Is an Endorectal Balloon Beneficial for Rectal Sparing After Spacer Implantation in Prostate Cancer Patients Treated With Hypofractionated Intensity-modulated Proton Beam Therapy? A Dosimetric and Radiobiological Comparison Study

BackgroundThe aim of this study is to examine the dosimetric influence of endorectal balloons (ERB) in rectal sparing in prostate cancer patients with implanted hydrogel rectum spacers treated with dose escalated/hypofractionated intensity modulated proton beam therapy (IMPT). MethodsTen patients with localised prostate cancer included in the ProRegPros study and treated at our centre were invastigated in this study. All patients underwent a placement of hydrogel rectum spacers before planning. Two planning CTs (with and without 120 cm3 fluid-filled ERB) were acquired for each patient. Dose prescription was set according to the used simultaneous integrated boost strategy with 72 Gray (Gy)/2.4 Gy/5 x weekly to prostate+1 cm of the seminal vesicle, and 60 Gy/2 Gy/5 x weekly to prostate+2 cm of the seminal vesicle. Planning with two lateral-opposed IMPT beams was performed in both CTs. Rectal dosimetry values including dose-volume statistics and normal tissue complication probability (NTCP) in both plans were compared (non-ERB plans vs. ERB plans).ResultsFor ERB plans compared to non-ERB, the reductions were 8.51 ± 5.25 Gy (RBE) (p= 0.000) and 15.76 ± 11.11Gy (P= 0.001) for the mean and the median rectal dose, respectively. No significant reductions in rectal volumes receiving high dose levels were found. The use of ERB resulted in significant reduction in rectal volume receiving 50 Gy (RBE), 40 Gy (RBE), 30 Gy (RBE), 20 Gy (RBE), and 10 Gy (RBE) with P values of 0.034, 0.008, 0.003, 0.001, and 0.001, respectively. For the anterior rectum, no differences between ERB and non-ERB plans were observed. For the posterior rectum, ERB reduced rectal volumes received 30 Gy (RBE), 20 Gy (RBE), and 10 Gy (RBE) with P values of 0.019, 0.003, and 0.001, respectively. No significant reductions in mean or median rectal toxicity (Late rectal bleeding ≥2, necrosis/stenosis, and Late rectal toxicity ≥ 3) were observed when using the ERB according to NTCP models.ConclusionThe ERB reduced rectal volumes exposed to intermediate/low dose levels. However, no significant reduction in rectal volumes receiving high/intermediate doses could be observed. No benefit but also no disadvantage of the ERB for late rectal toxicity was found according to available NTCP models.

Preliminary result of carbon-ion radiotherapy using the spot scanning method for prostate cancer

Background: Carbon-ion radiotherapy (CIRT) for prostate cancer was initiated at Kanagawa Cancer Center in 2015. The present study analyzed the preliminary clinical outcomes of CIRT for prostate cancer. Methods: The clinical outcomes of 253 patients with prostate cancer who were treated with CIRT delivered using the spot scanning method between December 2015 and December 2017 were retrospectively analyzed. The irradiation dose was set at 51.6 Gy (relative biological effectiveness) delivered in 12 fractions over 3 weeks. Biochemical relapse was defined using the Phoenix definition. Toxicities were assessed according to CTCAE version 4.0. Results: The median patient age was 70 (47–86) years. The median follow-up duration was 35.3 (4.1–52.9) months. According to the D’Amico classification system, 8, 88, and 157 patients were classified as having low, intermediate, and high risks, respectively. Androgen deprivation therapy was administered in 244 patients. The biochemical relapse-free rate in the low-, intermediate-, and high-risk groups at 3 years was 87.5%, 88.0%, and 97.5%, respectively (P = 0.036). Grade 2 acute urinary toxicity was observed in 12 (4.7%) patients. Grade 2 acute rectal toxicity was not observed. Grade 2 late urinary toxicity and grade 2 late rectal toxicity were observed in 17 (6.7%) and 3 patients (1.2%), respectively. Previous transurethral resection of the prostate was significantly associated with late grade 2 toxicity in univariate analysis. The predictive factor for late rectal toxicity was not detected.Conclusion: The present study demonstrated that CIRT using the spot scanning method for prostate cancer produces favorable outcomes.

