International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation
Optimization of Radiation Therapy Techniques for Prostate Cancer With Prostate-Rectum Spacers: A Systematic Review Gary Mok, MD, FRCPC,*,y,z Eileen Benz,* Jean-Paul Vallee, MD,x Raymond Miralbell, MD,* and Thomas Zilli, MD* *Department of Radiation Oncology, Geneva University Hospital, Geneva, Switzerland; yDepartment of Radiation Oncology, Centre Inte´gre´ de Cance´rologie de Laval, Centre de Sante´ et de Services Sociaux de Laval, Laval, Que´bec, Canada; zDepartment of Radiology, Radiation Oncology, and Nuclear Medicine, Centre Hospitalier Universitaire de Montre´al, Montre´al, Que´bec, Canada; and x Department of Radiology, Geneva University Hospital, Geneva, Switzerland Received Feb 17, 2014, and in revised form May 12, 2014. Accepted for publication Jun 18, 2014.
Dose-escalated radiation therapy for localized prostate cancer improves disease control but is also associated with worse rectal toxicity. A spacer placed between the prostate and rectum can be used to displace the anterior rectal wall outside of the high-dose radiation regions and potentially minimize radiation-induced rectal toxicity. This systematic review focuses on the published data regarding the different types of commercially available prostate-rectum spacers. Dosimetric results and preliminary clinical data using prostate-rectum spacers in patients with localized prostate cancer treated by curative radiation therapy are compared and discussed. Ó 2014 Elsevier Inc.
Introduction Randomized phase 3 clinical trials have demonstrated improved rates of locoregional and biochemical control for higher doses of conventionally fractionated external beam radiation therapy (RT) in the curative treatment of prostate cancer (1-5), whereas nonrandomized data suggest a reduction in distant metastasis rates (6-8). Despite these improvements in disease control, dose-escalated RT has also been associated with increased rates of rectal toxicity (9). Up to 2-fold increases in radiation-induced rectal toxicities have been reported in dose-escalated RT arms
Reprint requests to: Dr Thomas Zilli, MD, Radiation Oncology Department, Geneva University Hospital, CH-1211 Geneva 14, Switzerland. Tel: (41) 22 38 27 090; E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 90, No. 2, pp. 278e288, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2014.06.044
compared to lower dose control arms in a number of randomized studies (2, 10, 11). The original dose escalation studies were conceived and conducted nearly 20 years ago during the era of 2- and 3dimensional conformal RT (3D-CRT). RT techniques and technologies have progressed significantly, and many RT oncology centers routinely treat prostate cancer patients with intensity modulated RT (IMRT), and volumetric modulated arc therapy (VMAT). These techniques allow improved dose homogeneity and reductions in radiation dose to normal structures, such as the bladder and rectal wall. The development of image guided RT (IGRT), such as
Conflict of interest: none.
Volume 90 Number 2 2014
cone beam computed tomography, kilovoltage imaging of implanted fiducials or ultrasonographic visualization of the prostate, have allowed for reduction in planning target volumes (PTV) and consequently reductions of irradiated normal tissue volume. Low-dose-rate (LDR) and high-dose rate (HDR) brachytherapy (BT) permit further dose escalation to the prostate with relatively fewer rectal doses than with external beam RT (EBRT) to equivalent doses. These improvements in RT delivery and technique have led to an improvement in prostate cancer outcomes while reducing treatment-related morbidity (12-14). Despite the refined techniques and technologies, the anatomic proximity of the rectum to the prostate remains problematic, with high doses of RT delivered to the anterior rectal wall to assure adequate treatment of the prostate. Increasing the separation between the anterior rectal wall and the prostate gland can be achieved with the injection of a biodegradable substance in the prostate-rectum (PR) space. The increased PR separation displaces the anterior rectal wall away from the prostate and out of the regions of high-dose RT. The net effect is a reduction in maximum dose to the rectum and the total volume of irradiated rectum. The implanted spacer remains in place over the course of RT treatment and completely degrades over the course of several months. The objective of this critical review was to compare the different commercially available spacers with regard to their indications, dosimetric effects, and potential clinical advantages.
Methods and Materials A systematic review of the literature was performed in the MEDLINE database, using individual keywords or combinations of the keywords “prostate cancer,” “radiation therapy,” “rectal toxicity,” “spacer,” “hydrogel,” “hyaluronic gel,” “collagen,” and “biodegradable balloon.” Published articles and conference abstracts from preclinical and clinical studies were included. A total of 11 studies involving human prostate cancer patients in whom PR spaces were implanted were identified in 6 studies using implants in patients treated with EBRT and 5 studies treating patients with BT. Four studies used polyethylene-glycol (PEG) spacers, 5 used hyaluronic acid (HA) spacers, 1 study used implanted biodegradable balloons, and 1 study used collagen implants. An additional 3 preclinical studies were identified, 2 of which used PEG spacers and 1 used a biodegradable balloon spacer.
