Optimizing patient selection for stereotactic ablative radiotherapy in patients with locally advanced pancreatic cancer after initial chemotherapy - a single center prospective cohort.

Background: The role of stereotactic ablative radiation therapy (SABR) as local treatment option after chemotherapy for locally advanced pancreatic cancer (LAPC) is evolving. However adequate patient selection criteria for SABR in patients with LAPC are lacking. Methods: A prospective institutional database collected data of patients with LAPC treated with chemotherapy, mainly FOLFIRINOX, followed by SABR, which was delivered using magnetic resonance guided radiotherapy, 40 Gy in 5 fractions within two weeks. Primary endpoint was overall survival (OS). Cox regression analyses were performed to identify predictors for OS. Results: Overall, 74 patients were included, median age 66 years, 45.9% had a KPS score of ≥90. Median OS was 19.6 months from diagnosis and 12.1 months from start of SABR. Local control was 90% at one year. Multivariable Cox regression analyses identified KPS ≥90, age <70, and absence of pain prior to SABR as independent favorable predictors for OS. The rate of grade ≥3 fatigue and late gastro-intestinal toxicity was 2.7%. Conclusions: SABR is a well-tolerated treatment in patients with unresectable LAPC following chemotherapy, with better outcomes when applied in patients with higher performance score, age <70 years and absence of pain. Future randomized trials will have to confirm these findings.

Stereotactic ablative radiotherapy or best supportive care in patients with localized pancreatic cancer not receiving chemotherapy and surgery (PANCOSAR): a nationwide multicenter randomized controlled trial according to a TwiCs design.

BACKGROUND: Significant comorbidities, advanced age, and a poor performance status prevent surgery and systemic treatment for many patients with localized (non-metastatic) pancreatic ductal adenocarcinoma (PDAC). These patients are currently treated with 'best supportive care'. Therefore, it is desirable to find a treatment option which could improve both disease control and quality of life in these patients. A brief course of high-dose high-precision radiotherapy i.e. stereotactic ablative body radiotherapy (SABR) may be feasible. METHODS: A nationwide multicenter trial performed within a previously established large prospective cohort (the Dutch Pancreatic cancer project; PACAP) according to the 'Trial within cohorts' (TwiCs) design. Patients enrolled in the PACAP cohort routinely provide informed consent to answer quality of life questionnaires and to be randomized according to the TwiCs design when eligible for a study. Patients with localized PDAC who are unfit for chemotherapy and surgery or those who refrain from these treatments are eligible. Patients will be randomized between SABR (5 fractions of 8 Gy) with 'best supportive care' and 'best supportive care' only. The primary endpoint is overall survival from randomization. Secondary endpoints include preservation of quality of life (EORTC-QLQ-C30 and -PAN26), NRS pain score response and WHO performance scores at baseline, and, 3, 6 and 12 months. Acute and late toxicity will be scored using CTCAE criteria version 5.0: assessed at baseline, day of last fraction, at 3 and 6 weeks, and 3, 6 and 12 months following SABR. DISCUSSION: The PANCOSAR trial studies the added value of SBRT as compared to 'best supportive care' in patients with localized PDAC who are medically unfit to receive chemotherapy and surgery, or refrain from these treatments. This study will assess whether SABR, in comparison to best supportive care, can relieve or delay tumor-related symptoms, enhance quality of life, and extend survival in these patients. TRIAL REGISTRATION: Clinical trials, NCT05265663 , Registered March 3 2022, Retrospectively registered.

The clinical introduction of MR-guided radiation therapy from a RTT perspective.

The latest development in radiation oncology departments towards high precision and adaptive radiation therapy is the clinical introduction of magnetic resonance image guided radiation therapy (MRgRT). Early 2016, patient treatment using MRgRT was started at Amsterdam UMC, location VU University Medical Center. Introducing this novel technique in clinical practice requires thorough preparation with regard to important topics, such as MR-safety and training, equipping the treatment vault and console room, development of MRgRT workflow and logistical issues. Certainly when MRgRT is combined with daily plan adaptation, this indicates adjusting existing workflows and protocols. The MRgRT workflow requires a multidisciplinary process, and while each discipline has had its own tasks and responsibilities, with growing clinical experience there has been a shift towards RTT responsibilities. In this overview we discuss preclinical training and preparation for the implementation of (adaptive) MRgRT, with a particular focus on the perspective of RTTs. Although the reviewed logistics are partly the result of the decision to perform daily plan re-optimization, our experience can be extrapolated to implementation of alternative approaches for MRgRT.

