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Background: A uniform definition of a clinical near-complete response (near-CR) after neoadjuvant (chemo)radiotherapy for rectal cancer is lacking. A clear definition is necessary for uniformity in clinical practice and trial enrolment for organ-preserving treatments. This review aimed to provide an overview of the terminology, criteria, and features used in the literature to define a near-CR. Methods: A systematic review was performed based on the PRISMA statement. PubMed and Embase were searched up to May 2021 to identify the terminology, criteria, and features used to define a near-CR after (chemo)radiotherapy for rectal cancer. Studies with no clear cut-off point between a cCR and near-CR, studies using Response Evaluation Criteria In Solid Tumours, and studies including only complete responders were excluded. Results: A total of 1876 articles were found, of which 23 were included. Patients were managed by watchful waiting and/or additional local treatment in 11 and 17 of 23 studies respectively. Response evaluation included digital rectal examination (DRE) and/or endoscopy with MRI in 18 studies. The majority of studies used the term 'near-complete response'. In most studies, minor irregularities or a smooth induration with DRE and a small flat ulcer on endoscopy were considered to indicate a near-CR. On MRI, five studies used features (obvious downstaging with or without heterogeneous/irregular fibrosis on T2-weighted MRI or small spot of high signal on diffusion-weighted imaging), five studies used TNM criteria (ycT2), and four used magnetic resonance tumour regression grade (mrTRG) (mrTRG1-2/mrTRG2) to describe a near-CR. Conclusion: The terminology, criteria, and features used to describe a near-CR vary substantially, which can partly be explained by the different treatment strategies patients are selected for (watchful waiting or additional local treatment). A reproducible definition of near-CR is required. [ABSTRACT FROM AUTHOR]

Purpose There is an increasing interest for dose differentiation in prostate radiotherapy. The purpose of our study was to analyze the spatial distribution of tumor satellites inside the prostate. Methods and materials 61 prostatectomy specimens were stained with H&E. Tumor regions were delineated by the uro-pathologist. Volumes, distances and cell densities of all delineated tumor regions were measured and further analyzed. Results Multifocal disease was seen in 84% of the patients. The median number of tumor foci was 3. The median distance between the index lesion and the satellites was 1.0 cm, with a maximum of 4.4 cm. The index lesions accounted for 88% of the total tumor volume. The contribution of tumor foci < 0.1 cm 3 to the total tumor volume was 2%. The median cell density of the index lesion and all satellites, regardless of size, were significantly higher than that of the prostate. Conclusions Satellites do not appear in a limited margin around the index lesion (GTV). Consequently, a fixed CTV margin would not effectively cover all satellites. Thus if the aim is to treat all tumor foci, the entire prostate gland should be considered CTV. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To evaluate the safety and efficacy of an absorbable hydrogel when injected between the rectum and prostate to reduce rectal radiation toxicity in adult men undergoing Intensity Modulated Radiotherapy (IMRT) for treatment of low and intermediate risk prostate cancer. Methods: This prospective, non-randomized, multi-center, single arm, open-label study included 52 men with a confirmed diagnosis of prostate cancer. They received transperineal injection of the hydrogel and 3–5days after injection the simulation scans. All patients received IMRT (78Gy delivered, 2Gy per fraction). Space stability was evaluated by using MRI or CT. Gastrointestinal (GI) and genitourinary (GU) toxicity was assessed using RTOG/EORTC scoring system and proctoscopy after 12months. The median follow up time was 12months. Results: Hydrogel application was straight forward using brachytherapy equipment and techniques, with minimal patient discomfort. Six patients (12%) experienced acute GI Grade 2 toxicity, with no patients experiencing Grade 3 or 4 toxicity. In addition, no patients had early late GI toxicity⩾Grade 2 after 12months. The gel was stable during the course of radiotherapy and was not detectable in MRI after 9–12months due to absorption in 42 of 43 patients. Conclusion: These data demonstrated that the hydrogel is a safe method to displace the rectal wall away from the prostate therefore substantially reducing toxicity to the rectum. [Copyright &y& Elsevier]

Abstract: Our increased understanding of the molecular processes underlying cellular sensitivity to ionizing radiation has led to the identification of novel targets for intervention. New agents have become available for combined use to overcome radioresistance and enhance the clinical efficacy of radiotherapy. This rational selection of potential radiosensitizers contrasts with the empirical approach that has dominated the field of chemo-radiotherapy over the last decades. It allows the identification of those patients who will benefit most from a specific combination by exploiting new predictive biomarkers of response. In this review we present several approaches of targeted radiosensitization and discuss the available in vitro and in vivo results that support their translation into clinical trials. We focus on EGFR-inhibiting, anti-angiogenic, apoptosis-modulating and PARP-interfering strategies. [Copyright &y& Elsevier]