Results Polyethylene-glycol hydrogel Characteristics PEG hydrogel is a mesh-like network of PEG oligomers and polymers capable of retaining large quantities of water. The end result is a stable, flexible gel-like structure that is
Prostate-rectum spacers
279
primarily used as scaffolding for cell culture experiments. Several studies have demonstrated an excellent PEG hydrogel biocompatibility profile in humans, without evidence of serious inflammatory reactions or transmission of infectious agents (15-17). Products composed of PEG hydrogel are U.S. Food and Drug Administration approved and have been evaluated as a dural sealant in neurosurgical procedures and as scaffolding for bone regeneration around dental implants (15, 16). SpaceOAR (Augmenix, Waltham, MA) is a commercially developed PEG hydrogel designed specifically as a PR spacer for use in prostate cancer RT. The PEG hydrogel spacer will maintain integrity for 3 months prior to degradation by hydrolysis of ester bridges with elimination via renal metabolism (18). Application technique This spacer can be implanted in the ambulatory setting, using local, epidural, or general anesthesia. With the patient in the lithotomy position, an 18-gauge needle is inserted between Denonvilliers fascia and the anterior rectal wall under transrectal ultrasonography (TRUS) guidance. Once the needle is in the correct position, saline water is injected to create a potential space between the prostate and rectum. Ten milliliters of PEG hydrogel liquid are injected into this hydrodissected space. The PEG hydrogel will undergo polymerization in situ to form a gellike structure within seconds of injection (18, 19). Implantation time is relatively short, with a mean overall procedure time of 16 minutes (7.8 min) from time of TRUS insertion to TRUS removal (18). Prostate-rectum separation The insertion of a PEG hydrogel spacer creates a PR space ranging from 7 to 15 mm (18, 20-23). Stability of the spacer during the course of RT has been reported by 3 studies, with confirmation of comparable mean PR separations after PEG hydrogel implantation and imaging preformed during the last week of RT (18, 20, 24). Complete or nearly complete absorption occurs at 6 months postimplantation, and PR separation regresses to preimplantation distances (18, 21). Dosimetric profiles and clinical outcomes A preclinical study reporting the effect of implanted PEG spacers on dosimetric profiles was completed in 5 human cadavers, using pre- and postimplantation computed tomography (CT) simulation scans to generate IMRT plans (78 Gy in 39 fractions) (17). That study reported the mean rectal volume receiving 70 Gy (V70Gy) at 19.9% and 4.5% in cadavers that did not receive implants and those that did, respectively. This correlated to a relative reduction of 79.9% (61.0%-98.8%, P
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation
Optimization of Radiation Therapy Techniques for Prostate Cancer With Prostate-Rectum Spacers: A Systematic Review Gary Mok, MD, FRCPC,*,y,z Eileen Benz,* Jean-Paul Vallee, MD,x Raymond Miralbell, MD,* and Thomas Zilli, MD* *Department of Radiation Oncology, Geneva University Hospital, Geneva, Switzerland; yDepartment of Radiation Oncology, Centre Inte´gre´ de Cance´rologie de Laval, Centre de Sante´ et de Services Sociaux de Laval, Laval, Que´bec, Canada; zDepartment of Radiology, Radiation Oncology, and Nuclear Medicine, Centre Hospitalier Universitaire de Montre´al, Montre´al, Que´bec, Canada; and x Department of Radiology, Geneva University Hospital, Geneva, Switzerland Received Feb 17, 2014, and in revised form May 12, 2014. Accepted for publication Jun 18, 2014.
Dose-escalated radiation therapy for localized prostate cancer improves disease control but is also associated with worse rectal toxicity. A spacer placed between the prostate and rectum can be used to displace the anterior rectal wall outside of the high-dose radiation regions and potentially minimize radiation-induced rectal toxicity. This systematic review focuses on the published data regarding the different types of commercially available prostate-rectum spacers. Dosimetric results and preliminary clinical data using prostate-rectum spacers in patients with localized prostate cancer treated by curative radiation therapy are compared and discussed. Ó 2014 Elsevier Inc.
Introduction Randomized phase 3 clinical trials have demonstrated improved rates of locoregional and biochemical control for higher doses of conventionally fractionated external beam radiation therapy (RT) in the curative treatment of prostate cancer (1-5), whereas nonrandomized data suggest a reduction in distant metastasis rates (6-8). Despite these improvements in disease control, dose-escalated RT has also been associated with increased rates of rectal toxicity (9). Up to 2-fold increases in radiation-induced rectal toxicities have been reported in dose-escalated RT arms
Reprint requests to: Dr Thomas Zilli, MD, Radiation Oncology Department, Geneva University Hospital, CH-1211 Geneva 14, Switzerland. Tel: (41) 22 38 27 090; E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 90, No. 2, pp. 278e288, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2014.06.044
compared to lower dose control arms in a number of randomized studies (2, 10, 11). The original dose escalation studies were conceived and conducted nearly 20 years ago during the era of 2- and 3dimensional conformal RT (3D-CRT). RT techniques and technologies have progressed significantly, and many RT oncology centers routinely treat prostate cancer patients with intensity modulated RT (IMRT), and volumetric modulated arc therapy (VMAT). These techniques allow improved dose homogeneity and reductions in radiation dose to normal structures, such as the bladder and rectal wall. The development of image guided RT (IGRT), such as
Conflict of interest: none.