MR-guidance in clinical reality: current treatment challenges and future perspectives.

Magnetic Resonance-guided radiotherapy (MRgRT) marks the beginning of a new era. MR is a versatile and suitable imaging modality for radiotherapy, as it enables direct visualization of the tumor and the surrounding organs at risk. Moreover, MRgRT provides real-time imaging to characterize and eventually track anatomical motion. Nevertheless, the successful translation of new technologies into clinical practice remains challenging. To date, the initial availability of next-generation hybrid MR-linac (MRL) systems is still limited and therefore, the focus of the present preview was on the initial applicability in current clinical practice and on future perspectives of this new technology for different treatment sites.MRgRT can be considered a groundbreaking new technology that is capable of creating new perspectives towards an individualized, patient-oriented planning and treatment approach, especially due to the ability to use daily online adaptation strategies. Furthermore, MRL systems overcome the limitations of conventional image-guided radiotherapy, especially in soft tissue, where target and organs at risk need accurate definition. Nevertheless, some concerns remain regarding the additional time needed to re-optimize dose distributions online, the reliability of the gating and tracking procedures and the interpretation of functional MR imaging markers and their potential changes during the course of treatment. Due to its continuous technological improvement and rapid clinical large-scale application in several anatomical settings, further studies may confirm the potential disruptive role of MRgRT in the evolving oncological environment.

Fast and robust online adaptive planning in stereotactic MR-guided adaptive radiation therapy (SMART) for pancreatic cancer.

BACKGROUND AND PURPOSE: To implement a robust and fast stereotactic MR-guided adaptive radiation therapy (SMART) online strategy in locally advanced pancreatic cancer (LAPC). MATERIAL AND METHODS: SMART strategy for plan adaptation was implemented with the MRIdian system (ViewRay Inc.). At each fraction, OAR (re-)contouring is done within a distance of 3cm from the PTV surface. Online plan re-optimization is based on robust prediction of OAR dose and optimization objectives, obtained by building an artificial neural network (ANN). Proposed limited re-contouring strategy for plan adaptation (SMART3CM) is evaluated by comparing 50 previously delivered fractions against a standard (re-)planning method using full-scale OAR (re-)contouring (FULLOAR). Plan quality was assessed using PTV coverage (V95%, Dmean, D1cc) and institutional OAR constraints (e.g. V33Gy). RESULTS: SMART3CM required a significant lower number of optimizations than FULLOAR (4 vs 18 on average) to generate a plan meeting all objectives and institutional OAR constraints. PTV coverage with both strategies was identical (mean V95%=89%). Adaptive plans with SMART3CM exhibited significant lower intermediate and high doses to all OARs than FULLOAR, which also failed in 36% of the cases to adhere to the V33Gy dose constraint. CONCLUSIONS: SMART3CM approach for LAPC allows good OAR sparing and adequate target coverage while requiring only limited online (re-)contouring from clinicians.

Central neurotoxicity of standard treatment in patients with newly-diagnosed high-grade glioma: a prospective longitudinal study.

