Who Benefits From a Prostate Rectal Spacer? Secondary Analysis of a Phase III Trial.

PURPOSE: Previously a phase III trial of a hydrogel rectal spacer during prostate radiation therapy found decreased toxicity and a clinically significant improvement in bowel quality of life (QOL) at 3 years by the Expanded Prostate Cancer Index. We performed a secondary analysis to identify men less likely to benefit. METHODS AND MATERIALS: Clinical and dosimetric data for the 222 patients enrolled on the SpaceOAR phase III trial were analyzed. The volume of rectum treated to 70 Gy (V70) and the quantitative analysis of normal tissue effects in the clinic (QUANTEC) rectal dose goals were used as surrogates for clinical benefit and plan quality. Mean bowel QOL was assessed at 15 and 36 months posttreatment and the likelihood of 1× (5 points) or 2× (10 points) minimally important difference changes were assessed. RESULTS: Rectal V70 was correlated with physician scored toxicity (P = .033) and was used as a surrogate for plan quality. There was no correlation between prostate volume and rectal V70 (r = 0.077). Rectal V70 pre- and post-hydrogel was 13% and 3% for the smallest prostates (<40 mL) and 12% and 2% for the largest (>80 mL). The relative reduction in rectal V70 of 78% did not vary by prespacer V70, but the absolute reduction was greater for a higher V70. All spacer plans met the 5 QUANTEC rectal dose constraints, although 92% of control plans met all constraints. At 3 years, those not meeting all QUANTEC goals had a 15.0-point (standard deviation 15.1) decline, control patients meeting QUANTEC goals had a 4.0-point (9.5) decline, and spacer had >0.5 (7.6; P < .01). Previous surgery was not correlated with QOL (P = .8). Across prognostic groups, including age, body mass index, previous surgery, target volume, or quality of radiation plans, there was no statistically significant heterogeneity in the relative benefit of spacer in decreasing the risk of 1× or 2× the minimally important difference declines. CONCLUSIONS: There was little heterogeneity in the likelihood of spacer reducing the risk of declines in bowel QOL across clinical and dosimetric variables. Even for the >95% of plans meeting QUANTEC rectal criteria, hydrogel spacer provided potentially meaningful benefits.

Sexual quality of life following prostate intensity modulated radiation therapy (IMRT) with a rectal/prostate spacer: Secondary analysis of a phase 3 trial.

BACKGROUND: We previously reported the results of a phase 3 trial evaluating a prostate/rectal hydrogel spacer during prostate intensity modulated radiation therapy, which resulted in decreased rectal dose and toxicity and less decline in bowel quality of life (QOL). A secondary analysis was performed to correlate penile bulb dose and sexual QOL. METHODS AND MATERIALS: Sexual QOL was measured with the Expanded Prostate Cancer Index Composite (EPIC) by mean scores, the proportion of patients with a minimal clinically important difference (MID), and analyses of the different items composing the sexual domain. RESULTS: A total of 222 men enrolled with median follow-up of 37 months. Hydrogel reduced penile bulb mean dose, maximum dose, and percentage of penile bulb receiving 10 to 30 Gy (all P < .05) with mean dose indirectly correlated with erections sufficient for intercourse at 15 months (P = .03). Baseline EPIC was low (53 [standard deviation ± 24]) with no difference between arms (P > .1). A total of 41% (88/222) of men had adequate baseline sexual QOL (EPIC >60 (mean, 77 [± 8.3]). This subgroup at 3 years had better sexual function (P = .03) with a spacer with a smaller difference in sexual bother (P = .1), which resulted in a higher EPIC summary on the spacer arm (58 [±24.1] vs control 45 [± 24.4]) meeting threshold for MID without statistical significance (P = .07). There were statistically nonsignificant differences favoring spacer for the proportion of men with MID and 2× MID declines in sexual QOL with 53% vs 75% having an 11-point decline (P = .064) and 41% vs 60% with a 22-point decline (P = .11). At 3 years, more men potent at baseline and treated with spacer had "erections sufficient for intercourse" (control 37.5% vs spacer 66.7%, P = .046) as well as statistically higher scores on 7 of 13 items in the sexual domain (all P < .05). CONCLUSIONS: The use of a hydrogel spacer decreased dose to the penile bulb, which was associated with improved erectile function compared with the control group based on patient-reported sexual QOL.