Volume 90 Number 2 2014
cone beam computed tomography, kilovoltage imaging of implanted fiducials or ultrasonographic visualization of the prostate, have allowed for reduction in planning target volumes (PTV) and consequently reductions of irradiated normal tissue volume. Low-dose-rate (LDR) and high-dose rate (HDR) brachytherapy (BT) permit further dose escalation to the prostate with relatively fewer rectal doses than with external beam RT (EBRT) to equivalent doses. These improvements in RT delivery and technique have led to an improvement in prostate cancer outcomes while reducing treatment-related morbidity (12-14). Despite the refined techniques and technologies, the anatomic proximity of the rectum to the prostate remains problematic, with high doses of RT delivered to the anterior rectal wall to assure adequate treatment of the prostate. Increasing the separation between the anterior rectal wall and the prostate gland can be achieved with the injection of a biodegradable substance in the prostate-rectum (PR) space. The increased PR separation displaces the anterior rectal wall away from the prostate and out of the regions of high-dose RT. The net effect is a reduction in maximum dose to the rectum and the total volume of irradiated rectum. The implanted spacer remains in place over the course of RT treatment and completely degrades over the course of several months. The objective of this critical review was to compare the different commercially available spacers with regard to their indications, dosimetric effects, and potential clinical advantages.
Methods and Materials A systematic review of the literature was performed in the MEDLINE database, using individual keywords or combinations of the keywords “prostate cancer,” “radiation therapy,” “rectal toxicity,” “spacer,” “hydrogel,” “hyaluronic gel,” “collagen,” and “biodegradable balloon.” Published articles and conference abstracts from preclinical and clinical studies were included. A total of 11 studies involving human prostate cancer patients in whom PR spaces were implanted were identified in 6 studies using implants in patients treated with EBRT and 5 studies treating patients with BT. Four studies used polyethylene-glycol (PEG) spacers, 5 used hyaluronic acid (HA) spacers, 1 study used implanted biodegradable balloons, and 1 study used collagen implants. An additional 3 preclinical studies were identified, 2 of which used PEG spacers and 1 used a biodegradable balloon spacer.
Results Polyethylene-glycol hydrogel Characteristics PEG hydrogel is a mesh-like network of PEG oligomers and polymers capable of retaining large quantities of water. The end result is a stable, flexible gel-like structure that is
Prostate-rectum spacers
279
primarily used as scaffolding for cell culture experiments. Several studies have demonstrated an excellent PEG hydrogel biocompatibility profile in humans, without evidence of serious inflammatory reactions or transmission of infectious agents (15-17). Products composed of PEG hydrogel are U.S. Food and Drug Administration approved and have been evaluated as a dural sealant in neurosurgical procedures and as scaffolding for bone regeneration around dental implants (15, 16). SpaceOAR (Augmenix, Waltham, MA) is a commercially developed PEG hydrogel designed specifically as a PR spacer for use in prostate cancer RT. The PEG hydrogel spacer will maintain integrity for 3 months prior to degradation by hydrolysis of ester bridges with elimination via renal metabolism (18). Application technique This spacer can be implanted in the ambulatory setting, using local, epidural, or general anesthesia. With the patient in the lithotomy position, an 18-gauge needle is inserted between Denonvilliers fascia and the anterior rectal wall under transrectal ultrasonography (TRUS) guidance. Once the needle is in the correct position, saline water is injected to create a potential space between the prostate and rectum. Ten milliliters of PEG hydrogel liquid are injected into this hydrodissected space. The PEG hydrogel will undergo polymerization in situ to form a gellike structure within seconds of injection (18, 19). Implantation time is relatively short, with a mean overall procedure time of 16 minutes (7.8 min) from time of TRUS insertion to TRUS removal (18). Prostate-rectum separation The insertion of a PEG hydrogel spacer creates a PR space ranging from 7 to 15 mm (18, 20-23). Stability of the spacer during the course of RT has been reported by 3 studies, with confirmation of comparable mean PR separations after PEG hydrogel implantation and imaging preformed during the last week of RT (18, 20, 24). Complete or nearly complete absorption occurs at 6 months postimplantation, and PR separation regresses to preimplantation distances (18, 21). Dosimetric profiles and clinical outcomes A preclinical study reporting the effect of implanted PEG spacers on dosimetric profiles was completed in 5 human cadavers, using pre- and postimplantation computed tomography (CT) simulation scans to generate IMRT plans (78 Gy in 39 fractions) (17). That study reported the mean rectal volume receiving 70 Gy (V70Gy) at 19.9% and 4.5% in cadavers that did not receive implants and those that did, respectively. This correlated to a relative reduction of 79.9% (61.0%-98.8%, P
![[Prostate-rectum spacers: optimization of prostate cancer irradiation].](/assets/img/hold.png)
