Biochemical Recurrence Surrogacy for Clinical Outcomes After Radiotherapy for Adenocarcinoma of the Prostate.

PURPOSE: The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods. MATERIALS AND METHODS: Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R2). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed. RESULTS: Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively. CONCLUSION: BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.

High-dose radiotherapy and risk-adapted androgen deprivation in localised prostate cancer (DART 01/05): 10-year results of a phase 3 randomised, controlled trial.

BACKGROUND: The optimal duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains controversial. The DART 01/05 trial was designed to determine whether long-term androgen deprivation is superior to short-term androgen deprivation when combined with high-dose radiotherapy. The 5-year results showed that 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy significantly improved biochemical control, metastasis, and overall survival, especially in patients with high-risk disease. In this report, we present the 10-year final results of the trial. METHODS: This open-label, phase 3, randomised, controlled trial was done in ten hospitals in Spain. The eligibility criteria included patients aged 18 years or older with histologically confirmed T1c to T3, N0, and M0 adenocarcinoma of the prostate, according to the 2002 classification of the American Joint Committee on Cancer, with intermediate-risk and high-risk factors, prostate-specific antigen (PSA) less than 100 ng/mL, and a Karnofsky performance score of at least 70%. Patients were randomly assigned (1:1) to receive 4 months of neoadjuvant and concomitant short-term androgen deprivation (STAD) plus high-dose radiotherapy (minimum dose 76 Gy; median dose 78 Gy) or to receive the same treatment followed by 24 months of adjuvant long-term androgen deprivation (LTAD), via a randomisation scheduled generated by Statistical Analysis Software programme (version 9.1) and an interactive web response system. Patients assigned to the STAD group received 4 months of neoadjuvant and concomitant androgen deprivation (oral flutamide 750 mg per day or oral bicalutamide 50 mg per day) with subcutaneous goserelin (2 months before and 2 months combined with high-dose radiotherapy). Anti-androgen therapy was added during the first 2 months of treatment. Patients assigned to LTAD continued with goserelin every 3 months for another 24 months. The primary endpoint was biochemical disease-free survival at 5 years. For this 10-year study we analysed overall survival, metastasis-free survival, biochemical disease-free survival, and cause-specific survival. Analysis was by intention to treat. This trial is closed and is registered at ClinicalTrials.gov (NCT02175212) and in the EU Clinical Trials Register (EudraCT 2005-000417-36). FINDINGS: Between Nov 7, 2005, and Dec 20, 2010, 355 patients were enrolled. One patient in the STAD group withdrew from the trial, hence 354 participants were randomly assigned to STAD (n=177) or LTAD (n=177). The median follow-up was 119·4 months (IQR 100·6-124·3). The 10-year biochemical disease-free survival for LTAD was 70·2% (95% CI 63·1-77·3) and for STAD was 62·3% (54·9-69·7; hazard ratio [HR] 0·84; 95% CI 0·50-1·43; p=0·52). At 10 years, overall survival was 78·4% (72·1-84·8) for LTAD and 73·3% (66·6-80·0) for STAD (HR 0·84; 95% CI 0·55-1·27; p=0·40), and metastasis-free survival was 76·0% (69·4-82·7) for LTAD and 70·9% (64·0-77·8) for STAD (HR 0·90; 95% CI, 0·37-2·19; p=0·81). For the subgroup of high-risk patients, the 10-year biochemical disease-free survival was 67·2% (57·2-77·2) for LTAD and 53·7% (43·3-64·1) for STAD (HR 0·90; 95% CI 0·49-1·64; p=0·73), the 10-year overall survival was 78·5% (69·6-87·3) for LTAD and 67·0% (57·3-76·7) for STAD (HR 0·58; 95% CI 0·33-1·01; p=0·054), and the 10-year metastasis-free survival was 76·6% (95% CI 67·6-85·6) for LTAD and 65·0% (55·1-74·8) for STAD (HR 0·89; 95% CI 0·33-2·43; p=0·82). Only 11 (3%) of 354 patients died from prostate cancer, all of them in the high-risk subgroup (five in the LTAD group and six in the STAD group). 76 (21%) patients died from other causes (mainly second malignancies in 31 [9%] and cardiovascular disease in 21 [6%]). No treatment-related deaths were observed. INTERPRETATION: After an extended 10-year follow-up, we were unable to support the significant benefit of LTAD reported at 5 years. However, the magnitude of the benefit was clinically relevant in high-risk patients. Intermediate-risk patients treated with high-dose radiotherapy do not benefit from LTAD. A biological characterisation with the inclusion of genomic testing is needed in the decision-making process. FUNDING: Grupo de Investigación en Oncología Radioterápica and Sociedad Española de Oncología Radioterápica, the National Health Investigation Fund, and AstraZeneca.

