Publications by authors named "Evert J Van Limbergen"

21 Publications

  • Page 1 of 1

Development of a Management Algorithm for Acute and Chronic Radiation Urethritis and Cystitis.

Urol Int 2021 Jun 15:1-12. Epub 2021 Jun 15.

Department of Urology, St. Antonius Hospital, Gronau, Germany.

Objective: The purpose of this review was to summarize the current literature on the assessment and treatment of radiation urethritis and cystitis (RUC) for the development of an evidenced-based management algorithm.

Material And Methods: The PubMed/MEDLINE database was searched by a multidisciplinary group of experts in January 2021.

Results: In total, 48 publications were identified. Three different types of RUC can be observed in clinical practice: inflammation-predominant, bleeding-predominant, and the combination of inflammation- and bleeding-RUC. There is no consensus on the optimal treatment of RUC. Inflammation-predominant RUC should be treated symptomatically based on the existence of bothersome storage or voiding lower urinary tract symptom as well as on pain. When bleeding-predominant RUC has occurred, hydration and hyperbaric oxygen therapy (HOT) should be used first and, if HOT is not available, oral drugs instead (sodium pentosane polysulfate, aminocaproic acid, immunokine WF 10, conjugated estrogene, or pentoxifylline + vitamin E). If local bleeding persists, focal therapy of bleeding vessels with a laser or electrocoagulation is indicated. In case of generalized bleeding, intravesical installation should be initiated (formalin, aluminium salts, and hyaluronic acid/chondroitin). Vessel embolization is a less invasive treatment with potentially less complications and good clinical outcomes. Open- or robot-assisted surgery is indicated in patients with permanent, life-threatening bleeding, or fistulae.

Conclusions: Treatment of RUC, if not self-limiting, should be done according to the type of RUC and in a stepwise approach. Conservative/medical treatment (oral and topic agents) should primarily be used before invasive (transurethral) treatments.
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http://dx.doi.org/10.1159/000515716DOI Listing
June 2021

An overview of the published and running randomized phase 3 clinical results of radiotherapy in combination with immunotherapy.

Transl Lung Cancer Res 2021 Apr;10(4):2048-2058

Department of Radiation Oncology (MAASTRO Clinic), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.

Several studies have established that radiotherapy (RT) in combination with immunotherapy (IO) has a strong synergistic effect. RT changes the tumor microenvironment, generates local inflammation reactions, and enhances immunostimulatory effects, which are able to assist IO with improving local and systemic tumor control. In several pre-clinical reports, RT in combination with IO reveals regression of tumors locally (irradiated sites) and systemically (non-irradiated sites). Several clinical trials are currently running, mostly as phase I and II studies. This article provides an overview of the randomized, prospective reported and recruiting phase 3 clinical trials of RT in combination with IO. To date, three phase 3 trials have been published on RT and sequential IO with variable results, ranging from no significant difference (Kwon , START) to absolute differences in overall survival of 13.5% after 3 years (PACIFIC), respectively. No phase 3 randomized trials have been published on the simultaneous combination of RT with IO. Thirty trials are presently under way, and still recruiting patients to quantify the response to RT with IO. These studies fall into three categories of research interests: (I) to discover an enhancement effect of IO as induction therapy with RT; (II) to determine the additional effect of concurrent IO on the local effect of RT; and (III) to determine the additional effect of adjuvant or consolidation IO on the local effect of RT. Most of the ongoing studies are a combination of these interests, with 15 trials evaluating the concurrent RT+IO with IO consolidation strategy. The results in coming years will provide more insights in the role of RT as an activator of the immune system, the effect of IO as local sensitizer of RT, the optimal sequencing of IO with RT, and the total RT doses needed to obtain the optimal local and systemic effect.
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http://dx.doi.org/10.21037/tlcr-20-304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107766PMC
April 2021

Radiation for Oligometastatic Lung Cancer in the Era of Immunotherapy: What Do We (Need to) Know?

Cancers (Basel) 2021 Apr 28;13(9). Epub 2021 Apr 28.

Department of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW, 6229 ET Maastricht, The Netherlands.

