: Radiotherapy combined with androgen-deprivation therapy (ADT) is superior to radiotherapy alone in localised prostate cancer; however, data comparing ADT alone are somewhat limited. OBJECTIVE: To compare 3-yr ADT plus radiotherapy with ADT alone in locally advanced prostate cancer patients. DESIGN, SETTING, AND PARTICIPANTS: A multicentre randomised open controlled phase 3 trial in 264 histologically confirmed T3-4 or pT3N0M0 prostate cancer patients randomised from March 2000 to December 2003. INTERVENTION: ADT (11.25mg subcutaneous depot injection of leuprorelin every 3 mo for 3 yr) plus external-beam radiotherapy or ADT alone. Flutamide (750 g/d) was administered for 1 mo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary objective was 5 yr progression-free survival (PFS) according to clinical or biologic criteria, using the American Society for Therapeutic Radiology and Oncology (ASTRO) and the newer (Phoenix) definition (nadir plus 2 ng/ml), by intention to treat. Secondary objectives included time to locoregional recurrence and distant metastases, and overall and disease-specific survival. Our Analyses: intent-to-treat analysis, multivariate analyses using a Cox model with a 5% threshold from univariate analysis, and Kaplan-Meier estimates. RESULTS AND LIMITATIONS: ADT alone was administered to 130 patients and combined therapy to 133. With a median follow-up of 67 mo, 5-yr PFS was 60.9% for combined therapy versus 8.5% with ADT alone (ASTRO; p<0.0001), and 64.7% versus 15.4%, respectively, for Phoenix (p<0.0011). Locoregional progression was reported in 9.8% of combined-therapy patients versus 29.2% with ADT alone (p<0.0001) and metastatic progression in 3.0% versus 10.8%, respectively (p<0.018). Overall survival was 71.4% with combined therapy versus 71.5% with ADT alone; disease-specific survival was 93.2% versus 86.2%. Limitations included the relatively small population and a relatively short follow-up period. CONCLUSIONS: Combined therapy strongly favoured improved PFS, locoregional control, and metastasis-free survival. Longer follow-up is needed to assess the potential survival impact.

[Indications for pelvic lymphadenectomy in clinically localized prostate cancer]. / Indications de la lymphadénectomie ilio-obturatrice dans le cancer de la prostate cliniquement localisé.

INTRODUCTION: Pelvic lymphadenectomy for localized prostate cancer (stage T1-T2) provides prognostic information. It can be performed by laparoscopy or by open surgery. Systematic lymphadenectomy is controversial and should be performed according to the stage of the tumour and the type of management. Frozen section examination of lymph nodes during total prostatectomy is also controversial due to its low sensitivity (66%). The objective of this article is to define the indications for lymphadenectomy and frozen section examination. METHODS: Systematic review of the literature. RESULTS: Recommendations concerning the indications for bilateral pelvic lymphadenectomy and frozen section examination for stage T1-T2 prostate cancer as a function of the risk of lymph node metastases. A low risk (<5%) of lymph node metastases is defined by an initial PSA < 10 ng/ml, a Gleason score of biopsies < 7 (3 + 4 or < 50% of grade 4) and possibly non-suspicious lymph node imaging. In this case, prior pelvic lymphadenectomy either some time before or immediately before local treatment is optional (Level of Evidence III-2). Due to the morbidity related to lymphadenectomy, the benefit of the procedure is not justified. However, the following situations are distinguished for open or laparoscopic total prostatectomy: --if open total prostatectomy is considered, exploration of the lymph nodes by palpation at the beginning of the operation is recommended. If exploration does not suggest any lymph node invasion, lymphadenectomy is then optional (without frozen section examination). If exploration shows induration or a mass deforming the shape of the lymph nodes, lymphadenectomy is recommended. Frozen section examination is requested only when the surgeon decides not to perform prostatectomy in the case of lymph node invasion. Lymphadenectomy without frozen section examination is optional in the case of laparoscopic total prostatectomy. Macroscopic examination of any lymph node invasion is less accurate via laparoscopy. A high risk (> 5%) of lymph node metastases is defined by a PSA > 10 ng/ml and/or a Gleason score > 7 (4 + 3 or > 50% of grade 4), and/or suspicious lymph node imaging. Pelvic lymphadenectomy is then recommended (Level of Evidence III-2). The following situations can be distinguished according to the type of treatment envisaged (total prostatectomy or external radiotherapy): when the surgeon decides not to perform total prostatectomy in the case of microscopic or macroscopic lymph node invasion (pN1), lymphadenectomy (open or laparoscopic) may be performed either before or at the same time as prostatectomy with frozen section examination. In the case of external radiotherapy, laparoscopic (or open) lymphadenectomy is recommended (without frozen section examination) when it is decided to extend the irradiation field to pelvic lymph nodes in the case of stage pN1 (1st option) or withhold radiotherapy (2nd option). Lymphadenectomy is optional in other cases, as lymphadenectomy induces considerable morbidity and the benefit of systematic pelvic lymph node irradiation has not been demonstrated. It should be stressed that all indications for lymphadenectomy for localized prostate cancer proposed in the literature are based on the results of standard or limited pelvic lymphadenectomy. These indications could be revised if it is confirmed that lymphadenectomy extended to the internal iliac nodes, for patients at high risk of lymph node invasion, is truly informative and contributive to the treatment decision.