High-dose Radiotherapy or Androgen Deprivation Therapy (HEAT) as Treatment Intensification for Localized Prostate Cancer: An Individual Patient-data Network Meta-analysis from the MARCAP Consortium.

BACKGROUND: The relative benefits of radiotherapy (RT) dose escalation and the addition of short-term or long-term androgen deprivation therapy (STADT or LTADT) in the treatment of prostate cancer are unknown. OBJECTIVE: To perform a network meta-analysis (NMA) of relevant randomized trials to compare the relative benefits of RT dose escalation ± STADT or LTADT. DESIGN, SETTING, AND PARTICIPANTS: An NMA of individual patient data from 13 multicenter randomized trials was carried out for a total of 11862 patients. Patients received one of the six permutations of low-dose RT (64 to <74 Gy) ± STADT or LTADT, high-dose RT (≥74 Gy), or high-dose RT ± STADT or LTADT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Metastasis-free survival (MFS) was the primary endpoint. Frequentist and Bayesian NMAs were performed to rank the various treatment strategies by MFS and biochemical recurrence-free survival (BCRFS). RESULTS AND LIMITATIONS: Median follow-up was 8.8 yr (interquartile range 5.7-11.5). The greatest relative improvement in outcomes was seen for addition of LTADT, irrespective of RT dose, followed by addition of STADT, irrespective of RT dose. RT dose escalation did not improve MFS either in the absence of ADT (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.80-1.18) or with STADT (HR 0.99, 95% CI 0.8-1.23) or LTADT (HR 0.94, 95% CI 0.65-1.37). According to P-score ranking and rankogram analysis, high-dose RT + LTADT was the optimal treatment strategy for both BCRFS and longer-term outcomes. CONCLUSIONS: Conventionally escalated RT up to 79.2 Gy, alone or in the presence of ADT, does not improve MFS, while addition of STADT or LTADT to RT alone, regardless of RT dose, consistently improves MFS. RT dose escalation does provide a high probability of improving BCRFS and, provided it can be delivered without compromising quality of life, may represent the optimal treatment strategy when used in conjunction with ADT. PATIENT SUMMARY: Using a higher radiotherapy dose when treating prostate cancer does not reduce the chance of developing metastases or death, but it does reduce the chance of having a rise in prostate-specific antigen (PSA) signifying recurrence of cancer. Androgen deprivation therapy improves all outcomes. A safe increase in radiotherapy dose in conjunction with androgen deprivation therapy may be the optimal treatment.

[Biochemical recurrence criteria after radiotherapy (external beam, brachytherapy). Natural history of the disease after radiotherapy]. / Criterios de recidiva bioquímica tras radioterapia (externa, braquiterapia ). Historia natural de la enfermedad después de radioterapia.

Prostate specific antigen (PSA) is the main tool in the follow-up of prostate cancer patients after definitive therapy. It's widely used as an early marker to value treatment success. Biochemical recurrence predicts metastatic disease progression and prostate cancer-specific mortality. In 1996, the American Society for Therapeutic Radiology and Oncology (ASTRO) provided a definition of biochemical failure after radiotherapy, based on three consecutive increases in PSA after nadir. As more experience was gained using the proposed definition and follow up duration in the PSA era matured, deficiencies and controversial issues emerged, so more recently proposed candidate definitions have provided consistent outcome. In view of the criticisms, a second consensus conference was held on 2005, with "nadir + 2 ng/ml" accepted as standard definition. The natural history and evidence of PSA kinetic parameters and different definitions of biochemical failure after external beam radiation therapy and/or brachytherapy are reviewed in the following article.