Continued Benefit to Rectal Separation for Prostate Radiation Therapy: Final Results of a Phase III Trial.

PURPOSE: SpaceOAR, a Food and Drug Administration-approved hydrogel intended to create a rectal-prostate space, was evaluated in a single-blind phase III trial of image guided intensity modulated radiation therapy. A total of 222 men were randomized 2:1 to the spacer or control group and received 79.2 Gy in 1.8-Gy fractions to the prostate with or without the seminal vesicles. The present study reports the final results with a median follow-up period of 3 years. METHODS AND MATERIALS: Cumulative (Common Terminology Criteria for Adverse Events, version 4.0) toxicity was evaluated using the log-rank test. Quality of life (QOL) was examined using the Expanded Prostate Cancer Index Composite (EPIC), and the mean changes from baseline in the EPIC domains were tested using repeated measures models. The proportions of men with minimally important differences (MIDs) in each domain were tested using repeated measures logistic models with prespecified thresholds. RESULTS: The 3-year incidence of grade ≥1 (9.2% vs 2.0%; P=.028) and grade ≥2 (5.7% vs 0%; P=.012) rectal toxicity favored the spacer arm. Grade ≥1 urinary incontinence was also lower in the spacer arm (15% vs 4%; P=.046), with no difference in grade ≥2 urinary toxicity (7% vs 7%; P=0.7). From 6 months onward, bowel QOL consistently favored the spacer group (P=.002), with the difference at 3 years (5.8 points; P<.05) meeting the threshold for a MID. The control group had a 3.9-point greater decline in urinary QOL compared with the spacer group at 3 years (P<.05), but the difference did not meet the MID threshold. At 3 years, more men in the control group than in the spacer group had experienced a MID decline in bowel QOL (41% vs 14%; P=.002) and urinary QOL (30% vs 17%; P=.04). Furthermore, the control group were also more likely to have experienced large declines (twice the MID) in bowel QOL (21% vs 5%; P=.02) and urinary QOL (23% vs 8%; P=.02). CONCLUSIONS: The benefit of a hydrogel spacer in reducing the rectal dose, toxicity, and QOL declines after image guided intensity modulated radiation therapy for prostate cancer was maintained or increased with a longer follow-up period, providing stronger evidence for the benefit of hydrogel spacer use in prostate radiation therapy.

Hydrogel Spacer Prospective Multicenter Randomized Controlled Pivotal Trial: Dosimetric and Clinical Effects of Perirectal Spacer Application in Men Undergoing Prostate Image Guided Intensity Modulated Radiation Therapy.

PURPOSE: Perirectal spacing, whereby biomaterials are placed between the prostate and rectum, shows promise in reducing rectal dose during prostate cancer radiation therapy. A prospective multicenter randomized controlled pivotal trial was performed to assess outcomes following absorbable spacer (SpaceOAR system) implantation. METHODS AND MATERIALS: Overall, 222 patients with clinical stage T1 or T2 prostate cancer underwent computed tomography (CT) and magnetic resonance imaging (MRI) scans for treatment planning, followed with fiducial marker placement, and were randomized to receive spacer injection or no injection (control). Patients received postprocedure CT and MRI planning scans and underwent image guided intensity modulated radiation therapy (79.2 Gy in 1.8-Gy fractions). Spacer safety and impact on rectal irradiation, toxicity, and quality of life were assessed throughout 15 months. RESULTS: Spacer application was rated as "easy" or "very easy" 98.7% of the time, with a 99% hydrogel placement success rate. Perirectal spaces were 12.6 ± 3.9 mm and 1.6 ± 2.0 mm in the spacer and control groups, respectively. There were no device-related adverse events, rectal perforations, serious bleeding, or infections within either group. Pre-to postspacer plans had a significant reduction in mean rectal V70 (12.4% to 3.3%, P<.0001). Overall acute rectal adverse event rates were similar between groups, with fewer spacer patients experiencing rectal pain (P=.02). A significant reduction in late (3-15 months) rectal toxicity severity in the spacer group was observed (P=.04), with a 2.0% and 7.0% late rectal toxicity incidence in the spacer and control groups, respectively. There was no late rectal toxicity greater than grade 1 in the spacer group. At 15 months 11.6% and 21.4% of spacer and control patients, respectively, experienced 10-point declines in bowel quality of life. MRI scans at 12 months verified spacer absorption. CONCLUSIONS: Spacer application was well tolerated. Increased perirectal space reduced rectal irradiation, reduced rectal toxicity severity, and decreased rates of patients experiencing declines in bowel quality of life. The spacer appears to be an effective tool, potentially enabling advanced prostate RT protocols.