Following tumor resection, the majority of high-grade glioma (HGG) patients are treated with a combined modality regimen of radiotherapy and temozolomide. As a result of the tumor itself or as treatment-related neurotoxic side-effects, these patients may experience cognitive deficits. Additionally, radiological abnormalities expressed as white matter hyperintensities (WMH) and cerebral atrophy (CA) can develop. In this study, these functional and morphological parameters are evaluated, and their relation is investigated. After surgery, HGG patients underwent chemo-irradiation for six weeks, followed by six cycles of temozolomide. Assessments were performed before chemo-irradiation, post-concomitantly, after the third and sixth adjuvant cycle, and 3 and 7 months after treatment. Degree of WMH and CA was scored on MRI. Patients' neuropsychological performance was compared to healthy matched controls, yielding six cognitive domain z-scores. Development or progression of pre-existing WMH and CA during follow-up was observed in 36 and 45 % of the patients (n = 39) respectively. Cognitive functioning remained stable or improved in 70 % of the patients and deteriorated in 30 % of the patients (n = 33). Of the cognitive decliners, 80 % had tumor progression within 4 months thereafter. No clear association between cognitive functioning and WMH or CA was found. Central neurotoxic effects of combined modality treatment in HGG patients expressed by radiological abnormalities are encountered in approximately 40 % of patients. However, functional impact as indexed by cognitive functioning was found to be limited. Furthermore, development or progression of pre-existing WMH and CA does not consistently result in functional impairment as measured by cognitive tests.

Stage I-II non-small-cell lung cancer treated using either stereotactic ablative radiotherapy (SABR) or lobectomy by video-assisted thoracoscopic surgery (VATS): outcomes of a propensity score-matched analysis.

BACKGROUND: Video-assisted thoracoscopic surgery (VATS) lobectomy and stereotactic ablative radiotherapy (SABR) are both used for early-stage non-small-cell lung cancer. We carried out a propensity score-matched analysis to compare locoregional control (LRC). PATIENTS AND METHODS: VATS lobectomy data from six hospitals were retrospectively accessed; SABR data were obtained from a single institution database. Patients were matched using propensity scores based on cTNM stage, age, gender, Charlson comorbidity score, lung function and performance score. Eighty-six VATS and 527 SABR patients were matched blinded to outcome (1:1 ratio, caliper distance 0.025). Locoregional failure was defined as recurrence in/adjacent to the planning target volume/surgical margins, ipsilateral hilum or mediastinum. Recurrences were either biopsy-confirmed or had to be PET-positive and reviewed by a tumor board. RESULTS: The matched cohort consisted of 64 SABR and 64 VATS patients with the median follow-up of 30 and 16 months, respectively. Post-SABR LRC rates were superior at 1 and 3 years (96.8% and 93.3% versus 86.9% and 82.6%, respectively, P = 0.04). Distant recurrences and overall survival (OS) were not significantly different. CONCLUSION: This retrospective analysis found a superior LRC after SABR compared with VATS lobectomy, but OS did not differ. Our findings support the need to compare both treatments in a randomized, controlled trial.

Developments in early-stage NSCLC: advances in radiotherapy.

An increase in the number of predominantly elderly patients with early-stage non-small-cell lung cancer is anticipated in many Western populations. Patients often have major co-morbidities and are at increased risk for surgical morbidity and mortality. In the past decade, the use of stereotactic ablative radiotherapy (SABR) has achieved excellent results, with only mild toxicity in such vulnerable patient groups, leading to SABR becoming accepted as a standard of care for unfit patients in several countries. The planning and delivery of SABR has rapidly improved in recent years, particularly with the use of 'on-board' imaging at treatment units, and shortened treatment delivery times. Increasingly, more central tumors are being treated using lower doses per fraction (so-called risk-adapted schemes). It is also becoming clear that long-term follow-up should take place at specialist centers in order to distinguish the evolving fibrosis that is frequently observed from the relatively infrequent local recurrences. Given the high local control rates and limited toxicity, increasing attention is being paid to the use of SABR in the subgroup of so-called borderline operable patients, and clinical trials comparing surgery and SABR in these patients are ongoing.

Early-stage lung cancer in elderly patients: a population-based study of changes in treatment patterns and survival in the Netherlands.

