SBRT in pancreatic cancer: What is the therapeutic window?

doi:10.1016/j.radonc.2014.10.015

Radiotherapy and Oncology

Volume 114, Issue 1, January 2015, Pages 109-116

https://doi.org/10.1016/j.radonc.2014.10.015 Get rights and content

Abstract

Purpose/objective: To analyse outcome and toxicity of stereotactic body radiotherapy (SBRT) in pancreatic cancer (PDAC). Material/methods: We systematically reviewed full reports on outcome and toxicity transforming prescription doses to equivalent doses of 2 Gy (EQD2) and biological equivalent doses (BED). Pearson product-moment correlation coefficient, regression analysis and Lyman–Kutcher–Burman modelling were used. Results: Sixteen trials (572 patients) were identified. Local control correlated with dose. Additionally 4 upper gastrointestinal-SBRT trials (149 patients) were included for toxicity analysis. Acute toxicity was mild but late toxicity ⩾G2 was substantial and predominantly gastrointestinal. Late toxicity ⩾G2 and ⩾G3 correlated highly with EQD2/BED after linear (R² = 0.85 and 0.77, respectively) and Lyman–Kutcher–Burman modelling. Linear regression lines indicated ⩾G2 and ⩾G3 toxicity frequencies of 5% at 65 Gy and 80 Gy EQD2-α/β = 3, respectively. A comparison of toxicity with dose constraints for duodenum revealed partly inadequate dose constraints. Conclusion: Results from multiple fraction regimens could be successfully interpreted to estimate toxicity according to EQD2/BED prescription doses, and dose constraints for the duodenum were derived, whereas local control appeared to be less dose-dependent. This analysis may be useful to plan clinical trials for SBRT and hypofractionated radiotherapy in pancreatic cancer.

Section snippets

Methods

We performed a systematic literature search for fully published studies on SBRT in PDAC. English-language papers from 01/2000 to 11/2013 were searched. The inclusion criteria were: studies reporting clinical outcomes after SBRT for PDAC; studies specifically reporting toxicities after SBRT for upper abdominal tumours. To identify studies we used PubMed, EMBASE and Cochrane databases and the search was completed in May 2014. The search strategy was (sbrt [tw] OR sabr [tw] OR stereotactic [tw])

Results

We included a total of 16 studies with outcome data on SBRT of pancreatic cancer [13], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30]. One of the studies included patients from three previously reported prospective trials [31]. Another four studies of upper abdominal SBRT reporting on toxicity and providing sufficient dose information were additionally chosen for the toxicity analysis [32], [33], [34], [35], [36], [37], [38]. From the respective studies, a total of 572

Discussion

This analysis shows that SBRT was highly effective controlling local disease in about 75% with 75 Gy BED. Increasing dose beyond 75 Gy BED did neither prolong survival nor was it safe. Our analysis showed that the inverse correlation of survival with BED at the high dose end was probably caused by insufficient systemic therapy employed in SBRT series with high BED [21], [22], [23]. On the other hand high prescription doses clearly correlated with increased toxicity [13], [21], [36], [38]. We

Conflict of interest statement

None.

Acknowledgements

We would like to thank Ms Gerta Rücker from the Institute of Medical Biometry and Medical Informatics, University Medical Center Freiburg for her input for statistical analysis.

Mike Partridge is funded by the CRUK/MRC Oxford Institute for Radiation Oncology (grant ref. C5255/A15935).