Purpose: Hydrogel injected between the rectum and prostate prior to radiotherapy provides a possible means of increased dose sparing to the rectum. Here the authors evaluate the overlap volume histogram (OVH) metric as a means to predict the rectal dose following hydrogel injection. Whether OVH predicted dose can serve as the dose objective or constraint for automated treatment planning was also investigated. Methods: Treatment planning was performed on 21 prostate cancer patients both pre- and posthydrogel injection, with five-field IMRT delivering 78 Gy to the planning target volume (PTV). The authors quantify the geometrical relationship between the rectum and the prostate PTV using an OVH metric which determines the fractional volume of the rectum that is within a specified distance of the PTV. For an OVH distance the authors selected, L20, the PTV expansion distance at which 20% of the rectum overlaps. The authors calculated the rectal dose, D20, received by 20% of the rectum volume on the dose volume histogram. Linear regression was used to examine the correlation between the L20 and D20, and between ΔL20 and ΔD20 (i.e., the change of L20 and D20 posthydrogel injection). Additionally, rectal dose D15, D25, D35, D50, and bladder dose D15 were predicted from the OVH (L15, L25, L35, L50, for rectum and L15 for bladder) by the Lx-Dx linear regression. The predicted doses were applied to the objectives for automated treatment planning of ten plans from five patients. Automatically generated plans were compared with plans manually generated on trial-and-error basis. Results: The rectal L20 was increased and dose D20 decreased due to the enlarged separation of rectum caused by the hydrogel injection. Linear regression showed an inverse linear correlation between L20 and D20, and between ΔL20 and ΔD20 (r2 = 0.77, 0.60, respectively; p < 0.0001). The increase in rectal sparing (ΔD20) is only weakly correlated with the volume of injected hydrogel (r2 = 0.17; p = 0.07), indicating OVH is a more predictive indicator of rectal sparing than the volume of hydrogel itself. Application of the predicted rectum and bladder doses to automated planning produced acceptable treatment plans, with rectal dose reduced for eight of ten plans. Conclusions: The OVH metric can predict the rectal dose in the external beam prostate radiotherapy for patients with hydrogel injection. The predicted doses can be applied to the objectives of optimization in automated treatment planning to produce acceptable treatment plans. [ABSTRACT FROM AUTHOR]

Highlights • Gold Anchor and Visicoil 0.75 fiducials were the most consistently identified. • Using a corresponding CT or CBCT improves fiducial detection on MRI. • The use of a T1 3D GRE MRI sequence for fiducial detection is recommended. Abstract Background and purpose A GTV boost is suggested to result in higher complete response rates in rectal cancer patients, which is attractive for organ preservation. Fiducials may offer GTV position verification on (CB)CT, if the fiducial-GTV spatial relationship can be accurately defined on MRI. The study aim was to evaluate the MRI visibility of fiducials inserted in the rectum. Materials and methods We tested four fiducial types (two Visicoil types, Cook and Gold Anchor), inserted in five patients each. Four observers identified fiducial locations on two MRI exams per patient in two scenarios: without (scenario A) and with (scenario B) (CB)CT available. A fiducial was defined to be consistently identified if 3 out of 4 observers labeled that fiducial at the same position on MRI. Fiducial visibility was scored on an axial and sagittal T2-TSE sequence and a T1 3D GRE sequence. Results Fiducial identification was poor in scenario A for all fiducial types. The Visicoil 0.75 and Gold Anchor were the most consistently identified fiducials in scenario B with 7 out of 9 and 8 out of 11 consistently identified fiducials in the first MRI exam and 2 out of 7 and 5 out of 10 in the second MRI exam, respectively. The consistently identified Visicoil 0.75 and Gold Anchor fiducials were best visible on the T1 3D GRE sequence. Conclusion The Visicoil 0.75 and Gold Anchor fiducials were the most visible fiducials on MRI as they were most consistently identified. The use of a registered (CB)CT and a T1 3D GRE MRI sequence is recommended. [ABSTRACT FROM AUTHOR]

