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A rapid increase in the incidence of anal squamous cell carcinoma (SCC) was reported in several countries over the past decades. This study assessed trends in epidemiology and primary treatment over a 32‐year period (1990–2021) using the Netherlands Cancer Registry. The study population included 4273 patients, 44.2% male and 55.8% female (median age 63 years). The age‐standardised incidence rate (European Standardised Rate, ESR) increased from 0.5 to 1.6 per 100,000, which entailed an average annual percentage change (AAPC) of 5.0% (95% confidence interval [CI]: 4.5%–5.8%). While incidence among females increased continuously over the total period (AAPC 4.9%; 95%CI: 4.4%–5.6%), to 1.8 per 100,000 ESR in 2021, incidence among males increased until 2016 (annual percentage change [APC] of 6.3%; 95%CI: 5.6%–10.7%), after which it seemed to stabilise (APC −2.1%; 95%CI: −16.8%–4.5%). Significant trends were also observed in distribution of age, tumour stage and primary treatment modalities. Five‐year relative survival (RS) was estimated using the Pohar–Perme estimator, and this improved from 56.1% in 1990–1997 (95%CI: 49.3%–62.4%) to 67.9% in 2014–2021 (95%CI: 64.7%–70.9%), but remained poor for stage IV disease. Evaluation through a multivariable Poisson regression model demonstrated diagnosis in the most recent period to be independently associated with better RS, in addition to female sex, younger age, early disease stage and any treatment. In conclusion, the rising incidence of anal SCC seems to decline in males, but not in females, and advances in diagnostics and therapeutic management have likely contributed to improved prognosis. [ABSTRACT FROM AUTHOR]

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]

Simple Summary: Contact X-ray brachytherapy (CXB) after neoadjuvant (chemo)radiotherapy for rectal cancer is applied in selected patients aiming at organ preservation. However, limited data exist on features observed on endoscopy and MRI after treatment with CXB. On endoscopy, features observed in most patients 6 months after CXB are a flat, white scar, indicative for a clinical complete response (cCR), or tumor mass. On MRI, features indicative for a residual tumor are a focal tumor signal on T2W-MRI and a mass-like high signal on DWI. Due to treatment-related features observed early in follow-up, an irregular ulcer on endoscopy and a diffuse "reactive" mucosal signal on DWI, the distinction between a cCR and a residual tumor generally can be made at 6 months of follow-up. These results can help clinicians to interpret imaging features following CXB, ultimately, to identify patients with a cCR for Watch-and-Wait and to identify patients with a residual tumor for subsequent total mesorectal excision. After neoadjuvant (chemo)radiotherapy for rectal cancer, contact X-ray brachytherapy (CXB) can be applied aiming at organ preservation. This explorative study describes the early features on endoscopy and MRI after CXB. Patients treated with CXB following (chemo)radiotherapy and a follow-up of ≥12 months were selected. Endoscopy and MRI were performed every 3 months. Expert readers scored all the images according to structured reporting templates. Thirty-six patients were included, 15 of whom obtained a cCR. On endoscopy, the most frequently observed feature early in follow-up was an ulcer, regardless of whether patients developed a cCR. A flat, white scar and tumor mass were common at 6 months. Focal tumor signal on T2W-MRI and mass-like high signal on DWI were generally absent in patients with a cCR. An ulceration on T2W-MRI and "reactive" mucosal signal on DWI were observed early in follow-up regardless of the final tumor response. The distinction between a cCR and a residual tumor generally can be made at 6 months. Features associated with a residual tumor are tumor mass on endoscopy, focal tumor signal on T2W-MRI, and mass-like high signal on DWI. Early recognition of these features is necessary to identify patients who will not develop a cCR as early as possible. [ABSTRACT FROM AUTHOR]