Oligometastatic cancer is recognized as a separate entity within the spectrum of metastatic disease. It was suggested that patients with oligometastatic disease can obtain long-term survival by giving local ablative therapy (LAT) to all visible disease locations. However, the true extent from which metastatic cancer should be called "oligometastatic" is unknown, although a consensus definition for oligometastatic disease is proposed by research organizations, such as the EORTC (maximum of five metastases in three organs). Different states of the oligometastatic disease are defined, such as synchronous vs. metachronous, oligopersistent vs. oligoprogressive disease. All clinical trials including patients with non-small cell lung cancer (NSCLC) are small and most are not randomized. Two small randomized phase II trials on synchronous disease showed an improvement in progression free survival, with the addition of LAT, and one also demonstrated an overall survival benefit. Immune checkpoint inhibitors (ICI) were not part of the treatment in these trials, while ICI significantly improved long-term outcomes of patients with metastatic NSCLC. Radiotherapy might improve the prognosis of patients treated with ICI because of its immunostimulatory effects and the possibility to eradicate metastatic deposits. Here, we summarize the data for adding ablative radiotherapy to the treatment of oligometastatic NSCLC, especially in the ICI era, and discuss the challenges of combined treatment.
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http://dx.doi.org/10.3390/cancers13092132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125691PMC
April 2021

Is prostate cancer radiotherapy using implantable rectum spacers safe and effective in inflammatory bowel disease patients?

Clin Transl Radiat Oncol 2021 Mar 25;27:121-125. Epub 2021 Jan 25.

Department of Radiation Oncology (MAASTRO), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, the Netherlands.

Background: Prostate cancer radiotherapy (RT) in patients with (active) inflammatory bowel disease (IBD) remains controversial. We hypothesized that RT in combination with a biodegradable prostate-rectum spacer balloon implantation, might be a safe treatment approach with acceptable toxicities for these high risk for rectal toxicity patients.

Materials And Methods: We report on a small prospective mono-centric series of 8 patients with all-risk prostate cancer with the comorbidity of an IBD. Four patients had Crohn's disease and 4 patients had ulcerative colitis. One out of four had an active status of IBD. All patients were intended to be treated with curative high-dose RT: 5 patients were treated with external beam RT (70 Gray (Gy) in 28 fractions), and 3 patients were treated with I-implant (145 Gy). Toxicities were scored according to the CTCAE v4.03: acute side effects occur up to 3 months after RT, and late side effects start after 3 months.

Results: Median follow-up was 13 months (range: 3-42 months). Only one acute grade 2 gastro-intestinal (GI) toxicity was observed: an increased diarrhea (4-6 above baseline) during RT, which resolved completely 6 weeks after treatment. No late grade 3 or more GI toxicity was reported, and no acute and late grade ≥2 genitourinary toxicity events were observed.

Conclusion: Prostate cancer patients with IBD are a challenge to treat with RT. Our results suggest that RT in combination with a balloon implant in selective patients with (active) IBD may be promising, however additional validation is needed.
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http://dx.doi.org/10.1016/j.ctro.2021.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875819PMC
March 2021

Immunotherapy as sensitizer for local radiotherapy.

Oncoimmunology 2020 10 30;9(1):1832760. Epub 2020 Oct 30.

Department of Radiation Oncology (MAASTRO Clinic), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.

The purpose of this report was to systematically review the radiation enhancement factor (REF) effects of immunotherapy on radiotherapy (RT) to the local tumor in comparison with other traditional radiation sensitizers such as cisplatin. PubMed and Medline databases were searched until February 2019. Reports with abscopal effect in the results were excluded. Graphs of the selected papers were digitized using Plot Digitizer (Sourceforge.net) in order to calculate the tumor growth delay (TGD) caused by immunotherapy. To enable comparison between different studies,the TGD were used to define the REF between RT versus the RT/immunotherapy combination. Thirty-two preclinical papers, and nine clinical series were selected. Different mouse models were exposed to RT doses ranging from 1 to 10 fractions of 1.8 to 20 Gray (Gy) per fraction. Endpoints were heterogeneous, ranging from regression to complete local response. No randomized clinical studies were identified. The median preclinical REF effect of different immunotherapy was varying from 1.7 to 9.1. There was no relationship observed either with subclasses of immunotherapy orRT doses. In the clinical studies, RT doses ranged from 1 to 37 fractions of 1.8 to 24 Gy per fraction. Most clinical trials used ipilimumab and interleukin-2. Local control rate in the clinical series ranged from 66% to 100%. A strong REF of immunotherapy (1.7 to 9.1) was observed, this being higher than traditionally sensitizers such as cisplatin (1.1). This result implies that for the same RT dose, a higher local control was achieved with a combination of immunotherapy and RT in preclinical settings. This study therefore supports the use of combined RT and immunotherapy to improve local tumor control in clinical settings without exacerbation of toxicities.
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http://dx.doi.org/10.1080/2162402X.2020.1832760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605354PMC
October 2020

Stereotactic ablative body radiotherapy (SABR) combined with immunotherapy (L19-IL2) versus standard of care in stage IV NSCLC patients, ImmunoSABR: a multicentre, randomised controlled open-label phase II trial.