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MRI-guided stereotactic ablative body radiotherapy versus CT-guided percutaneous irreversible electroporation for locally advanced pancreatic cancer (CROSSFIRE): a single-centre, open-label, randomised phase 2 trial
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Pancreatic ductal adenocarcinoma is an aggressive disease with a dismal prognosis. Stage III locally advanced pancreatic cancer is considered unresectable and current palliative chemotherapy regimens only modestly improve survival. Guidelines suggest chemoradiation or stereotactic ablative body radiotherapy (SABR) could be beneficial in certain circumstances. Other local treatments such as irreversible electroporation could enhance patient outcomes by extending survival while preserving quality of life. We aimed to compare the efficacy and safety of MRI-guided SABR versus CT-guided percutaneous irreversible electroporation following standard FOLFIRINOX chemotherapy.
CROSSFIRE was an open-label, randomised phase 2 superiority trial conducted at the Amsterdam University Medical Centre (Amsterdam, Netherlands). Eligible patients were aged 18 years or older with confirmed histological and radiological stage III locally advanced pancreatic cancer. The maximum tumour diameter was 5 cm and patients had to be pretreated with three to eight cycles of FOLFIRINOX. Patients were randomly assigned (1:1) to MRI-guided SABR (five fractions of 8 Gy delivered on non-consecutive days) or CT-guided percutaneous irreversible electroporation using a computer-generated variable block randomisation model. The primary endpoint was overall survival from randomisation, assessed in the intention-to-treat population. Safety was assessed in the per-protocol population. A prespecified interim futility analysis was done after inclusion of half the original sample size, with a conditional probability of less than 0·2 resulting in halting of the study. The trial was registered at ClinicalTrials.gov, NCT02791503.
Between May 1, 2016, and March 31, 2022, 68 patients were enrolled and randomly assigned to SABR (n=34) or irreversible electroporation (n=34), of whom 64 were treated according to protocol. Of the 68 participants, 36 (53%) were male and 32 (47%) were female, with a median age of 65 years (IQR 57–70). Median overall survival from randomisation was 16·1 months (95% CI 12·1–19·4) in the SABR group versus 12·5 months (10·9–17·0) in the irreversible electroporation group (hazard ratio [HR] 1·39 [95% CI 0·84–2·30]; p=0·21). The conditional probability to demonstrate superiority of either technique was 0·13; patient accrual was therefore stopped early for futility. 20 (63%) of 32 patients in the SABR group versus 19 (59%) of 32 patients in the irreversible electroporation group had adverse events (p=0·8) and five (16%) patients in the SABR group versus eight (25%) in the irreversible electroporation group had grade 3–5 adverse events (p=0·35). The most common grade 3–4 adverse events were cholangitis (two [6%] in the SABR group vs one [3%] in the irreversible electroporation group), abdominal pain (one [3%] vs two [6%]), and pancreatitis (none vs two [6%]). One (3%) patient in the SABR group and one (3%) in the irreversible electroporation group died from a treatment-related adverse event.
CROSSFIRE did not identify a difference in overall survival or incidence of adverse events between MRI-guided SABR and CT-guided percutaneous irreversible electroporation after FOLFIRINOX. Future studies should further assess the added value of local ablative treatment over chemotherapy alone.
Adessium Foundation, AngioDynamics.
Stereotactic body radiotherapy for pancreatic cancer – A systematic review of prospective data
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This systematic review aims to comprehensively summarize the current prospective evidence regarding Stereotactic Body Radiotherapy (SBRT) in various clinical contexts for pancreatic cancer including its use as neoadjuvant therapy for borderline resectable pancreatic cancer (BRPC), induction therapy for locally advanced pancreatic cancer (LAPC), salvage therapy for isolated local recurrence (ILR), adjuvant therapy after radical resection, and as a palliative treatment. Special attention is given to the application of magnetic resonance-guided radiotherapy (MRgRT).
Following PRISMA guidelines, a systematic review of the Medline database via PubMed was conducted focusing on prospective studies published within the past decade. Data were extracted concerning study characteristics, outcome measures, toxicity profiles, SBRT dosage and fractionation regimens, as well as additional systemic therapies.
31 studies with in total 1,571 patients were included in this review encompassing 14 studies for LAPC, 9 for neoadjuvant treatment, 2 for adjuvant treatment, 2 for ILR, with an additional 4 studies evaluating MRgRT. In LAPC, SBRT demonstrates encouraging results, characterized by favorable local control rates. Several studies even report conversion to resectable disease with substantial resection rates reaching 39%. The adoption of MRgRT may provide a solution to the challenge to deliver ablative doses while minimizing severe toxicities. In BRPC, select prospective studies combining preoperative ablative-dose SBRT with modern induction systemic therapies have achieved remarkable resection rates of up to 80%. MRgRT also holds potential in this context. Adjuvant SBRT does not appear to confer relevant advantages over chemotherapy. While prospective data for SBRT in ILR and for palliative pain relief are limited, they corroborate positive findings from retrospective studies.
Feasibility of abdominal fat quantification on MRI and impact on effectiveness of abdominal compression for radiotherapy motion management
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The impact of fat on abdominal compression effectiveness in abdominal cancers was determined using magnetic resonance imaging (MRI). Visceral and subcutaneous fat were delineated on T2W 3D MRI, and motion change with compression was measured on 2D cine MRI. Results from 16 participants showed no correlation between fat percentage, body mass index (BMI), and motion change. Median BMI was 28.7 (SD, 4.9). Mean motion reduction was 7.8 mm (IQR, 5.0; p = 0.001) with compression. While no direct link was found between fat, BMI, and compression effectiveness, abdominal compression remains crucial for motion management in radiotherapy planning, providing dosimetric benefits.