[Rescue cryotherapy for prostate cancer after radiotherapy]. / Crioterapia de rescate en el cáncer de próstata después de radioterapia.

Radical Radiotherapy constitutes a useful therapeutic option for localized prostate cancer. Almost one third of prostate cancer patients choose this alternative to treat the disease. Despite modifications in the technique as intensity modulation, 3D conformational radiotherapy or computer-assisted brachytherapy, a significant percentage of these patients will show an increase in PSA values after radiation. Local relapse without distant disease and PSA less than 10 ng/ml are candidates for salvage therapy. Cryotherapy has already become a curative treatment option in this group of patients. Recent technological as well as surgical advances in salvage-cryotherapy have reduced dramatically complications and progressively increase the interest on this alternative.

[Biochemical recurrence in patients with prostate cancer after radical treatment. Comparative study of prostatectomy vs. radiotherapy]. / Recidiva bioquímica en los pacientes con cáncer de próstata después de tratamiento radical. Estudio comparativo entre prostatectomía y radioterapia.

OBJECTIVES: To compare the biochemical relapse-free survival between radical prostatectomy and radiotherapy in patients with localized prostate cancer of low and intermediate recurrence risk. METHODS: A retrospective study of 435 patients with localized prostate cancer, radical prostatectomy was performed in 65% of patients and radiotherapy was in 35%. The Kaplan-Meier Estimator was used to assess the biochemical relapse-free survival and long-rank test, Breslow and Tarone-Ware to evaluate the differences between the groups with confidence intervals at 95%. RESULTS: The median follow-up of the series was 60 months (3-106). Biochemical recurrence was diagnosed in 21% of patients: 22% of those were treated with prostatectomy and 19% with radiotherapy (p = 0.47). No significant differences were observed according to risk group (p = 0.60 in the low risk and p = 0.32 in the intermediate risk). Tree, five and seven-year actuarial biochemical recurrence-free survival for prostatectomy were 84%, 75%and 70%, while for radiotherapy were 97%, 84% and 64% respectively. CONCLUSIONS: There are no significant differences in actuarial biochemical recurrence free survival in patients with localized prostate cancer of low and intermediate risk treated with prostatectomy or radiation therapy. Due to the crossing of the survival curves we do not rule out that with longer follow-up these results could be modified.

[Incidence and prognostic factors for biochemical recurrence after radical radiotherapy]. / Incidencia y factores pronósticos de recidiva bioquímica después de radioterapia radical. Experiencia del Gregorio Marañón.

OBJECTIVES: The aim of this study is to analyze the outcomes obtained after External-Beam Radiotherapy (3D EBRT)in patients with prostate cancer. METHODS: The study includes 503 patients (p) treated at the Hospital General Universitario Gregorio Marañón in Madrid, diagnosed between 2000-2007, with low, intermediate or high risk prostate cancer (D'Amico risk groups), treated with 3D EBRT. Biochemical recurrence (BR) was defined as nadir +2 following Phoenix's criterion. The median follow-up was 59 months (range 3.4-104.2). RESULTS: Biochemical relapse-free survival (bRFS) rates at 5 and 8 years were 88 ± 2% and 76 ± 3%, respectively. Multivariate analysis indicated initial PSA (p <0.02), perineural invasion in biopsy specimen (p <0.00), EBRT dose (p = 0.01) and the use of androgen deprivation therapy (ADT)(p = 0.00) to be independent predictors of relapse. Nadir PSA value <0.3 ng/ml was associated with the best 5-year bRFS (96.6% versus 56.5% if nadir PSA > 1.3 ng/ml). Late urinary and rectal toxicity ≥ 3 was lower than 5%. Active rescue treatment was indicated in 85% of patients. Only 10 patients died of prostate cancer. CONCLUSION: The biochemical failure rate is determined by classical pretreatment features (initial PSA level, risk group, perineural invasion) and low- dose EBRT (≤ 72 Gy), nadir PSA value and the use of ADT in intermediate and high risk groups.