BMC Cancer 2020 Jun 15;20(1):557. Epub 2020 Jun 15.

The D-Lab and The M-Lab, Department of Precision Medicine, GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.

Background: About 50% of non-small cell lung cancer (NSCLC) patients have metastatic disease at initial diagnosis, which limits their treatment options and, consequently, the 5-year survival rate (15%). Immune checkpoint inhibitors (ICI), either alone or in combination with chemotherapy, have become standard of care (SOC) for most good performance status patients. However, most patients will not obtain long-term benefit and new treatment strategies are therefore needed. We previously demonstrated clinical safety of the tumour-selective immunocytokine L19-IL2, consisting of the anti-ED-B scFv L19 antibody coupled to IL2, combined with stereotactic ablative radiotherapy (SABR).

Methods: This investigator-initiated, multicentric, randomised controlled open-label phase II clinical trial will test the hypothesis that the combination of SABR and L19-IL2 increases progression free survival (PFS) in patients with limited metastatic NSCLC. One hundred twenty-six patients will be stratified according to their metastatic load (oligo-metastatic: ≤5 or poly-metastatic: 6 to 10) and randomised to the experimental-arm (E-arm) or the control-arm (C-arm). The C-arm will receive SOC, according to the local protocol. E-arm oligo-metastatic patients will receive SABR to all lesions followed by L19-IL2 therapy; radiotherapy for poly-metastatic patients consists of irradiation of one (symptomatic) to a maximum of 5 lesions (including ICI in both arms if this is the SOC). The accrual period will be 2.5-years, starting after the first centre is initiated and active. Primary endpoint is PFS at 1.5-years based on blinded radiological review, and secondary endpoints are overall survival, toxicity, quality of life and abscopal response. Associative biomarker studies, immune monitoring, CT-based radiomics, stool collection, iRECIST and tumour growth rate will be performed.

Discussion: The combination of SABR with or without ICI and the immunocytokine L19-IL2 will be tested as 1st, 2nd or 3rd line treatment in stage IV NSCLC patients in 14 centres located in 6 countries. This bimodal and trimodal treatment approach is based on the direct cytotoxic effect of radiotherapy, the tumour selective immunocytokine L19-IL2, the abscopal effect observed distant from the irradiated metastatic site(s) and the memory effect. The first results are expected end 2023.

Trial Registration: ImmunoSABR Protocol Code: NL67629.068.18; EudraCT: 2018-002583-11; Clinicaltrials.gov: NCT03705403; ISRCTN ID: ISRCTN49817477; Date of registration: 03-April-2019.
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http://dx.doi.org/10.1186/s12885-020-07055-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296663PMC
June 2020

Advanced design, simulation, and dosimetry of a novel rectal applicator for contact brachytherapy with a conventional HDR Ir source.

Brachytherapy 2020 Jul - Aug;19(4):544-553. Epub 2020 May 6.

Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands. Electronic address:

Purpose: Dose escalation yields higher complete response to rectal tumors, which may enable the omission of surgery. Dose escalation using 50 kVp contact x-ray brachytherapy (CXB) allow the treatment of a selective volume, resulting in low toxicity and organs-at-risk preservation. However, the use of CXB devices is limited because of its high cost and lack of treatment planning tools. Hence, the MAASTRO applicator (for HDR Ir sources) was developed and characterized by measurements and Monte Carlo simulations to be a cost-effective alternative to CXB devices.

Methods And Materials: A cylindrical applicator with lateral shielding was designed to be used with a rectoscope using its tip as treatment surface. Both the applicator and the rectoscope have a slanted edge to potentially allow easier placement against tumors. The applicator design was achieved by Monte Carlo modeling and validated experimentally with film dosimetry, using the Papillon 50 (P50) device as reference.

Results: The applicator delivers CXB doses in less than 9 min using a 20375 U source for a treatment area of approximately 20 × 20 mm at 2 mm depth. Normalized at 2 mm, the dose falloff for depths of 0 mm, 5 mm, and 10 mm are 130%, 70%, and 43% for the P50 and 140%, 67%, and 38% for the MAASTRO applicator, respectively.