BACKGROUND: Elderly patients with stage I non-small-cell lung cancer are less likely to undergo curative treatment. However, the introduction of new treatment options such as stereotactic ablative radiotherapy (SABR) may improve treatment rates. We evaluated time trends in treatment patterns and survival in the entire Netherlands population for patients diagnosed between 2001 and 2009. PATIENTS AND METHODS: Details of 4605 elderly Dutch patients were obtained from the Netherlands Cancer Registry, containing data on all cancer patients in a population of 16 million. Three consecutive time periods were studied: 2001-2003 (A, before SABR became available), 2004-2006 (B, increasing availability), and 2007-2009 (C, full availability). RESULTS: Between period A and C, there was a 7% absolute reduction in patients going untreated, corresponding to an 8-month improvement in median survival (P < 0.001). Radiotherapy utilization increased from 31% to 38%, whereas surgical utilization remained constant (37%). Significant improvements in survival were observed in the radiotherapy subgroup (P < 0.001) and surgery subgroup (P < 0.001), not in patients going untreated. There was no evidence of stage migration. CONCLUSIONS: Population-based increases in survival of elderly stage I lung cancer patients were seen between 2001 and 2009. The introduction of SABR correlated with a decline in the number of untreated patients.

The predictive value of 3D time-of-flight MR angiography in assessment of brain arteriovenous malformation obliteration after radiosurgery.

BACKGROUND AND PURPOSE: The purpose of radiosurgery of bAVMs is complete angiographic obliteration of its nidus. We assessed the diagnostic accuracy of 1.5T T2-weighted MR imaging and TOF-MRA images for detecting nidus obliteration after radiosurgery. MATERIALS AND METHODS: The pre- and postradiosurgery MR images and DSA images from 120 patients who were radiosurgically treated for a bAVM were re-evaluated by 2 observers for patency of the nidus (preradiosurgery) and obliteration (postradiosurgery: final follow-up MR imaging), by using a 3-point scale of confidence. Consensus reading of the DSA after radiosurgery was considered the criterion standard for obliteration. Sensitivity, specificity, PPVs, and NPVs, and overall diagnostic performance by using ROC were determined. RESULTS: Mean bAVM volume during radiosurgery was 3.4 mL (95% CI, 2.6-4.3 mL). Sixty-six patients (55%) had undergone previous endovascular embolization. The mean intervals between radiosurgery and follow-up MR imaging and for DSA, respectively, were 35.6 months (95% CI, 32.3-38.9 months) and 42.1 months (95% CI, 40.3-44.0 months). With ROC, an area under curve of 0.81-0.83 was found. PPVs of final follow-up MR-imaging for definitive obliteration varied between 0.89 [corrected] and 0.95. NPV was 0.52 [corrected] . An average false-positive rate, meaning overestimation of nidus obliteration of 0.10 [corrected] and an average false-negative rate, meaning underestimation of nidus obliteration of 0.42 [corrected] were found. CONCLUSIONS: MRA is insufficient to diagnose obliteration in the follow-up of bAVMs after radiosurgery. A remaining nidus diameter <10 mm seems to be the major limiting factor for reliable assessment of obliteration. We highly recommend follow-up DSA for definitive diagnosis of complete obliteration.

Brain arteriovenous malformations: from diagnosis to treatment.

Brain arteriovenous malformations (bAVM) are a major cause of morbidity in young people. The main mode of presentation is with a cerebral bleeding or seizures, although nowadays, due to the increased use of MRI, more asymptomatic bAVMs are encountered. The clinical course of asymptomatic bAVMs seems to be mild in comparison to bAVMs that presented with a cerebral hemorrhage. This finding may lead to a paradigm shift regarding treatment of asymptomatic bAVMs. This review discusses the latest findings in bAVM epidemiology and natural history, and compares the optimal imaging modalities and best treatment options.

[Practice guideline 'Brain metastases' (revision)]. / Richtlijn 'Hersenmetastasen' (revisie).

Improved survival of cancer patients results in an increase in the incidence of brain metastases. In addition, asymptomatic brain metastases are more often detected as a consequence of active screening. In patients with cancer and new neurological symptoms, MRI of the brain is indicated to assess the presence and number of brain metastases. Decisions concerning treatment of brain metastases should take place within a multidisciplinary team. Treatment is in the first instance focused on improvement or preservation of neurological functioning. The main treatment options for patients with brain metastases are whole brain radiotherapy, stereotactic radiosurgery/radiotherapy, and neurosurgical resection. The choice of treatment depends on the number and the location of the brain metastases, the general and neurological condition of the patient, the extent of extracranial tumour activity, and the expected results of treatment. The revised guideline supports the policy of whole brain radiotherapy not being the standard treatment following stereotactic radiosurgery or radiotherapy. In the case of complete resection, confirmed using early postoperative MRI, whole brain radiotherapy does not add to survival benefit, while patients may suffer from radiation-induced toxicity.