Preliminary result of carbon-ion radiotherapy using the spot scanning method for prostate cancer

Background Carbon-ion radiotherapy (CIRT) for prostate cancer was initiated at Kanagawa Cancer Center in 2015. The present study analyzed the preliminary clinical outcomes of CIRT for prostate cancer. Methods The clinical outcomes of 253 patients with prostate cancer who were treated with CIRT delivered using the spot scanning method between December 2015 and December 2017 were retrospectively analyzed. The irradiation dose was set at 51.6 Gy (relative biological effectiveness) delivered in 12 fractions over 3 weeks. Biochemical relapse was defined using the Phoenix definition. Toxicities were assessed according to CTCAE version 4.0. Results The median patient age was 70 (47–86) years. The median follow-up duration was 35.3 (4.1–52.9) months. According to the D’Amico classification system, 8, 88, and 157 patients were classified as having low, intermediate, and high risks, respectively. Androgen deprivation therapy was administered in 244 patients. The biochemical relapse-free rate in the low-, intermediate-, and high-risk groups at 3 years was 87.5%, 88.0%, and 97.5%, respectively (P = 0.036). Grade 2 acute urinary toxicity was observed in 12 (4.7%) patients. Grade 2 acute rectal toxicity was not observed. Grade 2 late urinary toxicity and grade 2 late rectal toxicity were observed in 17 (6.7%) and three patients (1.2%), respectively. Diabetes mellitus and previous transurethral resection of the prostate were significantly associated with late grade 2 toxicity in univariate analysis. The predictive factor for late rectal toxicity was not detected. Conclusion The present study demonstrated that CIRT using the spot scanning method for prostate cancer produces favorable outcomes.

A prospective comparison of MRI-planned versus CT-planned radiotherapy for prostate cancer.

312 Background: Chronic rectal toxicity significantly decreases the quality of life for men who receive radiotherapy for prostate cancer. The volume of rectum exposed to 70 Gy or more is a validated metric that predicts the risk of late rectal toxicity. We hypothesized that MRI as compared to CT-based prostate radiotherapy treatment planning can reduce the volume of rectum exceeding 70 Gy. Methods: This prospective study single arm study enrolled 15 men treated with external beam radiation therapy for localized prostate cancer. At the time of treatment planning a 3 Tesla T2-weighted magnetic resonance imaging examination of the prostate was obtained. A radiotherapy plan was designed by a medical physicist using identical constraints for both CT and MRI-based consensus volumes defined by a radiologist and radiation oncologist. The volume of rectum exposed to 70 Gy or more was calculated and compared using the paired Signed Rank Test. Results: The median age was 70 years (range 56-84), median PSA 7.3 ng/mL (range 3.2 – 22.1), and median prostate volume 40 mL (range 25 - 65) by transrectal ultrasound. Sixty percent (n=9) were intermediate risk and 40 percent (n=6) high risk by NCCN guidelines. The majority were either clinical stage T1c (n=7) or T2 (n=6). Two men had extracapsular extension (T3a). None of the participants had seminal vesicle invasion (T3b), rectal or bladder involvement (T4), or lymph node metastasis (N1). All 15 men enrolled on the study completed both a standard radiation planning CT and research MRI examination. For CT-based treatment plans the median volume of rectum receiving 70 Gy or more was 9.3 cubic centimeters (cc) [IQR 7.0 to 10.2] compared with 4.9 cc [IQR 4.1 to 8.7] for MRI-based plans. This resulted in a median volume reduction of 2.1 cc [IQR 0.5 to 5.3, P < .001]. Conclusions: MRI-planned prostate radiotherapy can reduce the volume of rectum receiving radiation doses in excess of tolerance (70 Gy or more) and should be considered in men who are at high risk for late rectal toxicity. Clinical trial information: NCT02470910.