Stereotactic body radiotherapy in pancreatic adenocarcinoma
2024, Hepatobiliary and Pancreatic Diseases International
Stereotactic body radiotherapy (SBRT) in pancreatic cancer allows high delivery of radiation doses on tumors without affecting surrounding tissue. This review aimed at the SBRT application in the treatment of pancreatic cancer.
We retrieved articles published in MEDLINE/PubMed from January 2017 to December 2022. Keywords used in the search included: “pancreatic adenocarcinoma” OR “pancreatic cancer” AND “stereotactic ablative radiotherapy (SABR)” OR “stereotactic body radiotherapy (SBRT)” OR “chemoradiotherapy (CRT)”. English language articles with information on technical characteristics, doses and fractionation, indications, recurrence patterns, local control and toxicities of SBRT in pancreatic tumors were included. All articles were assessed for validity and relevant content.
Optimal doses and fractionation have not yet been defined. However, SBRT could be the standard treatment in patients with pancreatic adenocarcinoma in addition to CRT. Furthermore, the combination of SBRT with chemotherapy may have additive or synergic effect on pancreatic adenocarcinoma.
SBRT is an effective modality for patients with pancreatic cancer, supported by clinical practice guidelines as it has demonstrated good tolerance and good disease control. SBRT opens a possibility of improving outcomes for these patients, both in neoadjuvant treatment and with radical intent.
Dosimetric analysis of brachial plexopathy after stereotactic body radiotherapy: Significance of organ delineation
2024, Radiotherapy and Oncology
Examine the significance of contouring the brachial plexus (BP) for toxicity estimation and select metrics for predicting radiation-induced brachial plexopathy (RIBP) after stereotactic body radiotherapy.
Patients with planning target volume (PTV) ≤ 2 cm from the BP were eligible. The BP was contoured primarily according to the RTOG 1106 atlas, while subclavian-axillary veins (SAV) were contoured according to RTOG 0236. Apical PTVs were classified as anterior (PTV-A) or posterior (PTV-B) PTVs. Variables predicting grade 2 or higher RIBP (RIBP2) were selected through least absolute shrinkage and selection operator regression and logistic regression.
Among 137 patients with 140 BPs (median follow-up, 32.1 months), 11 experienced RIBP2. For patients with RIBP2, the maximum physical dose to the BP (BP-D_max) was 46.5 Gy (median; range, 35.7 to 60.7 Gy). Of these patients, 54.5 % (6/11) satisfied the RTOG limits when using SAV delineation; among them, 83.3 % (5/6) had PTV-B. For patients with PTV-B, the maximum physical dose to SAV (SAV-D_max) was 11.2 Gy (median) lower than BP-D_max. Maximum and 0.3 cc biologically effective doses to the BP based on the linear-quadratic-linear model (BP-BED_{max LQL} and BP-BED_{0.3cc LQL}, α/β = 3) were selected as predictive variables with thresholds of 118 and 73 Gy, respectively.
Contouring SAV may significantly underestimate the RIBP2 risk in dosimetry, especially for patients with PTV-B. BP contouring indicated BP-BED_{0.3cc LQL} and BP-BED_{max LQL} as potential predictors of RIBP2.
Deep Learning–Based Fluence Map Prediction for Pancreas Stereotactic Body Radiation Therapy With Simultaneous Integrated Boost
2021, Advances in Radiation Oncology
Treatment planning for pancreas stereotactic body radiation therapy (SBRT) is a challenging task, especially with simultaneous integrated boost treatment approaches. We propose a deep learning (DL) framework to accurately predict fluence maps from patient anatomy and directly generate intensity modulated radiation therapy plans.
The framework employs 2 convolutional neural networks (CNNs) to sequentially generate beam dose prediction and fluence map prediction, creating a deliverable 9-beam intensity modulated radiation therapy plan. Within the beam dose prediction CNN, axial slices of combined structure contour masks are used to predict 3-dimensional (3D) beam doses for each beam. Each 3D beam dose is projected along its beam’s-eye-view to form a 2D beam dose map, which is subsequently used by the fluence map prediction CNN to predict its fluence map. Finally, the 9 predicted fluence maps are imported into the treatment planning system to finalize the plan by leaf sequencing and dose calculation. One hundred patients receiving pancreas SBRT were retrospectively collected for this study. Benchmark plans with unified simultaneous integrated boost prescription (25/33 Gy) were manually optimized for each case. The data set was split into 80/20 cases for training and testing. We evaluated the proposed DL framework by assessing both the fluence maps and the final predicted plans. Further, clinical acceptability of the plans was evaluated by a physician specializing in gastrointestinal cancer.
The DL-based planning was, on average, completed in under 2 minutes. In testing, the predicted plans achieved similar dose distribution compared with the benchmark plans (-1.5% deviation for planning target volume 33 V_33Gy), with slightly higher planning target volume maximum (+1.03 Gy) and organ at risk maximum (+0.95 Gy) doses. After renormalization, the physician rated 19 cases clinically acceptable and 1 case requiring minor improvement.
The DL framework can effectively plan pancreas SBRT cases within 2 minutes. The predicted plans are clinically deliverable, with plan quality approaching that of manual planning.

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Systematic reviewSBRT in pancreatic cancer: What is the therapeutic window?

Abstract

Section snippets

Methods

Results

Discussion

Conflict of interest statement

Acknowledgements

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Systematic review
SBRT in pancreatic cancer: What is the therapeutic window?