Purpose To evaluate the impact of GTV-CTV dose differentiation by simulating response of prostate patients to radiotherapy, considering histopathology of prostatectomy specimens. Material and methods Tumors’ cell numbers ( N 0 ) and Gleason Scores (GS) were derived from histopathology of 25 specimens. Index lesions and tumors ⩾0.5 cm 3 were considered GTV. Satellites <0.5 cm 3 constituted the tumor load in the CTV. Each patient’s tumor control probability (TCP) was simulated using the linear quadratic model and considering the N 0 while assuming either a constant or GS-dependent α and β . Results 19/25 patients had multi-focal disease. In 11 patients the CTV contained GS 4 + 3 or 4 + 4 tumors. Compared to the GTV, the CTV pathology was more favorable. For an α = 0.140 Gy −1 , a GTV dose of 79 Gy with a CTV dose of 72 Gy achieved an 80% TCP in the population. Varying α between 0.160–0.118 Gy −1 with GS, a GTV and CTV dose of 80 Gy and 70 Gy also gave an 80% TCP. Conclusions Considering only N 0 , our simulations suggest that a GTV-CTV dose differentiation of 7 Gy would not compromise TCP of the patient population. When assuming an increased radiosensitivity with lower GS, a further dose differentiation of 10 Gy might be feasible. [ABSTRACT FROM AUTHOR]

Purpose: To characterize the effect of a prostate-rectum spacer on dose to rectum during external beam radiation therapy for prostate cancer and to assess for factors correlated with rectal dose reduction. Methods and Materials: Fifty-two patients at 4 institutions were enrolled into a prospective pilot clinical trial. Patients underwent baseline scans and then were injected with perirectal spacing hydrogel and rescanned. Intensity modulated radiation therapy plans were created on both scans for comparison. The objectives were to establish rates of creation of ≥7.5 mm of prostate-rectal separation, and decrease in rectal V70 of ≥25%. Multiple regression analysis was performed to evaluate the associations between preinjection and postinjection changes in rectal V70 and changes in plan conformity, rectal volume, bladder volume, bladder V70, planning target volume (PTV), and postinjection midgland separation, gel volume, gel thickness, length of PTV/gel contact, and gel left-to-right symmetry. Results: Hydrogel resulted in ≥7.5-mm prostate-rectal separation in 95.8% of patients; 95.7% had decreased rectal V70 of ≥25%, with a mean reduction of 8.0 Gy. There were no significant differences in preinjection and postinjection prostate, PTV, rectal, and bladder volumes. Plan conformities were significantly different before versus after injection (P=.02); plans with worse conformity indexes after injection compared with before injection (n=13) still had improvements in rectal V70. In multiple regression analysis, greater postinjection reduction in V70 was associated with decreased relative postinjection plan conformity (P=.01). Reductions in V70 did not significantly vary by institution, despite significant interinstitutional variations in plan conformity. There were no significant relationships between reduction in V70 and the other characteristics analyzed. Conclusions: Injection of hydrogel into the prostate-rectal interface resulted in dose reductions to rectum for >90% of patients treated. Rectal sparing was statistically significant across a range of 10 to 75 Gy and was demonstrated within the presence of significant interinstitutional variability in plan conformity, target definitions, and injection results. [Copyright &y& Elsevier]

Abstract: Purpose: To quantify the potential margin reduction with adaptive radiotherapy (ART) during neo-adjuvant treatment of locally-advanced rectal cancer. Methods and materials: Repeat CT scans were acquired for 28 patients treated with 25×2Gy, daily during the first week, and followed by weekly scans. The CTV was delineated on all scans, and shape variation was estimated. Five ART strategies were tested, consisting of an average CTV over the planning CT and one to five repeat CTs. Required PTV margins were calculated for adapted and non-adapted treatment. The strategy with the least PTV volume over the whole treatment was selected and bowel area dose reduction was estimated. Results: Substantial systematic and random shape variation demanded for a PTV margin up to 2.4cm at the upper-anterior part of the CTV. Plan adaptation after fraction 4 resulted in a maximum 0.7cm margin reduction and a significant PTV reduction from 1185 to 1023cc (p <0.0001). The bowel area volume receiving 15, 45, and 50Gy was reduced from 436 to 402cc, 111 to 81cc, and 49 to 29cc, respectively (p <0.0001). Conclusions: With adaptive radiotherapy, maximum required PTV margins can be reduced from 2.4 to 1.7cm, resulting in significantly less dose to the bowel area. [Copyright &y& Elsevier]