Erasmus MC : Prostate cancer – linac-based EBRT

Scope and outline
Research on linac-based external beam radiotherapy for prostate cancer is focused on (1) hypofractionation (on-going national trial), (2) prevention of erectile dysfunction, and (3) IGRT and minimization of CTV-to-PTV margins. The investigations do also include analyses of a previous Dutch randomized dose escalation trial, comparing 68 and 78 Gy.

Hypofractionation for prostate cancer could lead to improved therapeutic gain and patient comfort, as well as economic and logistic advantages. Erasmus MC is one of the initiators of a Dutch multicenter trial, comparing a standard schedule of 78 Gy in 2 Gy fractions (5 per week) with a hypofractionated schedule of 64.6 Gy in 3.4 Gy fractions (3 per week). The study investigates whether hypofractionation can yield a reduced relapse rate without increasing toxicity. 800 patients will be included in approximately 5 years.
Apart from gastro-intestinal and genito-urinary toxicity, particular attention is given to erectile dysfunction. Although one of the common sequelae in prostate radiotherapy, the dose-volume relations for potentially involved structures (e.g. penile bulb, crura, neurovascular bundles) are largely unknown and therefore remain under continuous investigation (Fig. 1).

Fig. 1. Average absolute dose–volume histograms (DVH) of the crura, the superiormost 1-cm segment of the crura and the penile bulb of patients with and without erectile dysfunction (ED) at 2 years after external beam radiotherapy. The error bars indicate 1 standard deviation. No statistically significant differences were found between the dose–volume parameters of patients with, respectively without ED (van der Wielen et al, 2007).

In today’s treatments, a high accuracy of daily delivered dose is achieved by fast, on-line corrections based on implanted fiducial markers, a crossfire of MV and kV imaging beams, and automated image analysis and couch repositioning (stereographic targeting (SGT), Mutanga et al, 2008).  SGT results in residue translational errors that are small compared to the dose gradients as well as compared to the residue rotation and deformation errors at the seminal vesicles (SV) and rectum. In this case, standard margin recipes (weighted combination of systematic and random error magnitudes) are of limited applicability. To derive appropriate margins, we therefore developed a system that rigorously determines the influence of all known geometric uncertainties on delivered dose, using distributions of measured geometric uncertainties (organ motion, rotation and deformation; van der Wielen et al, 2008; Fig. 2) and computer simulations (Figs 3 and 4).

Fig. 2. Deformation of the prostate and seminal vesicles. Standard deviations of the deformations have been projected color-coded onto the average shape of prostate and vesicles in the studied population. Left: view from superior-anterior. Right: view from  inferior-posterior (van der Wielen et al, 2008).

Fig. 3. Simulation of daily organ position, rotation and deformation within a fixed planned dose distribution Simulated CTVs include errors due to: rotation, deformation, intra-fraction motion and SGT setup residue errors.

Fig. 4.  Results from simulations of daily delivered dose in prostate (Left) and prostate + seminal vesicles (Right), using SGT for on-line corrections. The probability of CTV underdosage ( CTV out of PTV) is shown here for different prostate (P) and semincal vesicle (SV)  planning margins. The higher probabilities observed for the semincal vesicles (Right) are largely due to the significantly larger deformation errors (Fig. 2). The 5mm prostate clinical margin is sufficient in the presence of all measured uncertainties. For the vesicles, even a margin of 8 mm results in a significant probability of underdosage (Right).

Recently, the analysis of the Dutch dose-escalation trial, comparing 68 Gy with 78 Gy was updated (Al-Mamgani et al, 2008). After a median follow-up of 70 months, the freedom from failure (FFF) using the American Society for Therapeutic Radiology and Oncology definition was significantly better in the 78-Gy arm than in the 68-Gy arm (7-year FFF rate, 54% vs. 47%, respectively; p = 0.04). The FFF using the Phoenix definition was also significantly better in the 78-Gy arm than in the 68-Gy arm (7-year FFF rate, 56% vs. 45%, respectively; p = 0.03). However, no differences in freedom from clinical failure or overall survival were observed. The incidence of late Grade 2 or greater genitourinary toxicity was similar in both arms (40% and 41% at 7 years; p = 0.6). However, the cumulative incidence of late Grade 2 or greater gastrointestinal toxicity was increased in the 78-Gy arm compared with the 68-Gy arm (35% vs. 25% at 7 years; p = 0.04).

