Niclas Pettersson

Radiation-induced rib fractures after hypofractionated stereotactic body radiation therapy of non-small cell lung cancer: A dose– and volume–response analysis

BACKGROUND AND PURPOSE The aim of this study is to analyse the dose-response and the volume-response of radiation-induced rib fractures after hypofractionated stereotactic body radiation therapy (SBRT). MATERIALS AND METHODS During the period 1998-2005, 68 patients with medically inoperable stage I non-small cell lung cancer (NSCLC) were treated with hypofractionated SBRT to 45 Gy in 3 fractions. Among the 33 patients with complete treatment records and radiographic follow-up exceeding 15 months (median: 29 months), 13 fractures were found in seven patients. Identifying all ribs receiving at least 21 Gy, 81 ribs (13 with and 68 without fracture) in 26 patients were separately contoured and their dose-volume histograms (DVHs) were obtained. The DVHs were assessed with the mean dose and cut-off models. Maximum likelihood estimation was used to fit dose-response and volume-response curves to each model. RESULTS It was possible to quantify the risk of radiation-induced rib fracture using response curves and information contained in the DVHs. Absolute volumes provided better fits than relative volumes and dose-response curves were more suitable than volume-response curves. For the dose given by the 2 cm(3) cut-off volume, D(2 cm(3)), the logistic dose-response curve for three fractions was parameterised by D(50)=49.8 Gy and gamma(50)=2.05. Consequently, for a median follow-up of 29 months, if D(2 cm(3))<3 x 7.0 Gy the risk is close to 0, and the 5% and 50% risks are given by D(2 cm(3))=3 x 9.1 Gy and 3 x 16.6 Gy, respectively. CONCLUSIONS In this group of patients, the risk for radiation-induced rib fracture following hypofractionated SBRT was related to the dose to 2 cm(3) of the rib.

Relationships between dose to the gastro-intestinal tract and patient-reported symptom domains after radiotherapy for localized prostate cancer.

ABSTRACT Background. Gastrointestinal (GI) morbidity after radiotherapy (RT) for prostate cancer is typically addressed by studying specific single symptoms. The aim of this study was to explore the interplay between domains of patient- reported outcomes (PROs) on GI morbidity, and to what extent these are explained by RT dose to the GI tract. Material and methods. The study included men from two Scandinavian studies (N = 211/277) who had undergone primary external beam radiotherapy (EBRT) for localized prostate cancer to 70–78 Gy (2 Gy/fraction). Factor analysis was applied to previously identified PRO-based symptom domains from two study-specific questionnaires. Number of questions: 43; median time to follow-up: 3.6–6.4 years) and dose-response outcome variables were defined from these domains. Dose/volume parameters of the anal sphincter (AS) or the rectum were tested as predictors for each outcome variable using logistic regression with 10-fold cross-validation. Performance was assessed using area under the receiver operating characteristic curve (Az) and model frequency. Results. Outcome variables from Defecation urgency (number of symptoms: 2–3), Fecal leakage (4–6), Mucous (4), and Pain (3–6) were defined. In both cohorts, intermediate rectal doses predicted Defecation urgency (mean Az: 0.53–0.54; Frequency: 70–75%), and near minimum and low AS doses predicted Fecal leakage (mean Az: 0.63–0.67; Frequency: 83–99%). In one cohort, high AS doses predicted Mucous (mean Az: 0.54; Frequency: 96%), whereas in the other, low AS doses and intermediate rectal doses predicted Pain (mean Az: 0.69; Frequency: 28–82%). Conclusion. We have demonstrated that Defecation urgency, Fecal leakage, Mucous, and Pain following primary EBRT for localized prostate cancer primarily are predicted by intermediate rectal doses, low AS doses, high AS doses, or a combination of low AS and intermediate rectal doses, respectively. This suggests that there is a domain-specific dose-response for the GI tract. To reduce risk of GI morbidity, dose distributions of both the AS region and the rectum should, therefore, be considered when prescribing prostate cancer RT.

Dose-dependent white matter damage after brain radiotherapy

BACKGROUND AND PURPOSE Brain radiotherapy is limited in part by damage to white matter, contributing to neurocognitive decline. We utilized diffusion tensor imaging (DTI) with multiple b-values (diffusion weightings) to model the dose-dependency and time course of radiation effects on white matter. MATERIALS AND METHODS Fifteen patients with high-grade gliomas treated with radiotherapy and chemotherapy underwent MRI with DTI prior to radiotherapy, and after months 1, 4-6, and 9-11. Diffusion tensors were calculated using three weightings (high, standard, and low b-values) and maps of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λ∥), and radial diffusivity (λ⊥) were generated. The region of interest was all white matter. RESULTS MD, λ∥, and λ⊥ increased significantly with time and dose, with corresponding decrease in FA. Greater changes were seen at lower b-values, except for FA. Time-dose interactions were highly significant at 4-6months and beyond (p<.001), and the difference in dose response between high and low b-values reached statistical significance at 9-11months for MD, λ∥, and λ⊥ (p<.001, p<.001, p=.005 respectively) as well as at 4-6months for λ∥ (p=.04). CONCLUSIONS We detected dose-dependent changes across all doses, even <10Gy. Greater changes were observed at low b-values, suggesting prominent extracellular changes possibly due to vascular permeability and neuroinflammation.