Rectum Dose Constraints for Carbon Ion Therapy: Relative Biological Effectiveness Model Dependence in Relation to Clinical Outcomes

The clinical application of different relative biological effectiveness (RBE) models for carbon ion RBE-weighted dose calculation hinders a global consensus in defining normal tissue constraints. This work aims to update the local effect model (LEM)-based constraints for the rectum using microdosimetric kinetic model (mMKM)-defined values, relying on RBE translation and the analysis of long-term clinical outcomes. LEM-optimized plans of treated patients, having suffered from prostate adenocarcinoma (n = 22) and sacral chordoma (n = 41), were recalculated with the mMKM using an in-house developed tool. The relation between rectum dose-volume points in the two RBE systems (DLEM|v and DMKM|v) was fitted to translate new LEM-based constraints. Normal tissue complication probability (NTCP) values, predicting late rectal toxicity, were obtained by applying published parameters. No late rectal toxicity events were reported within the patient cohort. The rectal toxicity outcome was confirmed using dosimetric analysis: DMKMVHs lay largely below original constraints; the translated DLEM|v values were 4.5%, 8.3%, 18.5%, and 35.4% higher than the nominal DMKM|v of the rectum volume, v—1%, 5%, 10% and 20%. The average NTCP value ranged from 5% for the prostate adenocarcinoma, to 0% for the sacral chordoma group. The redefined constraints, to be confirmed prospectively with clinical data, are DLEM|5cc ≤ 61 Gy(RBE) and DLEM|1cc ≤ 66 Gy(RBE).

Daily versus weekly prostate cancer image-guided radiotherapy: A phase 3, multicenter, randomized trial.

4 Background: The optimal frequency of prostate cancer image-guided radiation therapy (IGRT) has not yet been clearly identified. This study sought to compare the safety and efficacy of daily versus weekly IGRT. Methods: This Phase III randomized trial recruited 470 patients with N0 localized prostate cancer, from 21 centers between June 2007 and November 2012. Total IGRT doses ranged from 70 to 80 Gy. Patients were randomly assigned (1:1) to two prostate IGRT control frequency groups: daily or weekly (Days 1, 2, and 3, then weekly). The primary outcome was 5-year recurrence-free survival (RFS). Secondary outcomes included overall survival (OS) and toxicity (CTCAE V.3.0). Post-hoc analyses included biochemical progression-free interval (BPFI), clinical progression-free interval (CPFI) and second cancer-free interval (SCFI). Results: Median follow-up was 4.1 years (Q1 – Q3 = 3.1 – 5.1).There was no statistically-significant difference in RFS between the groups (hazard ratio [HR] = 0.81 [95% CI: 0.52 – 1.25]; p = 0.330). OS was worse in the daily control group versus the weekly control group (HR = 2.12 [95% CI: 1.03 – 4.37]; p = 0.042). Late rectal toxicity (Grade ≥1) incidence was significantly lower in the daily control group (HR = 0.71 [95% CI: 0.53 – 0.96]; p = 0.027). BPFI was better in the daily control group versus the weekly control group (HR = 0.45 [95% CI: 0.25 – 0.80]; p = 0.007). CPFI was better in the daily control group (HR = 0.50 [95% CI: 0.24 – 1.02]; p = 0.057). SCFI was worse in the daily control group versus the weekly control group (HR = 2.21 [95% CI: 1.10 – 4.44]; p = 0.026). Conclusions: Compared to weekly control, daily IGRT control in prostate cancer significantly decreases the risks of recurrence and late rectal toxicity but is associated with an increased risk of second cancer. Clinical trial information: NCT00433706.

Evaluation of Mediators Associated with the Inflammatory Response in Prostate Cancer Patients Undergoing Radiotherapy

A recent “hot topic” in prostate cancer radiotherapy is the observed association between acute/late rectal toxicity and the presence of abdominal surgery before radiotherapy. The exact mechanism is unclear. Our working hypothesis was that a previous surgery may influence plasma level of inflammatory molecules and this might result in enhanced radiosensitivity. We here present results on the feasibility of monitoring the expression of inflammatory molecules during radiotherapy. Plasma levels of a panel of soluble mediators associated with the inflammatory response were measured in prostate cancer patients undergoing radical radiotherapy. We measured 3 cytokines (IL-1b, IL-6, and TNF alpha), 2 chemokines (CCL2 and CXCL8), and the long pentraxin PTX3. 20 patients were enrolled in this feasibility evaluation. All patients were treated with IMRT at 78 Gy. 3/20 patients reported grade 2 acute rectal toxicity, while 4/20 were scored as grade 2 late toxicity. CCL2 was the most interesting marker showing significant increase during and after radiotherapy. CCL2 levels at radiotherapy end could be modelled using linear regression including basal CCL2, age, surgery, hypertension, and use of anticoagulants. The 4 patients with late toxicity had CCL2 values at radiotherapy end above the median value. This trial is registered with ISRCTN64979094.