Dosimetric Feasibility of Moderately Hypofractionated/dose Escalated Radiation Therapy for Localised Prostate Cancer With Intensity-modulated Proton Beam Therapy Using Simultaneous Integrated Boost (SIB-IMPT) and Impact of Hydrogel Prostate-rectum Spacer

Purpose: To examine the dosimetric feasibility of hypofractionated/dose escalated radiation therapy in patients with localized prostate carcinoma using simultaneous integrated boost intensity-modulated proton beam therapy (SIB-IMPT) in absence or presence of prostate-rectum spacer. Methods: IMPT technique was implemented in 23 patients with intermediate- and high-risk prostate cancer treated at West German Proton Therapy Centre from March 2016 till June 2018, using SIB technique prescribing 60 GyRBE and 72 GyRBE in 30 fractions to PTV1 (prostate and seminal vesicle) and PTV2 boost (prostate and proximal seminal vesicle), respectively. In 15 patients, a transperineal injection of hydrogel was applied prior to radiotherapy to increase the distance between prostate and rectum. Planning and all treatments were performed with a 120 ml fluid-filled endorectal balloon customised daily for each patient. For each patient, 2 lateral IMPT beams were implemented taking a field-specific range uncertainty (RU) into account. Dose volume histograms (DVH) were analyzed for PTV2, PTV2 with range uncertainty margin (PTV2RU), rectum, bladder, right/left femoral heads, and penile bulb. For late rectal toxicities, the normal tissue complication probabilities (NTCP) were calculated using different biological models. A DVH- and NTCP-based dosimetric comparison was carried out between non-spacer and spacer groups. Results: For the 23 patients, high-quality plans could be achieved for target volume and for other organs at risk (OARs). For PTV2, the V107% was 0% and the Dmax did not exceed 106.2% of the prescribed dose. The volume PTV2RU covered by 95% of the dose ranged from 96.16- 99.95%. The conformality index (CI) for PTV2RU was 1.12±0.057 and the homogeneity index (HI) was 1.04±0.014. Rectum Dmax and rectal volume receiving 73 to 50 Gy could be further reduced for the spacer-group. Significant reductions in mean and median rectal NTCPs (stenosis/necrosis, late rectal bleeding ≥ 2, and late rectal toxicities ≥ 3) were predicted for the spacer group in comparison to the non-spacer group. Conclusion: Hypofractionated/dose escalated radiotherapy with SIB-IMPT is dosimetrically feasible. Further reduction of the rectal volumes receiving high and medium dose levels (73 -50 Gy) and rectal NTCP could be achieved through injection of spacers between rectum and prostate.

Are simple verbal instructions sufficient to ensure that bladder volume does not deteriorate prostate position reproducibility during spot scanning proton therapy?

Objectives: The purpose of this study is to investigate whether verbal instructions are sufficient for bladder volume (BV) control not to deteriorate prostate position reproducibility in image-guided spot scanning proton therapy (SSPT) for localized prostate cancer. Methods: A total of 268 treatment sessions in 12 consecutive prostate cancer patients who were treated with image-guided SSPT with fiducial markers were retrospectively analyzed. In addition to strict rectal volume control procedures, simple verbal instructions to void urine one hour before the treatment were used here. The BV was measured by a Bladder Scan just before the treatment and the prostate motion was measured by intraprostatic fiducial markers and two sets of X-ray fluoroscopy images. The correlation between the BV change and prostate motion was assessed by linear mixed-effects models and systematic and random errors according to the reproducibility of the BV. Results: The mean absolute BV change during treatment was from −98.7 to 86.3 ml (median 7.1 ml). The mean absolute prostate motion of the patients in the left-right direction was −1.46 to 1.85 mm, in the cranial-caudal direction it was −6.10 to 3.65 mm, and in the anteroposterior direction −1.90 to 5.23 mm. There was no significant relationship between the BV change and prostate motion during SSPT. The early and late genitourinary and gastrointestinal toxicity was minimal with a minimum follow-up of 4.57 years. Conclusions: Simple verbal instructions about urination was suggested to be sufficient to control the BV not to impact on the prostate motion and clinical outcomes in image-guided SSPT. Careful attention to BV change is still needed when the seminal vesicle is to be treated. Advances in knowledge: Our data demonstrated that there was no apparent relationship between BV changes and prostate position reproducibility and simple verbal instruction about urination could be sufficient for image-guided SSPT.