A Phase II safety and effect on time to tumor progression study of intratumoral light infusion technology using talaporfin sodium in patients with metastatic colorectal cancer.

BACKGROUND AND OBJECTIVES: Twenty-seven patients with refractory liver metastases from colorectal cancer took part in a Phase II study of the light infusion technology (Litx) light-activated drug/device system to assess safety and evaluate time to tumor progression (TTP). METHODS: Litx consists of the light-activated drug, talaporfin sodium (LS11), activated intratumorally by a catheter-like array of light-emitting diodes (LEDs). After placement of the array via ultrasound or computed tomography (CT) guidance, LS11 was administered intravenously, followed 15-60 min later by light infusion for 2.8 hr. Patients were assessed for adverse events and tumor response using physical examination, laboratory values, and CT scan evaluation over a period of 60 days. RESULTS: The observed occurrence of Litx treatment-related adverse events was minimal and cumulative toxicity did not occur when combined with chemotherapy. Assessment of TTP and tumor response rate, although statistically non-robust, suggest potential improvement. CONCLUSIONS: The Litx system was shown to be safe for treating liver metastases from colorectal cancer and there was no cumulative toxicity when combined with standard systemic therapy. Preliminary assessments of TTP and tumor response rate justify further evaluation in a Phase III follow-up study.

Stereotactic hypofractionated accurate radiotherapy of the prostate (SHARP), 33.5 Gy in five fractions for localized disease: first clinical trial results.

PURPOSE: To evaluate the feasibility and toxicity of stereotactic hypofractionated accurate radiotherapy (SHARP) for localized prostate cancer. METHODS AND MATERIALS: A Phase I/II trial of SHARP performed for localized prostate cancer using 33.5 Gy in 5 fractions, calculated to be biologically equivalent to 78 Gy in 2 Gy fractions (alpha/beta ratio of 1.5 Gy). Noncoplanar conformal fields and daily stereotactic localization of implanted fiducials were used for treatment. Genitourinary (GU) and gastrointestinal (GI) toxicity were evaluated by American Urologic Association (AUA) score and Common Toxicity Criteria (CTC). Prostate-specific antigen (PSA) values and self-reported sexual function were recorded at specified follow-up intervals. RESULTS: The study includes 40 patients. The median follow-up is 41 months (range, 21-60 months). Acute toxicity Grade 1-2 was 48.5% (GU) and 39% (GI); 1 acute Grade 3 GU toxicity. Late Grade 1-2 toxicity was 45% (GU) and 37% (GI). No late Grade 3 or higher toxicity was reported. Twenty-six patients reported potency before therapy; 6 (23%) have developed impotence. Median time to PSA nadir was 18 months with the majority of nadirs less than 1.0 ng/mL. The actuarial 48-month biochemical freedom from relapse is 70% for the American Society for Therapeutic Radiology and Oncology definition and 90% by the alternative nadir + 2 ng/mL failure definition. CONCLUSIONS: SHARP for localized prostate cancer is feasible with minimal acute or late toxicity. Dose escalation should be possible.

Hyperbaric oxygen therapy for radiation induced proctopathy in men treated for prostate cancer.