Urinary bladder dose–response relationships for patient-reported genitourinary morbidity domains following prostate cancer radiotherapy

BACKGROUND AND PURPOSE Radiotherapy (RT) induced genitourinary (GU) morbidity is typically assessed by physicians as single symptoms or aggregated scores including symptoms from various domains. Here we apply a method to group patient-reported GU symptoms after RT for localized prostate cancer based on their interplay, and study how these relate to urinary bladder dose. MATERIALS AND METHODS Data were taken from two Scandinavian studies (N=207/276) including men treated with external-beam RT (EBRT) to 78/70Gy (2Gy/fraction; median time-to-follow-up: 3.6-6.4y). Within and across cohorts, bladder dose-volume parameters were tested as predictors for GU symptom domains identified from two study-specific questionnaires (35 questions on frequency, incontinence, obstruction, pain, urgency, and sensory symptoms) using univariate and multivariate logistic regression analysis (MVA) with 10-fold cross-validation. Performance was evaluated using Area Under the Receiver Operating Characteristic Curve (Az). RESULTS For the identified Incontinence (2-5 symptoms), Obstruction (3-5 symptoms), and Urgency (2-7 symptoms) domains, MVA demonstrated that bladder doses close to the prescription doses were the strongest predictors for Obstruction (Az: 0.53-0.57) and Urgency (Az: 0.60). For Obstruction, performance increased for the across cohort analysis (Az: 0.61-0.64). CONCLUSIONS Our identified patient-reported GU symptom domains suggest that high urinary bladder doses, and increased focus on both obstruction and urgency is likely to further add to the understanding of GU tract RT responses.

Urethral pain among prostate cancer survivors 1 to 14 years after radiation therapy.

PURPOSE To investigate how treatment-related and non-treatment-related factors impact urethral pain among long-term prostate cancer survivors. METHODS AND MATERIALS Men treated for prostate cancer with radiation therapy at the Sahlgrenska University Hospital in Göteborg, Sweden from 1993 to 2006 were approached with a study-specific postal questionnaire addressing symptoms after treatment, including urethral burning pain during urination (n=985). The men had received primary or salvage external-beam radiation therapy (EBRT) or EBRT in combination with brachytherapy (BT). Prescribed doses were commonly 70 Gy in 2.0-Gy fractions for primary and salvage EBRT and 50 Gy plus 2×10.0 Gy for EBRT+BT. Prostatic urethral doses were assessed from treatment records. We also recruited 350 non-pelvic-irradiated, population-based controls matched for age and residency to provide symptom background rates. RESULTS Of the treated men, 16% (137 of 863) reported urethral pain, compared with 11% (27 of 242) of the controls. The median time to follow-up was 5.2 years (range, 1.1-14.3 years). Prostatic urethral doses were similar to prescription doses for EBRT and 100% to 115% for BT. Fractionation-corrected dose and time to follow-up affected the occurrence of the symptom. For a follow-up≥3 years, 19% of men (52 of 268) within the 70-Gy EBRT+BT group reported pain, compared with 10% of men (23 of 222) treated with 70 Gy primary EBRT (prevalence ratio 1.9; 95% confidence interval 1.2-3.0). Of the men treated with salvage EBRT, 10% (20 of 197) reported urethral pain. CONCLUSIONS Survivors treated with EBRT+BT had a higher risk for urethral pain compared with those treated with EBRT. The symptom prevalence decreased with longer time to follow-up. We found a relationship between fractionation-corrected urethral dose and pain. Among long-term prostate cancer survivors, the occurrence of pain was not increased above the background rate for prostatic urethral doses up to 70 Gy3.