To evaluate feasibility of chemoradiation as alternative for extensive surgery in patients with locally advanced vulvar cancer and to report on locoregional control, toxicity and survival. In a multicenter, prospective phase II trial patients with locally advanced vulvar cancer were treated with locoregional radiotherapy combined with sensitizing chemotherapy (capecitabine). Treatment feasibility, percentage locoregional control, survival and toxicity were evaluated. 52 patients with mainly T2/T3 disease were treated according to the study protocol in 10 centers in the Netherlands from 2007 to 2019. Full dose radiotherapy (tumor dose of 64.8Gy) was delivered in 92% and full dose capecitabine in 69% of patients. Most prevalent acute ≥ grade 3 toxicities were regarding skin/mucosa and pain (54% and 37%). Late ≥grade 3 toxicity was reported for skin/mucosa (10%), fibrosis (4%), GI incontinence (4%) and stress fracture or osteoradionecrosis (4%). Twelve weeks after treatment, local clinical complete response (cCR) and regional control (RC) rates were 62% and 75%, respectively. After 2 years, local cCR persisted in 22 patients (42%) and RC was 58%. Thirty patients (58%) had no evidence of disease at end of follow-up (median 35 months). In 9 patients (17%) extensive surgery with stoma formation was needed. Progression free survival was 58%, 51% and 45% and overall survival was 76%, 66%, 52% at 1,2, and 5 years. Definitive capecitabine-based chemoradiation as alternative for extensive surgery is feasible in locally advanced vulvar cancer and results in considerable locoregional control with acceptable survival rates with manageable acute and late toxicity. • Surgery for locally advanced vulvar cancer is often extensive with stoma formation or need for reconstructive surgery. • Definitive capecitabine-based chemoradiation is feasible with acceptable acute and late toxicity. • Local clinical complete response of 62% after 12 weeks and persistent local control of 42% after 2 years • Need for subsequent stoma formation in only 17% of patients. • Definitive chemoradiation can serve as alternative for extensive surgery in locally advanced vulvar cancer. [ABSTRACT FROM AUTHOR]

Background: With the large-scale introduction of volumetric modulated arc therapy (VMAT), selection of optimal beam angles for coplanar static-beam IMRT has increasingly become obsolete. Due to unavailability of VMAT in current MR-linacs, the problem has re-gained importance. An application for automated IMRT treatment planning with integrated, patient-specific computer-optimization of beam angles (BAO) was used to systematically investigate computer-aided generation of beam angle class solutions (CS) for replacement of computationally expensive patient-specific BAO. Rectal cancer was used as a model case. Materials and Methods: 23 patients treated at a Unity MR-linac were included. BAOx plans (x=7-12 beams) were generated for all patients. Analyses of BAO12 plans resulted in CSx class solutions. BAOx plans, CSx plans, and plans with equi-angular setups (EQUIx, x=9-56) were mutually compared. Results: For x>7, plan quality for CSx and BAOx was highly similar, while both were superior to EQUIx. E.g. with CS9, bowel/bladder Dmean reduced by 22% [11%, 38%] compared to EQUI9 (p<0.001). For equal plan quality, the number of EQUI beams had to be doubled compared to BAO and CS. Conclusions: Computer-generated beam angle CS could replace individualized BAO without loss in plan quality, while reducing planning complexity and calculation times, and resulting in a simpler clinical workflow. CS and BAO largely outperformed equi-angular treatment. With the developed CS, time consuming beam angle re-optimization in daily adaptive MR-linac treatment could be avoided. Further systematic research on computerized development of beam angle class solutions for MR-linac treatment planning is warranted. [ABSTRACT FROM AUTHOR]

Background and purpose: In this study we developed a workflow for fully-automated generation of deliverable IMRT plans for a 1.5 T MR-Linac (MRL) based on contoured CT scans, and we evaluated automated MRL planning for rectal cancer. Methods: The Monte Carlo dose calculation engine used in the clinical MRL TPS (Monaco, Elekta AB, Stockholm, Sweden), suited for high accuracy dose calculations in a 1.5 T magnetic field, was coupled to our in-house developed Erasmus-iCycle optimizer. Clinically deliverable plans for 23 rectal cancer patients were automatically generated in a two-step process, i.e., multi-criterial fluence map optimization with Erasmus-iCycle followed by a conversion into a deliverable IMRT plan in the clinical TPS. Automatically generated plans (AUTOplans) were compared to plans that were manually generated with the clinical TPS (MANplans). Results: With AUTOplanning large reductions in planning time and workload were obtained; 4–6 h mainly hands-on planning for MANplans vs ∼1 h of mainly computer computation time for AUTOplans. For equal target coverage, the bladder and bowel bag Dmean was reduced in the AUTOplans by 1.3 Gy (6.9%) on average with a maximum reduction of 4.5 Gy (23.8%). Dosimetric measurements at the MRL demonstrated clinically acceptable delivery accuracy for the AUTOplans. Conclusions: A system for fully automated multi-criterial planning for a 1.5 T MR-Linac was developed and tested for rectal cancer patients. Automated planning resulted in major reductions in planning workload and time, while plan quality improved. Negative impact of the high magnetic field on the dose distributions could be avoided. [ABSTRACT FROM AUTHOR]