Conclusions: The MAASTRO applicator was designed to use HDR Ir sources to deliver a dose distribution similar to those of CXB devices. The applicator may provide a cost-effective solution for endoluminal boosting with clinical treatment planning system integration.
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http://dx.doi.org/10.1016/j.brachy.2020.03.009DOI Listing
April 2021

Human fibronectin extra domain B as a biomarker for targeted therapy in cancer.

Mol Oncol 2020 07 15;14(7):1555-1568. Epub 2020 Jun 15.

The M-Lab, Department of Precision Medicine, GROW - School for Oncology and Developmental Biology, Maastricht University, The Netherlands.

The extracellular matrix protein fibronectin contains a domain that is rarely found in healthy adults and is almost exclusively expressed by newly formed blood vessels in tumours, particularly in solid tumours, different types of lymphoma and some leukaemias. This domain, called the extra domain B (ED-B), thus has broad therapeutic potential. The antibody L19 has been developed to specifically target ED-B and has shown therapeutic potential when combined with cytokines, such as IL-2. In this review article, we discuss the preclinical research and clinical trials that highlight the potential of ED-B targeting for the imaging and treatment of various types of cancer. ED-B-centred studies also highlight how proper patient stratification is of utmost importance for the successful implementation of novel antibody-based targeted therapies.
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http://dx.doi.org/10.1002/1878-0261.12705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332215PMC
July 2020

Microscopic intramural extension of rectal cancer after neoadjuvant chemoradiation: A meta-analysis based on individual patient data.

Radiother Oncol 2020 03 9;144:37-45. Epub 2019 Nov 9.

Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, The Netherlands. Electronic address:

Objective: In selected rectal cancer patients with residual local disease following neoadjuvant chemoradiation (CRT) and the preference of an organ preservation pathway, additional treatment with dose escalation by endoluminal radiotherapy (RT) may ultimately result in a clinical complete response. To date, the widespread introduction of selective endoluminal radiation techniques is hampered by a lack of evidence-based guidelines that describe the radiation treatment volume in relation to the residual tumor mass. In order to convert an incomplete response into a complete one with additional treatment such as dose-escalation with endoluminal RT from a theoretical perspective, it seems important to treat all remaining microscopic tumor cells after CRT. In this setting, residual tumor extension beneath normal appearing mucosa (microscopic intramural spread - MIS) becomes relevant for accurate tumor volume and margin estimation. With the goal of providing evidence-based guidelines that define an appropriate treatment volume and patient selection, we present results from a meta-analysis based on individual patient data of studies that have assessed the extent or range of MIS of rectal cancers after neoadjuvant CRT. This meta-analysis should provide an estimate of the residual tumor volume/extension that needs to be targeted by any additional radiation therapy boost in order to achieve complete tumor eradication after initial incomplete or near-complete response following standard CRT.

Methods And Materials: A PubMed search was performed. Additional articles were selected based on identification from reference lists. Papers were eligible when reporting MIS in patients who were treated by total mesorectal excision or local excision/transanal endoscopic microsurgery (TEM) after neo-adjuvant long-course CRT. The mean MIS was calculated for the entire group along with the 70th until 95th percentiles. Additional exploratory subgroup analyses were performed.

Results: Individual patient data from 349 patients with residual disease from five studies were analyzed. 80% of tumors showed no MIS. In order to appropriately treat MIS in 95% of rectal cancer patients after CRT, a margin of 5.5 mm around the macroscopic tumor would suffice. An exploratory subgroup analysis showed that T-stage after CRT (ypT) and time interval between neoadjuvant CRT and surgery are significant factors predicting the extent of MIS (p < 0.001.) The group of ypT1 had the smallest MIS, followed by the ypT3-4 group, while the ypT2 group had the largest MIS (p < 0.001). Regarding time interval between CRT and surgery, a statistically significant difference was seen when comparing the three time-interval groups (less than 8 weeks, 8-12 weeks, and more than 12 weeks), where waiting more than 12 weeks after CRT resulted in the largest MIS (p < 0.0001).