PURPOSE: Radiation proctitis is a common complication following external beam radiation therapy and brachytherapy for prostate cancer. While 95% percent of radiation induced proctitis is temporary and self-limiting, up to 5% of patients experience toxicities that are refractory to conservative management. Hyperbaric oxygen has a well-defined role in treating chronic wounds, osteomyelitis, hemorrhagic cystitis and necrotizing fasciitis. We reviewed our experience with hyperbaric oxygen therapy for radiation induced proctitis in patients undergoing radiation treatment for prostate cancer. MATERIALS AND METHODS: From October 1998 to December 2003, 27 patients with radiation induced proctitis secondary to brachytherapy (4), external beam radiation therapy (16) or combined modality (7) for prostate cancer were treated with hyperbaric oxygen therapy at Virginia Mason Medical Center in Seattle, Washington. In all patients primary medical or endoscopic management had failed. Patients received 100% oxygen in a multiplace hyperbaric chamber at a pressure of 2.4 atmospheres absolute for 90 minutes 5 to 7 days weekly for an average of 36 sessions (range 29 to 60). Data were collected from a retrospective review of medical records following approval by the Institutional Review Board at Virginia Mason Medical Center. RESULTS: All 27 men completed the planned course of therapy. Of patients with bleeding 48% showed complete resolution after therapy, while 28% reported significantly fewer bleeding episodes. Of patients 50% noted complete resolution of fecal urgency. Six of the 8 patients (75%) with pain noticed some improvement after therapy, although no patients reported complete resolution of rectal pain. Of patients with rectal ulceration 21% showed complete resolution of the ulcer on posttreatment endoscopy, while 29% showed evidence of improvement. Six patients (43%) had no change or worsening of rectal ulcers. Overall 67% of patients had a partial to good response, while 33% showed no response or disease progression. CONCLUSIONS: This series of patients showed a good overall response rate to hyperbaric oxygen for radiation induced proctopathy after other attempts at management had failed. Hyperbaric oxygen is generally well tolerated and it remains an important treatment option for managing this common and difficult disease.

Intrafractional stability of the prostate using a stereotactic radiotherapy technique.

PURPOSE: To evaluate the stability of the prostate during stereotactic radiation therapy. MATERIALS AND METHODS: Forty-seven patients underwent placement of three fiducial markers into the prostate as part of a pilot study of hypofractionated stereotactic radiotherapy. Portal images before and subsequent to 227 radiotherapy fractions were analyzed for prostate movement. Six patients also underwent localizing radiographs at 6-min intervals for 24 min. Relative motion of the bony landmarks and prostate markers was calculated. RESULTS: Analysis of portal images revealed the undirected average prostate movement of 2.0 mm (superior/inferior), 1.9 mm (anterior/posterior), and 1.4 mm (right/left) with maximum standard deviation (SD) of 2.0. Analysis of radiographs at 6-min intervals showed the greatest undirected average prostate motion between 0-6 min; 1.5 mm (superior/inferior), 1.4 mm (anterior/posterior), and 0.4 mm (right/left). Beyond 6 min, movements decreased to 0.4, 0.9, and 0.8 mm, respectively. Bony landmark motion was 0.9 mm (superior/inferior), 0.9 mm (anterior/posterior), and 0.4 mm (right/left) between 0-6 min. Beyond 6 min, motion decreased to less than 0.5 mm in any direction. CONCLUSIONS: Stereotactic prostate radiotherapy, utilizing fiducial marker localization, resulted in average intrafractional prostate movement of 2.0 mm or less. Most patient and organ movement occurs early and a settling-in period is advisable before treatment.

In vivo optical properties of normal canine prostate at 732 nm using motexafin lutetium-mediated photodynamic therapy.

The optical properties (absorption [mu(a)], transport scattering [mu('s)] and effective attenuation [mu(eff)] coefficients) of normal canine prostate were measured in vivo using interstitial isotropic detectors. Measurements were made at 732 nm before, during and after motexafin lutetium (MLu)-mediated photodynamic therapy (PDT). They were derived by applying the diffusion theory to the in vivo peak fluence rates measured at several distances (3, 6, 9, 12 and 15 mm) from the central axis of a 2.5 cm cylindrical diffusing fiber (CDF). Mu(a) and mu('s) varied between 0.03-0.58 and 1.0-20 cm(-1), respectively. Mu(a) was proportional to the concentration of MLu.Mu(eff) varied between 0.33 and 4.9 cm(-1) (mean 1.3 +/- 1.1 cm(-1)), corresponding to an optical penetration depth (8 = 1/(mu(eff)) of 0.5-3 cm (mean 1.3 +/- 0.8 cm). The mean light fluence rate at 0.5 cm from the CDF was 126 +/- 48 mW/cm2 (N = 22) when the total power from the fiber was 375 mW (150 mW/cm). This study showed significant inter- and intraprostatic differences in the optical properties, suggesting that a real-time dosimetry measurement and feedback system for monitoring light fluences during treatment should be advocated for future PDT studies. However, no significant changes were observed before, during and after PDT within a single treatment site.