This review summarizes the current applications and benefits of imaging modalities for organ preservation in the treatment of rectal cancer. The concept of organ preservation in the treatment of rectal cancer has revolutionized the way rectal cancer is managed. Initially, organ preservation was limited to patients with locally advanced rectal cancer who needed neoadjuvant therapy to reduce tumor size before surgery and achieved complete response. However, neoadjuvant therapy is now increasingly utilized for smaller and less aggressive tumors to achieve primary organ preservation. Additionally, more intensive neoadjuvant strategies are employed to improve complete response rates and increase the chances of successful organ preservation. The selection of patients for organ preservation is a critical component of treatment, and imaging techniques such as digital rectal exam, endoscopy, and MRI are commonly used for this purpose. In this review, we provide an overview of what imaging modalities should be chosen and how they can aid in the selection and follow‐up of patients undergoing organ‐preserving strategies. [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]

Background: Radiotherapy is one of the mainstays in the treatment for cancer, but its success can be limited due to inherent or acquired resistance. Mechanisms underlying radioresistance in various cancers are poorly understood and available radiosensitizers have shown only modest clinical benefit. There is thus a need to identify new targets and drugs for more effective sensitization of cancer cells to irradiation. Compound and RNA interference high-throughput screening technologies allow comprehensive enterprises to identify new agents and targets for radiosensitization. However, the gold standard assay to investigate radiosensitivity of cancer cells in vitro, the colony formation assay (CFA), is unsuitable for high-throughput screening. Methods: We developed a new high-throughput screening method for determining radiation susceptibility. Fast and uniform irradiation of batches up to 30 microplates was achieved using a Perspex container and a clinically employed linear accelerator. The readout was done by automated counting of fluorescently stained nuclei using the Acumen eX3 laser scanning cytometer. Assay performance was compared to that of the CFA and the CellTiter-Blue homogeneous uniform-well cell viability assay. The assay was validated in a whole-genome siRNA library screening setting using PC-3 prostate cancer cells. Results: On 4 different cancer cell lines, the automated cell counting assay produced radiation dose response curves that followed a linear-quadratic equation and that exhibited a better correlation to the results of the CFA than did the cell viability assay. Moreover, the cell counting assay could be used to detect radiosensitization by silencing DNA-PKcs or by adding caffeine. In a high-throughput screening setting, using 4 Gy irradiated and control PC-3 cells, the effects of DNA-PKcs siRNA and non-targeting control siRNA could be clearly discriminated. Conclusions: We developed a simple assay for radiation susceptibility that can be used for high-throughput screening. This will aid the identification of molecular targets for radiosensitization, thereby contributing to improving the efficacy of radiotherapy. [ABSTRACT FROM AUTHOR]

Background Radiation therapy is one of the recommended treatment options for localized prostate cancer. In randomized trials, dose escalation was correlated with better biochemical control but also with higher rectal toxicity. A prospective multicenter phase II study was carried out to evaluate the safety, clinical and dosimetric effects of the hydrogel prostate-rectum spacer. Here we present the 12 months toxicity results of this trial. Methods Fifty two patients with localized prostate cancer received a transperineal PEG hydrogel injection between the prostate and rectum, and then received IMRT to a dose of78Gy. Gastrointestinal and genitourinary toxicity were recorded during treatment and at 3, 6 and 12 months following irradiation by using the RTOG/EORTC criteria. Additionally, proctoscopy was performed 12 months after treatment and the results were scored using the Vienna Rectoscopy Scale (VRS). Results Of the patients treated 39.6% and 12.5% experienced acute Grade 1 and Grade 2 GI toxicity, respectively. There was no Grade 3 or Grade 4 acute GI toxicity experienced in the study. Only 4.3% showed late Grade 1 GI toxicity, and there was no late Grade 2 or greater GI toxicity experienced in the study. A total of 41.7%, 35.4% and 2.1% of the men experienced acute Grade 1, Grade 2 and Grade 3 GU toxicity, respectively. There was no Grade 4 acute GU toxicity experienced in the study. Late Grade 1 and Grade 2 GU toxicity was experienced in 17.0% and 2.1% of the patients, respectively. There was no late Grade 3 or greater GU toxicity experienced in the study. Seventy one percent of the patients had a VRS score of 0, and one patient (2%) had Grade 3 teleangiectasia. There was no evidence of ulceration, stricture or necrosis at 12 months. Conclusion The use of PEG spacer gel is a safe and effective method to spare the rectum from higher dose and toxicity. [ABSTRACT FROM AUTHOR]

