Background
Prospective trials have demonstrated the advantage of dose-escalated radiotherapy for the biochemical and clinical control of prostate cancer. This benefit observed with three-dimensional conformational irradiation is counterbalanced by an increase of the urinary and digestive toxicities [
1‐
4]. The Medical Research Council (MRC) conducted the MRC 01 randomized multicenter trial [
2] comparing a conformal RT (2 Gy / session) delivering either 64 Gy or 74 Gy, in combination with neoadjuvant hormone therapy during 3 to 6 months. The 5-year biochemical relapse–free survival was 71% versus 60% (
p = 0,0007) with 74 and 64 Gy respectively. In France the French Group for the Study of Uro-Genital Tumors (GETUG) conducted the GETUG 06 multicenter trial [
3]. Dose escalation from 70 to 80 Gy provided a better 5-year biochemical outcome with slightly greater toxicity. Peeters and al. [
4] reported the Dutch trial evaluating dose-response for 664 randomized patients in radiotherapy for prostate cancer. Patients were randomly assigned to a tridimensional conformal radiation treatment of either 68 Gy or 78 Gy (in 2 Gy fractions). The 5-year biological relapse–free survival was 54 and 64% respectively (
p = 0.02). In these randomized trials dose escalation improved biological relapse free survival but was associated with higher rate of rectal toxicity.
There are no randomized trials comparing conformational three-dimensional conformational irradiation with intensity modulated radiation therapy (IMRT), but experiments conducted by several teams, including historically that of the Memorial Sloan-Kettering Cancer Center (MSKCC) [
5] showed that it was possible to deliver increased radiation doses to the prostate while decreasing frequency of urinary and digestive complications of this “high dose” RT. However this approach imposes a very strict control of the position of the target volume (prostate) under the accelerator in order to translate this dosimetric advantage into clinical benefit. Image Guided Radiotherapy (IGRT) guarantees this positioning accuracy. First clinical benefits of using IGRT in combination with IMRT were published in 2012 by the MSKCC team in a retrospective analysis of 180 “IGRT” patients (fiducial markers implanted in the prostate and daily kV imaging) treated with 86.4 Gy, whatever the initial risk group, between 2008 and 2009 compared with a cohort of patients treated without IGRT between 2006 and 2007 [
6]. Patients in high risk group in this study showed a significant improvement in biochemical control (from 77 to 97%,
p = 0.041). For all analyzed patients, IGRT would lead to a significant reduction in urinary late toxicity: grade ≥ 2 toxicity rate decreased from 20 to 10.4% at 3 years thanks to the IGRT [
6]. Despite significant technical advances (IMRT, IGRT) rectum dose remains a limiting factor in dose escalation. Although the role of moderate doses has been recently shown, severe toxicity is strongly related to high doses. Patients with V70 below or above 26% had a risk of grade 2 rectal morbidity of 13 and 54%, respectively [
7].
Thanks to innovative techniques, rectal side effects could be reduced by moving the prostate away from the rectal wall through an injection of a biodegradable substance that creates a space in anterior perirectal fat. To date most of the evaluated devices were polyethylen glycol (PEG) and hyaluronic acid (HA). In Mok et al. review, a total of 11 studies involving human prostate cancer patients were identified in 6 studies using implants in patients treated with external beam radiotherapy and 5 studies treating patients with brachytherapy (BT). Four studies used PEG spacers, 5 used HA spacers, 1 study used implanted biodegradable balloons, and 1 study used collagen implants [
8]. Prostate rectum (PR) separation created by the different PR spacers varied between 7 and 20 mm and was largely dependent on implantation protocol. The increased PR separation was associated with improved dosimetric rectal profiles. Relative reduction of V70 Gy ranged from 46 to 61%; V40 and V60 Gy were decreased too, from 40 to 65%. The use of prophylactic antibiotic therapy is estimated to reduce the risk of infection to less than 5% [
8].