Conclusion: Based on this meta-analysis, in order to treat the MIS for 95% of rectal cancer patients after CRT, a Clinical Target Volume (CTV) margin of 5.5 mm from the lateral most edge of the macroscopic tumor would suffice. 80% of tumors showed no MIS and would not require an extra CTV margin for treatment. These findings support the feasibility of localized radiotherapy boosts for dose-escalation to improve response among patients with incomplete response after standard CRT and can also be applied in the surgical setting.
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http://dx.doi.org/10.1016/j.radonc.2019.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104917PMC
March 2020

Development and validation of a patient decision aid for prostate Cancer therapy: from paternalistic towards participative shared decision making.

BMC Med Inform Decis Mak 2019 07 11;19(1):130. Epub 2019 Jul 11.

Department of Radiation Oncology (MAASTRO Clinic), GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre+, Dr. Tanslaan 12, 6229, ET, Maastricht, The Netherlands.

Background: Patient decision aids (PDAs) can support the treatment decision making process and empower patients to take a proactive role in their treatment pathway while using a shared decision-making (SDM) approach making participatory medicine possible. The aim of this study was to develop a PDA for prostate cancer that is accurate and user-friendly.

Methods: We followed a user-centered design process consisting of five rounds of semi-structured interviews and usability surveys with topics such as informational/decisional needs of users and requirements for PDAs. Our user-base consisted of 8 urologists, 4 radiation oncologists, 2 oncology nurses, 8 general practitioners, 19 former prostate cancer patients, 4 usability experts and 11 healthy volunteers.

Results: Informational needs for patients centered on three key factors: treatment experience, post-treatment quality of life, and the impact of side effects. Patients and clinicians valued a PDA that presents balanced information on these factors through simple understandable language and visual aids. Usability questionnaires revealed that patients were more satisfied overall with the PDA than clinicians; however, both groups had concerns that the PDA might lengthen consultation times (42 and 41%, respectively). The PDA is accessible on http://beslissamen.nl/ .

Conclusions: User-centered design provided valuable insights into PDA requirements but challenges in integrating diverse perspectives as clinicians focus on clinical outcomes while patients also consider quality of life. Nevertheless, it is crucial to involve a broad base of clinical users in order to better understand the decision-making process and to develop a PDA that is accurate, usable, and acceptable.
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http://dx.doi.org/10.1186/s12911-019-0862-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624887PMC
July 2019

[Result of the STAMPEDE trial; plausibility and practical consequences].

Ned Tijdschr Geneeskd 2019 05 31;163. Epub 2019 May 31.

MAASTRO Clinic, Maastricht.

Recently, the results of the STAMPEDE trial arm H were reported. This trial investigated the effect of radiotherapy to the prostate only on the overall survival of patients with metastatic prostate cancer. Although on the whole the findings of the trial were negative, a significant increase in survival was noted in the prespecified subgroup of patients with a low metastatic burden. As only a few analyses were prespecified, the direction of the subgroup effect was prespecified and consistent with previous observations from the separate but comparable HORRAD trial. The subgroup effect was large and independent of other subgroup variables, and as there is a solid biological rationale for these results, they are to be considered trustworthy, and are likely to change clinical practice. Further research should focus on better specification of the low metastatic burden subgroup, if other locally ablative treatments such as surgery are equivalent, and if ablation of all metastatic lesions would give additional benefit.
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May 2019

Corrigendum to A systematic review comparing radiation toxicity after various endorectal techniques, by Verrijssen et al., Brachytherapy. 2019 Jan - Feb;18(1):71-86.e5.

Brachytherapy 2019 May - Jun;18(3):427

Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.

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http://dx.doi.org/10.1016/j.brachy.2019.03.010DOI Listing
May 2019

A systematic review comparing radiation toxicity after various endorectal techniques.

Brachytherapy 2019 Jan - Feb;18(1):71-86.e5. Epub 2018 Nov 3.

Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.

Purpose: A clinical complete response is seen after neoadjuvant chemoradiation for rectal tumors in 15%-20% of patients. These patients can potentially be spared mutilating total mesorectal excision surgery through a watch-and-wait policy. Recent studies show that dose escalation by a radiation boost increases the clinical complete response rate. The boost dose to the tumor can be administered through external beam radiotherapy or through internal radiotherapy using techniques like contact therapy, low-dose-rate or high-dose-rate brachytherapy (BT). However, limited information is available concerning treatment-related toxicity of these techniques. With this systematic review, we aim to summarize and compare published data concerning acute and late toxicity after contact X-ray therapy (CXT) and BT for rectal cancer.