Simple Summary: The cornerstone in rectal cancer treatment is total mesorectal excision, a major surgical procedure associated with morbidity and mortality, especially in older rectal cancer patients. To avoid major surgery, different radiotherapy techniques are being investigated. Studies on contact X-ray brachytherapy reveal promising oncological results. However, there are limited data on functional outcome and quality of life, which are highly important for older or inoperable patients. This study aims to report the oncological and functional outcome, quality of life, and patients' experiences of older or inoperable rectal cancer patients treated with contact X-ray brachytherapy to avoid major surgery. This study shows that contact X-ray brachytherapy can provide a good tumor response and is well tolerated, with minimal impact on functional outcome and quality of life. These data suggest contact X-ray brachytherapy can be considered an option for older or inoperable rectal cancer patients to avoid major rectal surgery. Total mesorectal excision for rectal cancer is a major operation associated with morbidity and mortality. For older or inoperable patients, alternatives are necessary. This prospective study evaluated the oncological and functional outcome and quality of life of older or inoperable rectal cancer patients treated with a contact X-ray brachytherapy boost to avoid major surgery. During follow-up, tumor response and toxicity on endoscopy were scored. Functional outcome and quality of life were assessed with self-administered questionnaires. Additionally, in-depth interviews regarding patients' experiences were conducted. Nineteen patients were included with a median age of 80 years (range 72–91); nine patients achieved a clinical complete response and in another four local control of the tumor was established. The 12 month organ-preservation rate, progression-free survival, and overall survival were 88%, 78%, and 100%, respectively. A transient decrease in quality of life and bowel function was observed at 3 months, which was generally restored at 6 months. In-depth interviews revealed that patients' experience was positive despite the side-effects shortly after treatment. In older or inoperable rectal cancer patients, contact X-ray brachytherapy can be considered an option to avoid total mesorectal excision. Contact X-ray brachytherapy is well-tolerated and can provide good tumor control. [ABSTRACT FROM AUTHOR]

Purpose: To compare conformal radiotherapy (CRT), intensity-modulated radiotherapy (IMRT), and respiration-gated radiotherapy (RGRT) planning techniques for pancreatic cancer. All target volumes were determined using four-dimensional computed tomography scans (4D CT). Methods and Materials: The pancreatic tumor and enlarged regional lymph nodes were contoured on all 10 phases of a planning 4D CT scan for 10 patients, and the planning target volumes (PTVall phases) were generated. Three consecutive respiratory phases for RGRT delivery in both inspiration and expiration were identified, and the corresponding PTVs (PTVinspiration and PTVexpiration) and organ at risk volumes created. Treatment plans using CRT and IMRT, with and without RGRT, were created for each PTV. Results: Compared with the CRT plans, IMRT significantly reduced the mean volume of right kidney exposed to 20 Gy from 27.7% ± 17.7% to 16.0% ± 18.2% (standard deviation) (p < 0.01), but this was not achieved for the left kidney (11.1% ± 14.2% to 5.7% ± 6.5%; p = 0.1). The IMRT plans also reduced the mean gastric, hepatic, and small bowel doses (p < 0.01). No additional reductions in the dose to the kidneys or other organs at risk were seen when RGRT plans were combined with either CRT or IMRT, and the findings for RGRT in end-expiration and end-inspiration were similar. Conclusion: 4D CT–based IMRT plans for pancreatic tumors significantly reduced the radiation doses to the right kidney, liver, stomach, and small bowel compared with CRT plans. The additional dosimetric benefits from RGRT appear limited in this setting. [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]

The master protocol trial design aims to increase efficiency in terms of trial infrastructure and protocol administration which may accelerate development of (technical) innovations in radiation oncology. A master protocol to study feasibility of techniques/software for MR-guided adaptive radiotherapy with the MR-Linac is described and discussed. [ABSTRACT FROM AUTHOR]