Late Gastrointestinal Tolerance After Prostate Radiotherapy: Is the Anal Canal the Culprit? A Narrative Critical Review

IntroductionLate gastro-intestinal toxicities (LGIT) secondary to pelvic radiotherapy (RT) are well described in the literature. LGIT are mainly related to rectal or ano-rectal irradiation; however, involvement of the anal canal (AC) in the occurrence of LGIT remains poorly described and understood.Materials and MethodsThe aim of this work was to explore the potential role of the AC in the development of LGIT after prostate irradiation and identify predictive factors that could be optimized in order to limit these toxicities. This narrative literature review was realized using the Pubmed database. We identified original articles published between June 1997 and July 2019, relating to LGIT after RT for localized prostate cancer and for which AC was identified independently. Articles defining the AC as part of an anorectal or rectal volume only were excluded.ResultsA history of abdominal surgery or cardio-vascular risk, anticoagulant or tobacco use, and the occurrence of acute GIT during RT increases the risk of LGIT. A dose-effect relationship was identified between dose to the AC and development of LGIT. Identification and contouring of the AC and adjacent anatomical structures (muscles or nerves) are justified to apply specific dose constraints. As a limitation, our review mainly considered on 3DCRT which is no longer the standard of care nowadays; we did not identify any reports in the literature using moderately hypofractionated RT for the prostate and AC specific dosimetry.ConclusionThese results suggest that the AC may have an important role in the development of LGIT after pelvic RT for prostate cancer. The individualization of the AC during planning should be recommended in prospective studies.

Effect of genetic variants in FAS and let-7a on radiation-induced intestinal toxicity in the treatment of prostate cancer

IntroductionThe present study aimed to explore the effects of pri-let-7a-1 rs10739971 and FAS-670 rs1800682 polymorphisms on the pathogenesis of radiation induced intestinal toxicity in prostate cancer (PC) patients.Material and methods380 PC patients with or without signs of intestinal toxicity were enrolled to study the effects of let-7a rs10739971 and FAS-670 rs1800682 polymorphisms on rectal volume and the risk of intestinal toxicity. In addition, real-time PCR, Western-blot analysis, immunohistochemistry, luciferase assays and computational analyses were performed to explore the mechanism underlying the role of let-7a rs10739971 polymorphism in radiation induced intestinal toxicity.ResultsThe let-7a rs10739971 polymorphism but not the FAS-670 rs1800682 polymorphism was closely related to the risk of radiation induced intestinal toxicity featured by a high rectal volume. In addition, there was no obvious association between the rectal volume and the genotype and allele frequencies of FAS -670 rs1800682 and Pri-let-7a-1 rs10739971 polymorphisms. The GG genotype of let-7a rs10739971 polymorphism reduced let-7a expression but enhanced FAS expression. In addition, the intestinal toxicity (-) group showed a much higher level of let-7a and a much lower level of FAS than the intestinal toxicity (+) group. FAS was a virtual target gene of let-7a, which decreased FAS protein expression in a dose-dependent manner.ConclusionsThe GG genotype of pri-let-7a-1 rs10739971 polymorphism could increase the risk of radiation induced intestinal toxicity in PC patients. Therefore, the pri-let-7a-1 rs10739971 polymorphism could be used as a putative marker to predict the risk of intestinal toxicity in PC patients undergoing radiotherapy.

Analysis of the Influence of Peripheral Anatomical Changes for CBCT-Guided Prostate Cancer Radiotherapy

Purpose: To analyze the influence of the bladder and rectum filling and the body contour changes on the prostate target dose. Methods: A total of 190 cone-beam CT (CBCT) image data sets from 16 patients with prostate cancer were used in this study. Dose reconstruction was performed on the virtual CT generated by the deformable planning CT. Then, the effects of the bladder filling, rectal filling, and the patient’s body contour changes of the PCTV1 (the prostate area, B1) and PCTV2 (the seminal vesicle area, B2) on the target dose were analyzed. Correlation analysis was performed for the ratio of bladder and rectal volume variation and the variation of the bladder and rectal dose. Results: The mean Dice coefficients of B1, B2, bladder, and rectum were 0.979, 0.975, 0.888 and 0.827, respectively, and the mean Hausdorff distances were 0.633, 1.505, 2.075, and 1.533, respectively. With the maximum volume variations of 142.04 ml for the bladder and 40.50 ml for the rectum, the changes of V100, V95, D2, and D98 were 1.739 ± 1.762 (%), 0.066 ± 0.169 (%), 0.562 ± 0.442 (%), and 0.496 ± 0.479 (%) in PCTV1 and 1.686 ± 1.051 (%), 0.240 ± 0.215 (%), 1.123 ± 0.925 (%), and 0.924 ± 0.662 (%) in PCTV2, respectively. With a 10% increase in the volume of the bladder and rectum, the V75, V70, and V65 of rectum increased at 0.73 (%), 0.71 (%), and 1.18 (%), and the V75, V70, and V65 of bladder changed at −0.21 (%), −0.32 (%), and −0.39 (%), respectively. Conclusion: Significant correlations were observed between the volume variation and the dose variation of the bladder and rectum. However, when a bladder and rectal filling protocol was adopted, the target dose coverage can be effectively ensured based on CBCT guidance to correct the prostate target position.