Methods And Materials/results: Thirty-eight studies reporting toxicity after endorectal radiation techniques for rectal cancer were included, resulting in 3682 patients for analysis. Direct comparison of toxicity by the different radiation modes was hampered by various combinations of endorectal techniques, a lack of clear reporting of toxicity scores, dose prescription, technique used, and treated volumes. ≥ Grade 3 rectal toxicity was reported in 2.9% of patients having received only CXT; 6.3% of patients who received only BT had Grade 3 rectal toxicity, and BT also caused Grade 3 urinary toxicity in 1 patient.

Conclusion: All techniques reported some ≥ Grade 3 toxicity. Toxicity after CXT was confined to the rectum, whereas after BT, urogenital toxicity and skin toxicity were seen as well. Unfortunately, few specific conclusions could be drawn regarding the dose-related risk of toxicity for the various techniques due to nonuniform reporting strategies and missing information. To enable future comparisons and improvements, the endorectal radiation field urgently needs consensus guidelines on dose reporting, dose prescription, treatment volume specification, and toxicity reporting.
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http://dx.doi.org/10.1016/j.brachy.2018.10.001DOI Listing
April 2019

A novel rectal applicator for contact radiotherapy with HDR Ir sources.

Brachytherapy 2018 Nov - Dec;17(6):1037-1044. Epub 2018 Aug 16.

Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands. Electronic address:

Purpose: Dose escalation to rectal tumors leads to higher complete response rates and may thereby enable omission of surgery. Important advantages of endoluminal boosting techniques include the possibility to apply a more selective/localized boost than using external beam radiotherapy. A novel brachytherapy (BT) rectal applicator with lateral shielding was designed to be used with a rectoscope for eye-guided positioning to deliver a dose distribution similar to the one of contact x-ray radiotherapy devices, using commonly available high-dose-rate Ir BT sources.

Methods And Materials: A cylindrical multichannel BT applicator with lateral shielding was designed by Monte Carlo modeling, validated experimentally with film dosimetry and compared with results found in the literature for the Papillon 50 (P50) contact x-ray radiotherapy device regarding rectoscope dimensions, radiation beam shape, dose fall-off, and treatment time.

Results: The multichannel applicator designed is able to deliver 30 Gy under 13 min with a 20350 U (5 Ci) source. The use of multiple channels and lateral shielding provide a uniform circular treatment surface with 22 mm in diameter. The resulting dose fall-off is slightly steeper (maximum difference of 5%) than the one generated by the P50 device with the 22 mm applicator.

Conclusions: A novel multichannel rectal applicator for contact radiotherapy with high-dose-rate Ir sources that can be integrated with commercially available treatment planning systems was designed to produce a dose distribution similar to the one obtained by the P50 device.
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http://dx.doi.org/10.1016/j.brachy.2018.07.012DOI Listing
April 2019

The immunocytokine L19-IL2: An interplay between radiotherapy and long-lasting systemic anti-tumour immune responses.

Oncoimmunology 2018;7(4):e1414119. Epub 2018 Jan 16.

Department of Radiotherapy, The M-Lab group, GROW - School for Oncology and Developmental Biology, Maastricht Comprehensive Cancer Centre, Maastricht University Medical Centre, Maastricht, The Netherlands.

Recently, we have shown that the administration of the tumour-targeted antibody-based immunocytokine L19-IL2 after radiotherapy (RT) resulted in synergistic anti-tumour effect. Here we show that RT and L19-IL2 can activate a curative abscopal effect, with a long-lasting immunological memory. Ionizing radiation (single dose of 15Gy, 5 × 2Gy or 5 × 5Gy) was delivered to primary C51 colon tumour-bearing immunocompetent mice in combination with L19-IL2 and response of secondary non-irradiated C51 or CT26 colon tumours was evaluated. 15Gy + L19-IL2 triggered a curative (20%) abscopal effect, which was T cell dependent. Moreover, 10Gy + L19-IL2 treated and cured mice were re-injected after 150 days with C51 tumour cells and tumour uptake was assessed. Age-matched controls (matrigel injected mice treated with 10Gy + L19-IL2, mice cured after treatment with surgery + L19-IL2 and mice cured after high dose RT 40Gy + vehicle) were included. Several immunological parameters in blood, tumours, lymph nodes and spleens were investigated. Treatment with 10Gy + L19-IL2 resulted in long-lasting immunological memory, associated with CD44CD127 expression on circulating T cells. This combination treatment can induce long-lasting curative abscopal responses, and therefore it has also great potential for treatment of metastatic disease. Preclinical findings have led to the initiation of a phase I clinical trial (NCT02086721) in our institute investigating stereotactic ablative radiotherapy with L19-IL2 in patients with oligometastatic solid tumours.
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http://dx.doi.org/10.1080/2162402X.2017.1414119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889197PMC
January 2018

A biodegradable rectal balloon implant to protect the rectum during prostate cancer radiotherapy for a patient with active Crohn's disease.