Intracranial radiosurgery in the Netherlands. A planning comparison of available systems with regard to physical aspects and workload.

Different planning and treatment systems for intracranial stereotactic radiosurgery available in the Netherlands are compared. The systems for intracranial radiosurgery include: Gamma Knife, Cyberknife, Novalis, and Tomotherapy. Electronic data of 5 patients was transferred to all participating centres and treatment plans were generated according to 2 different prescription protocols. For this study, plans were also generated for a conventional linac. Even systems with a high resolution (Gammaknife and Novalis) have conformity indices in violation with RTOG guidelines (CI > 2.5) when target volumes of <0.5 cc are treated. For medium sized targets (0.5-1 cc) all systems performed reasonably well, but for the different systems a large range of conformity indices was seen (1.1 to 3.7). The differences are partly system dependent but depend also on specific planning choices made. For larger target volumes (> 1 cc), all systems perform well. The workload of the different techniques was comparable although the treatment times were usually longer for Gamma Knife radiosurgery. We conclude that small targets should be treated by dedicated systems, larger volumes (> 0.5-1 cc) can also be treated using conventional treatment systems equipped with a MLC.

Comments on 'Single-Arc IMRT?'.

We read with interest the article titled 'Single-Arc IMRT?' (Bortfeld and Webb 2009 Phys. Med. Biol. 54 N9-20) and feel it imperative to draw the attention of your readers to comments suggesting that the authors may not be fully aware of current developments in this field. As their paper was first submitted on 19th of August 2008, it could not have taken into account data presented at the AAPM, ESTRO and ASTRO meetings in 2008. In this letter, we would like to clarify some relevant aspects of RapidArc (Varian Medical Systems) as a modality for delivering single-arc treatment.

Radiosurgery of brain arteriovenous malformations in children.

OBJECTIVE: The authors describe their experience in treating 22 children with a single brain arteriovenous malformation (bAVM) using a dedicated LINAC stereotactic radiosurgery unit. METHODS: The findings of 22 consecutive patients < or = 18 years of age who underwent radiosurgery for a single bAVM and with at least 24 months of follow-up, or earlier proven obliteration,were reviewed. The median age at radiosurgery was 13.8 years,with a hemorrhagic presentation in 86%. Median bAVM-volume was 1.8 ml, with a median prescribed marginal dose of 19.0 Gy. RESULTS: The crude complete obliteration-rate was 68% (n = 15) after a median follow-up of 24 months. The actuarial obliteration- rate was 45 % after two years and 64 % after three years. Patients with a radiosurgery-based AVM score < or = 1 more frequently had an excellent outcome than patients with a bAVM score > 1 (71% vs. 20%, P = 0.12), as well as an increased obliteration rate (P = 0.03) One patient died from a bAVM-related hemorrhage 27 months after radiosurgery, representing a postradiosurgery hemorrhage rate of 1.3%/year for the complete followup interval. Overall outcome was good to excellent in 68% (n = 15). Radiation-induced changes on MR imaging were seen in 36% (n = 8) after a median interval of 12.5 months, resulting in deterioration of pre-existing neurological symptoms in one patient. CONCLUSIONS: Radiosurgery is a relatively effective, minimally invasive treatment for small bAVMs in children. The rebleeding rate is low, provided that known predilection places for bleeding had been endovascularly eliminated.Our overall results compare unfavourably to recent pediatric microsurgical series, although comparison between series remains imprecise. Nevertheless, when treatment is indicated in a child with a bAVM that is amenable to both microsurgery or radiosurgery, microsurgery should carefully be advocated over radiosurgery, because of its immediate risk reduction.

Prognostic factors in patients with brain metastases.