To analyse target volume variations during SIB-IMRT of squamous cell carcinoma of uterine cervix

Purpose: To assess volume variations in target site due to changes in bladder filling and rectal content including air bubbles during simultaneous-integrated boost intensity-modulated radiotherapy (SIB-IMRT) of patients suffering from squamous cell carcinoma of uterine cervix. Materials and methods: A total of ten patients of squamous cell carcinoma of uterine cervix were enrolled in this analysis. All patients were planned to undergo SIB-IMRT using 10 MV beam. Planning target volume of the tumour (PTVtumour) and PTVnodal were prescribed with 5,040 and 4,500 cGy doses, respectively. During planning, PTVtumour V95%, PTVnodal V95% and organs at risk (OARs) (bladder, rectum, femoral heads and small bowel) volumes were measured from initial CT planning scans taken with full bladder. CT scans were acquired once in a week over a treatment period of 5·5 weeks. Intra-treatment scans with full bladder were then fused with the planning scans to determine variations in the target volume and the OAR volume. Changes in radiation dose to the PTVtumour and the PTVnodal were also assessed by comparing intra-treatment scans with the planning (first) scans. Results: All patients showed intra-treatment bladder volume larger than the planning bladder volume. Difference between planning bladder and intra-treatment bladder volumes ranged from 4·5 to 49%. Rectal volume varied from 17 to 60 cc. A wide variation between planning and intra-treatment air volumes was found in most of the patients. When comparing initial and inter-fraction air volumes, the maximum difference was 366·67%. Due to bladder and rectal volume variations, PTVtumour V95% and PTVnodal V95% doses did not remain constant throughout the treatment. The maximum discrepancy between intra-treatment PTVtumour dose and planning PTVtumour dose was 12·15%. The maximum difference between planning and inter-fraction PTV V95% was 48·28%. PTVnodal dose observed from scan taken in last week of treatment was 12·87% less than planning PTVnodal dose analysed from planning CT scan. Maximum difference in planning and inter-fraction PTVnodal V95% was 57·78%. Conclusion: Inconsistent bladder and rectal volumes had a significant impact on target volume and dosage during an entire course of SIB-IMRT. For radiotherapy of gynaecological malignancies, data on variations in PTV should be acquired on daily basis to target radiation dose to the tumour site with accuracy.

Dosimetric impact of organ at risk daily variation during prostate stereotactic ablative radiotherapy

Objective: Prostate stereotactic ablative radiotherapy (SABR) delivers large doses using a fast dose rate. This amplifies the effect geometric uncertainties have on normal tissue dose. The aim of this study was to determine whether the treatment dose–volume histogram (DVH) agrees with the planned dose to organs at risk (OAR). Methods: 41 low–intermediate risk prostate cancer patients were treated with SABR using a linac based technique. Dose prescribed was 35 Gy in five fractions delivered on alternate days, planned using volumetric modulated arc therapy (VMAT) with 10X flattening filter free (FFF). On treatment, prostate was matched to fiducial markers on cone beam CT (CBCT). OAR were retrospectively delineated on 205 pre-treatment CBCT images. Daily CBCT contours were overlaid on the planning CT for dosimetric analysis. Verification plan used to evaluate the daily DVH for each structure. The daily doses received by OAR were recorded using the D%. Results: The median rectum and bladder volumes at planning were 67.1 cm3 (interquartile range 56.4–78.2) and 164.4 cm3 (interquartile range 120.3–213.4) respectively. There was no statistically significant difference in median rectal volume at each of the five treatment scans compared to the planning scan (p = 0.99). This was also the case for median bladder volume (p = 0.79). The median dose received by rectum and bladder at each fraction was higher than planned, at the majority of dose levels. For rectum the increase ranged from 0.78–1.64Gy and for bladder 0.14–1.07Gy. The percentage of patients failing for rectum D35% < 18 Gy (p = 0.016), D10% < 28 Gy (p = 0.004), D5% < 32 Gy (p = 0.0001), D1% < 35 Gy (p = 0.0001) and bladder D1% < 35 Gy (p = 0.001) at treatment were all statistically significant. Conclusion: In this cohort of prostate SABR patients, we estimate the OAR treatment DVH was higher than planned. This was due to rectal and bladder organ variation. Advances in knowledge: OAR variation in prostate SABR using a FFF technique, may cause the treatment DVH to be higher than planned.