Outcomes following PEG spacer implantation was assessed by a prospective multicenter randomized controlled trial [
9]. Computed tomography (CT) and magnetic resonance imaging (MRI) scans for treatment planning were used for 222 patients with prostate cancer with clinical stage T1 or T2. They were randomized to receive spacer implantation or no implantation (control). Image guided IMRT (79.2 Gy in 1.8-Gy fractions) was used. In this trial, spacer implantation was rated as “easy” or “very easy” in 98.7% of the patients. The hydrogel placement success rate was 99%. Overall acute rectal adverse event rates were the same between groups, but fewer spacer patients presented with rectal pain (
p = 0.02). A significant decrease in late (3 to 15 months) rectal toxicity in the spacer group was noted (
p = 0.04), with a 2.0 and 7.0% late rectal toxicity incidence in the spacer and control arms, respectively. At 6, 12, and 15 months, a lower ratio of spacer patients presented with bowel quality of life (QOL) decrease. 11.6% of spacer patients and 21.4% of control patients experienced 10-point decrease at 15 months (
p = 0.087). Furthermore, at 6 months, 8.8% of spacer patients and 22.2% of control patients had 10-point urinary decreases (
p = 0.003). At 3-years patients on the spacer group had less bowel toxicity and less decrease in both urinary and bowel QOL in comparison to control patients. On the control arm, 41% of patients presented with a detectable decline in bowel QOL (5-points) by patient reported outcomes, and 21% had a more serious decline (10-points). These rates were both reduced by 70% on the spacer arm (14 and 5%, respectively) [
10].
The use of HA spacers in hypofractionated RT regimens were evaluated by Chapet et al. This phase II study aims to assess the rates of late rectal toxicities of grade ≥ 2 after hypofractionated radiotherapy of prostate cancer of 62 Gy in 20 fractions of 3.1 Gy with an HA spacer. Thirty-six patients with low- to intermediate-risk prostate cancer according to the D’Amico classification are included in the present protocol. As part of this phase 2 study, the patients received a 10 cm
3 transperineal HA injection. HA spacer significantly reduced rectal wall dose and could allow a dose escalation from 6.5 Gy to 8.5 Gy per fraction without increasing the dose to the rectum. A phase 2 study is under way to assess the rate of acute and late rectal toxicities when SBRT (5 × 7.5 Gy) is combined with an injection of HA [
11]. Other trials are currently evaluating rectal spacer in patients treated by stereotactic radiotherapy [
https://clinicaltrials.gov/ct2/show/NCT02353832,
https://clinicaltrials.gov/ct2/show/NCT02911922].
A biodegradable balloon can also be used: Bioprotect has designed an adapted device for this implantation procedure. Animal studies have confirmed its efficacy and also its good tolerance [
12]. ProSpace® system is a deflated balloon made of a biodegradable polymer which is inserted perineally after hydrodissection thanks to an introducer.
The implantation procedure is performed under general anesthesia through a small perineal incision [
13,
14]. A multi-institutional phase II study has been carried out in 6 centers using IMRT or 3D conformal RT [
13]. Twenty three patients were analyzable and balloon was biodegraded within 6 months. The space between the prostate and rectum created by balloon implantation was about 2 cm, rising from 0.22 ± 0.2 cm to 2.47 ± 0.47 cm. This gap lasted during all the RT. In this first study three patients experienced acute urinary retention which resolved quickly following bladder drainage. In Melchert et al. [
14] the prostate rectal wall separation resulted in an average reduction of the rectal V70% by 55.3% (±16.8%), V80% by 64.0% (±17.7%), V90% by 72.0% (±17.1%) in 26 patients.
Acknowledgements
S. Marchant for writing assistance.
List of investigators:
Principal Investigators:
David PASQUIER, Centre Oscar Lambret, Lille, France.
Franck DARLOY, Centre Léonard de Vinci, Dechy, France.
Alain TOLEDANO Clinique Hartmann, Levallois-Perret, France.
Denis FOSTER, Centre de Cancérologie Paris Nord, Sarcelles, France.
Co-coordonnator: Igor LATORZEFF.
Co-investigators:
François BONODEAU, Centre Oscar Lambret, Lille, France.
Xavier MIRABEL, Centre Oscar Lambret, Lille, France.
Gaelle JIMENEZ, Clinique Pasteur, Toulouse, France.
Louis GRAS, Centre Léonard de Vinci, Dechy, France.
Damien CARLIER, Centre Léonard de Vinci, Dechy, France.
Denis FOSTER, Clinique Hartmann, Levallois-Perret, France.
Hanah LAMALLEM-ALGHAZIRI, Clinique Hartmann, Levallois-Perret, France.
Marc BOLLET, Clinique Hartmann, Levallois-Perret, France.
Muriel BOTTI, Centre de Cancérologie Paris Nord, Sarcelles, France.
Cyril LAPORTE, Centre de Cancérologie Paris Nord, Sarcelles, France.
Guillaume SERGENT, Centre de Cancérologie Paris Nord, Sarcelles, France.