Tech Innov Patient Support Radiat Oncol 2018 Jun 20;6:1-4. Epub 2018 Mar 20.

Department of Radiation Oncology (MAASTRO), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, The Netherlands.

Background: Radiotherapy in patients with active inflammatory bowel disease (IBD) is usually considered an absolute exclusion criterion for prostate cancer radiotherapy treatment.There are no reports available on the use of a biodegradable rectal balloon implantation (RBI) in patients with active IBD for prostate cancer radiotherapy.

Case Presentation: We report on a patient with high-risk prostate cancer with the comorbidity of an active IBD with pancolitis location. He was treated with neo-adjuvant hormonal therapy and high-dose external beam radiotherapy to the prostate and the seminal vesicles. Before radiotherapy treatment, a biodegradable RBI was implanted between the prostate and the anterior rectal wall to push the rectum outside of the high-dose area. This patient at high-risk for rectal toxicity was successfully irradiated to his prostate with only a grade I urinary toxicity, no acute rectal toxicity or toxicity flare of the IBD.

Conclusions: This case describes the use of a RBI implantation in patients with active IBD for prostate cancer radiotherapy. The use of a biodegradable RBI proved to be a promised solution for such patients, and have to be further investigated.
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http://dx.doi.org/10.1016/j.tipsro.2018.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033750PMC
June 2018

Online pretreatment verification of high-dose rate brachytherapy using an imaging panel.

Phys Med Biol 2017 Jul;62(13):5440-5461

Department of Radiation Oncology (MAASTRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Dr. Tanslaan 12, Maastricht 6229 ET, Netherlands.

Brachytherapy is employed to treat a wide variety of cancers. However, an accurate treatment verification method is currently not available. This study describes a pre-treatment verification system that uses an imaging panel (IP) to verify important aspects of the treatment plan. A detailed modelling of the IP was only possible with an extensive calibration performed using a robotic arm. Irradiations were performed with a high dose rate (HDR) Ir source within a water phantom. An empirical fit was applied to measure the distance between the source and the detector so 3D Cartesian coordinates of the dwell positions can be obtained using a single panel. The IP acquires 7.14 fps to verify the dwell times, dwell positions and air kerma strength (Sk). A gynecological applicator was used to create a treatment plan that was registered with a CT image of the water phantom used during the experiments for verification purposes. Errors (shifts, exchanged connections and wrong dwell times) were simulated to verify the proposed verification system. Cartesian source positions (panel measurement plane) have a standard deviation of about 0.02 cm. The measured distance between the source and the panel (z-coordinate) have a standard deviation up to 0.16 cm and maximum absolute error of  ≈0.6 cm if the signal is close to sensitive limit of the panel. The average response of the panel is very linear with Sk. Therefore, Sk measurements can be performed with relatively small errors. The measured dwell times show a maximum error of 0.2 s which is consistent with the acquisition rate of the panel. All simulated errors were clearly identified by the proposed system. The use of IPs is not common in brachytherapy, however, it provides considerable advantages. It was demonstrated that the IP can accurately measure Sk, dwell times and dwell positions.
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http://dx.doi.org/10.1088/1361-6560/aa7028DOI Listing
July 2017

Combining radiotherapy with immunotherapy: the past, the present and the future.

Br J Radiol 2017 Aug 25;90(1076):20170157. Epub 2017 May 25.

1 Department of Radiation Oncology (MAASTRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, Netherlands.

The advent of immunotherapy is currently revolutionizing the field of oncology, where different drugs are used to stimulate different steps in a failing cancer immune response chain. This review gives a basic overview of the immune response against cancer, as well as the historical and current evidence on the interaction of radiotherapy with the immune system and the different forms of immunotherapy. Furthermore the review elaborates on the many open questions on how to exploit this interaction to the full extent in clinical practice.
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http://dx.doi.org/10.1259/bjr.20170157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603954PMC
August 2017

Prostate Cancer Radiation Therapy: What Do Clinicians Have to Know?

Biomed Res Int 2016 28;2016:6829875. Epub 2016 Dec 28.

