Phase III randomised trial Long-term results of the Dutch randomized prostate cancer trial: Impact of dose-escalation on local, biochemical, clinical failure, and survival Wilma D. Heemsbergen a,⇑,1 , Abrahim Al-Mamgani b , Annerie Slot c , Michel F.H. Dielwart d , Joos V. Lebesque a,1 a Department of Radiation Oncology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam; b Department of Radiation Oncology, Erasmus MC – Cancer Institute, Rotterdam; c Radiotherapeutic Institute Friesland, Leeuwarden; and d Zeeuws Radiotherapeutic Institute, Vlissingen, The Netherlands article info Article history: Received 18 June 2013 Received in revised form 29 August 2013 Accepted 1 September 2013 Available online 15 November 2013 Keywords: Prostate cancer Clinical trial Dose-escalation abstract Purpose: Nowadays, advanced irradiation techniques make it possible to escalate safely the dose in pros- tate cancer. We studied the effect of a higher dose on tumor control in a randomized trial with a median follow-up of 110 months. Patients and methods: Patients with T1b-T4N0 prostate cancer (n = 664) were randomized between 78 Gy and 68 Gy. Primary endpoint was biochemical and/or clinical failure (BCF) according to the American Society for Therapeutic Radiology and Oncology (ASTRO) guidelines (3 consecutive rises), and to Phoenix (nadir plus 2 lg/L). Secondary endpoints were clinical failure (CF), local failure (LF), prostate cancer death (PCD), and overall survival (OS). Explorative subgroup analyses were performed. Results: BCF rate (HR = 0.8; 20% less events) and LF rate (HR = 0.5; 50% less events) were significantly lower in the 78 Gy arm (p < 0.05). CF, PCD and OS were similar in both arms. A significant heterogeneity of treatment effect was found for PSA cutoffs between 7 and 10 lg/L. Conclusion: We observed significantly less BCF and LF in the high-dose arm. This suggests improvement of the therapeutic ratio. However, we observed similar rates of CF and PCD at the current update. More follow-up is needed to investigate which patients benefit in terms of prolonged OS. Ó 2013 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 110 (2014) 104–109 Clinical evidence that a higher dose is more effective in treating localized prostate cancer has become available from a number of randomized clinical trials, including low, intermediate and/or high-risk patients [1–8]. The prescription dose for external beam radiotherapy has therefore increased from levels of 60–70 Gy up to levels of 74–80 Gy, especially for intermediate and high-risk cases. The first publications of these trials mainly concerned the endpoint of any failure, biochemical or clinical (BCF), with a limited median follow-up of about 3–5 years. More recently, results with longer follow-up became available, revealing more information about long-term effects on clinical failures and (disease specific) survival [2,3,7,8]. We previously reported results from the Dutch escalation trial, randomizing between 68 and 78 Gy, with a median follow-up of 51 [6] and 70 months [1]. We reported improved free- dom from BCF for the high-dose arm. With the current update, we present the long-term results with a median follow-up of about 9 years (110 months). The hypothesis of our study was that better local control could be achieved by increasing the local dose, result- ing in improved freedom from BCF, and eventually improved (dis- ease specific) survival. Patients and methods The study was approved by local Ethics Committees of the four Dutch participating institutes. The trial was registered at Clinical- Trials.gov (NCT00692107). All patients gave written Informed Con- sent. Main inclusion criteria were: T1b-T4 tumor, initial PSA <60 lg/L, and no clinical signs of positive lymph nodes. Seminal vesicle dose depended on T stage, PSA and Gleason score (0, 50, 68 Gy or the total dose 68/78 Gy). Dose constraints were: rectum receiving P74 Gy <40%, and small bowel dose 668 Gy. Distribution of T stages (TNM 1997) was: (78, 68 Gy): T1 21%/18%, T2 41%/45%, T3 37%/35%, T4 1%/2%. Distribution among risk groups according to Chism [9] was: 119 low-risk (PSA 610, T1B-T2a, and Gleason <7), 179 intermediate-risk, and 366 high-risk (PSA >20 lg/L, or T3/4, or Gleason 8–10). (Neo) adjuvant hormonal therapy was allowed, and prescribed to 143 patients (mainly high-risk), evenly distrib- uted over both arms. More details on baseline characteristics, ran- domization, and treatment were described earlier [1,6]. Clinical evaluation and PSA measurements were scheduled every 3–4 months in the first two years, and twice a year thereaf- ter. Bone scan and prostate biopsy were recommended for increas- ing PSA levels and/or clinical signs. The first location of tumor progression was documented in the study forms (local, distant, re- gional, or combination). 0167-8140/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.radonc.2013.09.026 ⇑ Corresponding author. Address: Department of Radiation Oncology, The Neth- erlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. E-mail address: w.heemsbergen@nki.nl (W.D. Heemsbergen). 1 Both authors have equally contributed to this paper. Radiotherapy and Oncology 110 (2014) 104–109 Contents lists available at ScienceDirect Radiotherapy and Oncology journal homepage: www.thegreenjournal.com