• MRI is increasingly used for gross tumour volume (GTV) delineation in anal cancer. • GTV delineation is reproducible between radiologists and radiation oncologists. • Diffusion-weighted MRI (DWI) renders similar results as anatomical (T2-weighted) MRI. • Artefacts are common on DWI and may limit its use for radiotherapy planning. To assess how gross tumour volume (GTV) delineation in anal cancer is affected by interobserver variations between radiologists and radiation oncologists, expertise level, and use of T2-weighted MRI (T2W-MRI) vs. diffusion-weighted imaging (DWI), and to explore effects of DWI quality. We retrospectively analyzed the MRIs (T2W-MRI and b800-DWI) of 25 anal cancer patients. Four readers (Senior and Junior Radiologist; Senior and Junior Radiation Oncologist) independently delineated GTVs, first on T2W-MRI only and then on DWI (with reference to T2W-MRI). Maximum Tumour Diameter (MTD) was calculated from each GTV. Mean GTVs/MTDs were compared between readers and between T2W-MRI vs. DWI. Interobserver agreement was calculated as Intraclass Correlation Coefficient (ICC), Dice Similarity Coefficient (DSC) and Hausdorff Distance (HD). DWI image quality was assessed using a 5-point artefact scale. Interobserver agreement between radiologists vs. radiation oncologists and between junior vs. senior readers was good–excellent, with similar agreement for T2W-MRI and DWI (e.g. ICCs 0.72–0.94 for T2W-MRI and 0.68–0.89 for DWI). There was a trend towards smaller GTVs on DWI, but only for the radiologists (P = 0.03–0.07). Moderate-severe DWI-artefacts were observed in 11/25 (44%) cases. Agreement tended to be lower in these cases. Overall interobserver agreement for anal cancer GTV delineation on MRI is good for both radiologists and radiation oncologists, regardless of experience level. Use of DWI did not improve agreement. DWI artefacts affecting GTV delineation occurred in almost half of the patients, which may severely limit the use of DWI for radiotherapy planning if no steps are undertaken to avoid them. [ABSTRACT FROM AUTHOR]

Abstract: Background: APO866 is a highly specific inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), inhibition of which reduces cellular NAD+ levels. In this study we addressed the potential of NAD+ depletion as an anti-cancer strategy and assessed the combination with radiation. Methods: The anticipated radiosensitizing property of APO866 was investigated in prostate cancer cell lines PC3 and LNCaP in vitro and in PC3 xenografts in vivo. Results: We show that APO866 treatment leads to NAD+ depletion. Combination experiments with radiation lead to a substantial decrease in clonogenic cell survival in PC3 and LNCaP cells. In PC3 xenografts, treatment with APO866 resulted in reduced intratumoral NAD+ levels and induced significant tumor growth delay. Combined treatment of APO866 and fractionated radiation was more effective than the single modalities. Compared with untreated tumors, APO866 and radiation alone resulted in tumor growth delays of 14days and 33days, respectively, whereas the combination showed a significantly increased tumor growth delay of 65days. Conclusions: Our studies show that APO866-induced NAD+ depletion enhances radiation responses in tumor cell survival in prostate cancer. However, the in vitro data do not reveal a solid cellular mechanism to exploit further clinical development at this moment. [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]

Abstract: Purpose: To quantify the inter-fraction shape variation of the CTV in rectal-cancer patients treated with 5×5 (SCRT) and 25×2Gy (LCRT) and derive PTV margins. Methods and materials: Thirty-three SCRT with daily repeat CT scans and 30 LCRT patients with daily scans during the first week followed by weekly scans were included. The CTV was delineated on all scans and local shape variation was calculated with respect to the planning CT. Margin estimation was done using the local shape variation to assure 95% minimum dose for at least 90% of patients. Results: Using 482 CT scans, systematic and random CTV shape variation was heterogeneous, ranging from 0.2cm close to bony structures up to 1.0cm SD at the upper-anterior CTV region. A significant reduction in rectal volume during LCRT resulted in an average 0.5cm posterior shift of the upper-anterior CTV. Required margins ranged from 0.7cm close to bony structures up to 3.1 and 2.3cm in the upper-anterior region for SCRT and LCRT, respectively. Conclusions: Heterogeneous shape variation demands anisotropic PTV margins. Required margins were substantially larger in the anterior direction compared to current clinical margins. These larger margins were, however, based on strict delineated CTVs, resulting in smaller PTVs compared to current practice. [Copyright &y& Elsevier]