Management of patients with brain metastases (BrM) has been evolving over time, with a general tendency towards a more aggressive treatment approach. Although whole brain radiotherapy (WBRT) remains the mainstay of treatment for the majority of patients, the indications for stereotactic radiosurgery (SRS) with or without WBRT have been expanding rapidly. In order to select patients who would benefit from the improved intracranial control rates obtained with advanced radiation therapy techniques, knowledge of prognostic factors is essential. Literature findings indicate that performance status, age and systemic tumour activity (extracranial metastases and primary tumour status) are the major determinants of survival for patients with BrM. Based on recursive partitioning analysis (RPA) of these factors, the Radiation Therapy Oncology Group has developed a prognostic classification system for patients with BrM. RPA Class 1 represents the most favourable subset of patients with Karnofsky performance status of > or = 70, age under 65 years, controlled primary tumour and no extracranial metastases. RPA Class 3 patients have KPS < 70, associated with poor median survival rates. RPA Class 2 contains the remainder of patients, a rather heterogeneous subset of patients with intermediate survival rates. This RPA classification system, which has been validated for patients treated with WBRT, surgery and SRS, respectively, appears to be a valuable tool for assessment of prognosis in patients with BrM.

Multiple "slow" CT scans for incorporating lung tumor mobility in radiotherapy planning.

PURPOSE: The high local recurrence rates after radiotherapy in early-stage lung cancer may be due to geometric errors that arise when target volumes are generated using fast spiral CT scanners. A "slow" CT technique that generates more representative target volumes was evaluated. METHODS AND MATERIALS: Planning CT scans (slice thickness 3 mm, reconstruction index 2.5 mm) were performed during quiet respiration in 10 patients with peripheral lung lesions. Planning CT scans were repeated twice, followed by three slow CT scans (slice thickness 4 mm, index 3 mm, revolution time 4 s/slice). All, except the first scan, were limited to the tumor region. Three-dimensional registration of all scans was performed. The reproducibility of the imaged volumes was evaluated with each technique using (1) the common overlapping volume (COM), the component of the clinical target volume (CTV) covered by all three CT scans, and (2) the encompassing volume (SUM), which is the volume enveloped by all CTVs. RESULTS: In all patients, the target volumes generated using slow CT scans were larger than those derived using planning scans (mean ratio of planning-CTV:slow-CTV of 88.8% +/- 5.6%), and also more reproducible. The mean ratio of the respective COM:SUM volumes was 62.6% +/- 10.8% and 54.9% +/- 12.9%. CONCLUSIONS: Larger, and more reproducible, target volumes are generated for peripheral lung tumors with the use of slow CT scans, thereby indicating that slow scans can better capture tumor movement.

Dosimetric consequences of tumor mobility in radiotherapy of stage I non-small cell lung cancer--an analysis of data generated using 'slow' CT scans.

BACKGROUND: The target coverage for radiotherapy of early-stage lung cancer was evaluated using two different CT techniques. MATERIALS AND METHODS: A conventional planning CT scan and two limited scans of the tumor region were performed in seven patients with peripheral tumors. Three 'slow' scans (slice thickness 4mm, index 3mm, revolution time 4s/slice) were then performed, followed by three-dimensional image registration. Planning target volumes (PTV) were generated using these GTV-PTV margins: (a) 1cm (PTV1.0); (b) 1.5 cm (PTV1.5); and (c) 0.9, 1.0, and 0.9 cm ('PTV(clinical)') when set-up errors are avoided. RESULTS: PTVs derived from three 'slow' scans missed 1.9% of the volume derived from three planning scans for an immobile tumor and 9.3% in the case of a mobile tumor. For an immobile tumor, PTV1.5 achieved comparable coverage to that achieved using PTVclinical, which was generated from three 'slow' scans and a planning scan. For a mobile tumor, PTV(1.5) covered only 89% of the volume captured by PTVclinical. PTV1.0 resulted in inadequate target coverage in all the patients. Reductions in potential lung toxicity (V20) were achievable in six patients despite the larger GTVclinical when treatment set-up errors were minimized. CONCLUSIONS: PTVs derived using 'slow' CT scans consistently produce superior target coverage than that using conventional scans. This may account for the poor local control observed in stage I lung cancer.