Fig. 5. Results of national trial
Kaplan-Meier curves of 7-year rates of freedom from failure (FFF) by dose randomization (68 vs. 78 Gy), defined according to American Society for Therapeutic Radiology Oncology (ASTRO) definition.

Selected publications

• Kassim I, Dirkx ML, Heijmen BJM. Evaluation of the dosimetric impact of non-exclusion of the rectum from the boost PTV in IMRT treatment plans for prostate cancer patients. Radiother Oncol. 2009 Mar 9. [Epub ahead of print].
  
• Al-Mamgani A, Heemsbergen WD, Peeters ST, Lebesque JV. Role of intensity-modulated radiotherapy in reducing toxicity in dose escalation for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2009;73(3):685-91. Epub 2008 Aug 19.
  
• Al-Mamgani A, van Putten WL, Heemsbergen WD, van Leenders GJ, Slot A, Dielwart MF, Incrocci L, Lebesque JV. Update of Dutch multicenter dose-escalation trial of radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2008 Nov 15;72(4):980-8. Epub 2008 May 19.
  
• Van der Wielen GJ, Mutanga TF, Incrocci L, Kirkels WJ, Vasquez Osorio EM, Hoogeman MS, Heijmen BJ, de Boer HC. Deformation of prostate and seminal vesicles relative to intraprostatic fiducial markers. Int J Radiat Oncol Biol Phys. 2008 Dec 1;72(5):1604-1611.e3.
  
• Mutanga TF, de Boer JCJ, van der Wielen GJ, Wentzler D, Barnhoorn J, Incrocci L, Heijmen BJM. Stereographic Targeting in Prostate Radiotherapy: Speed and Precision by Daily Automatic Positioning Corrections Using Kilovoltage/Megavoltage Image Pairs. Int J Radiat Oncol Biol Phys. 2008 Jul 15;71(4):1074-83. Epub 2008 Jan 22.
  
• Van der Wielen GJ, Hoogeman MS, Dohle GR, van Putten WL, Incrocci L. Dose-Volume Parameters of the Corpora Cavernosa Do Not Correlate with Erectile Dysfunction After External Beam Radiotherapy for Prostate Cancer: Results from A Dose-Escalation Trial. Int J Radiat Oncol Biol Phys. 2008 Jul 1;71(3):795-800. Epub 2007 Dec 31.
  
• Van der Wielen GJ, Mulhall JP, Incrocci L. Erectile dysfunction after radiotherapy for prostate cancer and radiation dose to the penile structures: a critical review. Radiother Oncol. 2007 Aug;84(2):107-13.
  
• Heemsbergen WD, Hoogeman MS, Witte MG, Peeters ST, Incrocci L, Lebesque JV. Increased risk of biochemical and clinical failure for prostate patients with a large rectum at radiotherapy planning: results from the Dutch trial of 68 GY versus 78 Gy.Int J Radiat Oncol Biol Phys. 2007 Apr 1;67(5):1418-24.
  
• Incrocci L, Slagter C, Slob AK, Hop WC. A randomized, double-blind, placebo-controlled, cross-over study to assess the efficacy of tadalafil (Cialis) in the treatment of erectile dysfunction following three-dimensional conformal external-beam radiotherapy for prostatic carcinoma.Int J Radiat Oncol Biol Phys. 2006 Oct 1;66(2):439-44.
  
• Koper PC, Heemsbergen WD, Hoogeman MS, Jansen PP, Hart GA, Wijnmaalen AJ, van Os M, Boersma LJ, Lebesque JV, Levendag P. Impact of volume and location of irradiated rectum wall on rectal blood loss after radiotherapy of prostate cancer.Int J Radiat Oncol Biol Phys. 2004 Mar 15;58(4):1072-82.
  
• Stroom JC, Koper PC, Korevaar GA, van Os M, Janssen M, de Boer JCJ, Levendag PC, Heijmen BJM. Internal organ motion in prostate cancer patients treated in prone and supine treatment position. Radiother Oncol. 1999 Jun;51(3):237-48.

Contacts
Dr. L. Incrocci, Dr. J.C.J. de Boer and Dr. A. Al-Mamgani