Purpose: Respiratory gating can mitigate the effect of tumor mobility in radiotherapy (RT) for lung cancer. Because the tumor is generally not visualized, external surrogates of tumor position are used to trigger respiration-gated RT. We evaluated the suitability of the carina position as a surrogate in respiration-gated RT. Methods and Materials: A total of 30 four-dimensional (4D) computed tomography (CT) scans from 14 patients with lung cancer were retrospectively analyzed. Both uncoached (free breathing) and audio-coached 4D-CT scans were acquired from 9 patients, and 12 uncoached 4D-CT scans were acquired from 5 other patients during a 2–4-week period of stereotactic RT. The repeat scans were co-registered. The carina position was identified on the coronal cut planes in all 4D-CT phases. The correlation between the carina position and the total lung volume for each phase was determined, and the reproducibility of the carina position was studied in the 5 patients with repeat uncoached 4D-CT scans. Results: The mean extent of carina motion in 21 uncoached scans was 5.3 ± 1.6 mm in the craniocaudal (CC), 2.3 ± 1.4 mm in the anteroposterior, and 1.5 ± 0.7 mm in the mediolateral direction. Audio coaching resulted in a twofold increase in carina mobility in all directions. The CC carina position correlated with changes in the total lung volume (R = 0.89 ± 0.14), but the correlation was better for the audio-coached than for the uncoached 4D-CT scans (R = 0.93 ± 0.08 vs. R = 0.85 ± 0.17; paired t test, p = 0.034). Preliminary data from the 5 patients indicated that the CC carina motion correlated better with tumor motion than did the motion of the diaphragm. Conclusions: The CC position of the carina correlated well with the total lung volume, indicating that the carina is a good surrogate for verifying the total lung volume during respiration-gated RT. [Copyright &y& Elsevier]

Introduction: Standard treatment for patients with intermediate or locally advanced rectal cancer is (chemo)radiotherapy followed by total mesorectal excision (TME) surgery. In recent years, organ preservation aiming at improving quality of life has been explored. Patients with a complete clinical response to (chemo)radiotherapy can be managed safely with a watch-and-wait approach. However, the optimal organ-preserving treatment strategy for patients with a good, but not complete clinical response remains unclear. The aim of the OPAXX study is to determine the rate of organ preservation that can be achieved in patients with rectal cancer with a good clinical response after neoadjuvant (chemo)radiotherapy by additional local treatment options., Methods and Analysis: The OPAXX study is a Dutch multicentre study that investigates the efficacy of two additional local treatments aiming at organ preservation in patients with a good, but not complete response to neoadjuvant treatment (ie near-complete response or a small residual tumour mass <3 cm). The sample size will be 168 patients in total. Patients will be randomised (1:1) between two parallel single-arm phase II studies: study arm 1 involves additional contact X-ray brachytherapy (an intraluminal radiation boost), while in study arm 2 the observation period is extended followed by a second response evaluation and optional transanal local excision. The primary endpoint of the study is the rate of successful organ preservation at 1 year following randomisation. Secondary endpoints include toxicity, morbidity, oncological and functional outcomes at 1 and 2 years of follow-up. Finally, an observational cohort study for patients who are not eligible for randomisation is conducted., Ethics and Dissemination: The trial protocol has been approved by the medical ethics committee of the Netherlands Cancer Institute (METC20.1276/M20PAX). Informed consent will be obtained from all participants. The trial results will be published in an international peer-reviewed journal., Trial Registration Number: NCT05772923., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: PARP-inhibitors have potent radiosensitizing properties in pre-clinical models. To identify the maximum tolerated dose (MTD) of the PARP-inhibitor Olaparib in combination with radiotherapy in patients with head and neck cancer, a single institutional phase-I dose escalation trial was initiated., Patients and Methods: The starting dose of Olaparib was 25 mg BID, combined with radiotherapy (70 Gy in 35 fractions). The MTD was defined as the highest dose-level at which not more than 20 % of patients experience dose-limiting toxicities (DLT) or as the highest reached dose in the absence of DLT's., Results: One week Olaparib-only treatment (25 mg QD) was administered to all patients prior to the start of radiotherapy. In dose-level I, Olaparib (25 mg BID) was combined with accelerated radiotherapy (70 Gy in 6 weeks). Because of DLT's in 3 of the 4 treated patients (acute tracheotomy 5 and 7 months and osteoradionecrosis 7 months after treatment), the Olaparib dose was de-escalated to 25 mg QD, and combined with conventional radiotherapy (70 Gy in 7 weeks) (dose-level II). There were no DLT's observed in 5 patients treated within dose-level II. After a median follow-up of 60 months, the 4-year LRC and OS rates were 77.8 % and 88.9 %, respectively., Conclusion: Olaparib 25 mg QD combined with conventionally fractionated radiotherapy was well tolerated and identified as the MTD while severe DLT's were observed when Olaparib 25 mg BID was combined with accelerated radiation. This combination might be further explored in future Olaparib dose escalation studies in patients with locally-advanced HNSCC unfit for cisplatin-based chemoradiotherapy., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)