Department of Radiation Oncology (MAASTRO Clinic), GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, Netherlands.

Radiotherapy (RT) for prostate cancer (PC) has steadily evolved over the last decades, with improving biochemical disease-free survival. Recently population based research also revealed an association between overall survival and doses ≥ 75.6 Gray (Gy) in men with intermediate- and high-risk PC. Examples of improved RT techniques are image-guided RT, intensity-modulated RT, volumetric modulated arc therapy, and stereotactic ablative body RT, which could facilitate further dose escalation. Brachytherapy is an internal form of RT that also developed substantially. New devices such as rectum spacers and balloons have been developed to spare rectal structures. Newer techniques like protons and carbon ions have the intrinsic characteristics maximising the dose on the tumour while minimising the effect on the surrounding healthy tissue, but clinical data are needed for confirmation in randomised phase III trials. Furthermore, it provides an overview of an important discussion issue in PC treatment between urologists and radiation oncologists: the comparison between radical prostatectomy and RT. Current literature reveals that all possible treatment modalities have the same cure rate, but a different toxicity pattern. We recommend proposing the possible different treatment modalities with their own advantages and side-effects to the individual patient. Clinicians and patients should make treatment decisions together () while using patient decision aids.
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http://dx.doi.org/10.1155/2016/6829875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5225325PMC
February 2017

Chronic radiation proctitis: tricks to prevent and treat.

Int J Colorectal Dis 2015 Oct 23;30(10):1293-303. Epub 2015 Jul 23.

Department of Radiation Oncology (MAASTRO Clinic), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 3035, 6202 NA, Maastricht, The Netherlands.

Objective: The purpose of this study was to give an overview of the measures used to prevent chronic radiation proctitis (CRP) and to provide an algorithm for the treatment of CRP.

Methods: Medical literature databases including PubMed and Medline were screened and critically analyzed for relevance in the scope of our purpose.

Results: CRP is a relatively frequent late side effect (5-20%) and mainly dependent on the dose and volume of irradiated rectum. Radiation treatment (RT) techniques to prevent CRP are constantly improving thanks to image-guided RT and intensity-modulated RT. Also, newer techniques like protons and new devices such as rectum spacers and balloons have been developed to spare rectal structures. Biopsies do not contribute to diagnosing CRP and should be avoided because of the risk of severe rectal wall damage, such as necrosis and fistulas. There is no consensus on the optimal treatment of CRP. A variety of possibilities is available and includes topical and oral agents, hyperbaric oxygen therapy, and endoscopic interventions.

Conclusions: CRP has a natural history of improving over time, even without treatment. This is important to take into account when considering these treatments: first be conservative (topical and oral agents) and be aware that invasive treatments can be very toxic.
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http://dx.doi.org/10.1007/s00384-015-2289-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575375PMC
October 2015

Combination of radiotherapy with the immunocytokine L19-IL2: Additive effect in a NK cell dependent tumour model.

Radiother Oncol 2015 Sep 29;116(3):438-42. Epub 2015 Jun 29.

Department of Radiation Oncology (MAASTRO), Division of Hematology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, The Netherlands.

Background And Purpose: Recently, we have shown that radiotherapy (RT) combined with the immunocytokine L19-IL2 can induce long-lasting antitumour effects, dependent on ED-B expression and infiltration of cytotoxic T cells. On the other hand, in certain tumours, IL2 treatment can trigger a natural killer cell (NK) immune response. The aim of this study is to investigate the therapeutic effect of our combination therapy in the ED-B positive F9 teratocarcinoma model, lacking MHCI expression and known to be dependent on NK immune responses.

Material And Methods: In syngeneic F9 tumour bearing 129/FvHsd mice tumour growth delay was evaluated after local tumour irradiation (10Gy) combined with systemic administration of L19-IL2. Immunological responses were investigated using flow cytometry.

Results: Tumour growth delay of L19-IL2 can be further improved by a single dose of RT administered before immunotherapy, but not during immunotherapy. Furthermore, treatment of L19-IL2 favours a NK response and lacks cytotoxic T cell tumour infiltrating immune cells, which may be explained by the absence of MHCI expression.

Conclusion: An additive effect can be detected when the NK dependent F9 tumour model is treated with radiotherapy and L19-IL2 and therefore this combination could be useful in the absence of tumoural MHCI expression.
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http://dx.doi.org/10.1016/j.radonc.2015.06.019DOI Listing
September 2015
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