Risk structures for radiation-induced trismus in head and neck cancer

Treating head and neck cancer (HNC) is challenging as the tumors are located in a critical area where many essential functions originate. Amongst the late appearing side effects after radiotherapy (RT) for HNC, restricted mouth opening (trismus) occurs in more than one third of patients and have been described as persisting or even worsening five years after completed RT [1–3]. Trismus can lead to difficulties in eating, chewing, maintaining oral hygiene, and potentially to malnutrition and weight loss [2–6]. Irradiation of the temporomandibular joint (TM joint) and muscles of mastication, especially doses to the masseter and the pterygoid muscles, have been reported to be associated with radiation-induced trismus [7–11]. However, available data diverge as to which anatomical structure is more critical for trismus after RT in HNC. The aim of this prospective study was, therefore, to investigate if the use of both objectively and subjectively determined trismus can shed further light on this issue.

A Factor Analysis Approach for Clustering Patient Reported Outcomes

BACKGROUND In the field of radiation oncology, the use of extensive patient reported outcomes is increasingly common to measure adverse side effects after radiotherapy in cancer patients. Factor analysis has the potential to identify an optimal number of latent factors (i.e., symptom groups). However, the ultimate goal of treatment response modeling is to understand the relationship between treatment variables such as radiation dose and symptom groups resulting from FA. Hence, it is crucial to identify clinically more relevant symptom groups and improved response variables from those symptom groups for a quantitative analysis. OBJECTIVES The goal of this study is to design a computational method for finding clinically relevant symptom groups from PROs and to test associations between symptom groups and radiation dose. METHODS We propose a novel approach where exploratory factor analysis is followed by confirmatory factor analysis to determine the relevant number of symptom groups. We also propose to use a combination of symptoms in a symptom group identified as a new response variable in linear regression analysis to investigate the relationship between the symptom group and dose-volume variables. RESULTS We analyzed patient-reported gastrointestinal symptom profiles from 3 datasets in prostate cancer patients treated with radiotherapy. The final structural model of each dataset was validated using the other two datasets and compared to four other existing FA methods. Our systematic EFA-CFA approach provided clinically more relevant solutions than other methods, resulting in new clinically relevant outcome variables that enabled a quantitative analysis. As a result, statistically significant correlations were found between some dose-volume variables to relevant anatomic structures and symptom groups identified by FA. CONCLUSIONS Our proposed method can aid in the process of understanding PROs and provide a basis for improving our understanding of radiation-induced side effects.

Patient-reported gastrointestinal symptoms among long-term survivors after radiation therapy for prostate cancer.

BACKGROUND AND PURPOSE With modern radiotherapy technology we have the means to substantially reduce late gastrointestinal toxicities after radiation therapy for prostate cancer. However, there is still a lack of knowledge regarding the spectrum of patient-reported gastrointestinal symptoms after such treatment. MATERIALS AND METHODS We conducted a cross-sectional study using a study-specific questionnaire to survey gastrointestinal symptoms 2-14years after prostate cancer radiation therapy. We included 985 men treated between 1994 and 2006 with primary (EBRT) or salvage (POSTOP) external beam radiation therapy or EBRT and high-dose rate brachytherapy (EBRT BT). We also included 350 non-irradiated population-based controls randomly matched 1:3 for age and area of residence. RESULTS Survey participation rate was 89% (874/985) for survivors and 73% (243/332) for controls. We found significant increased prevalence ratios for 13/34 symptoms in the primary EBRT group, 10/34 symptoms in the EBRT BT group and 9/34 symptoms in the POSTOP group, several of which have not been described previously. Bother due to these symptoms increased with increasing symptom intensity and was highest for fecal leakage and defecation urgency. CONCLUSIONS Our results can be used to inform clinical evaluation and future studies of long-term gastrointestinal toxicity after radiotherapy for prostate cancer.

Associations between volume changes and spatial dose metrics for the urinary bladder during local versus pelvic irradiation for prostate cancer

Abstract Background: Inter-fractional variation in urinary bladder volumes during the course of radiotherapy (RT) for prostate cancer causes deviations between planned and delivered doses. This study compared planned versus daily cone-beam CT (CBCT)-based spatial bladder dose distributions, for prostate cancer patients receiving local prostate treatment (local treatment) versus prostate including pelvic lymph node irradiation (pelvic treatment). Material and Methods: Twenty-seven patients (N = 15 local treatment; N = 12 pelvic treatment) were treated using daily image-guided RT (1.8 Gy@43-45 fx), adhering to a full bladder/empty rectum protocol. For each patient, 9-10 CBCTs were registered to the planning CT, using the clinically applied translations. The urinary bladder was manually segmented on each CBCT, 3 mm inner shells were generated, and semi and quadrant sectors were created using axial/coronal cuts. Planned and delivered DVH metrics were compared across patients and between the two groups of treatment (t-test, p < .05; Holm–Bonferroni correction). Associations between bladder volume variations and the dose-volume histograms (DVH) of the bladder and its sectors were evaluated (Spearman’s rank correlation coefficient, rs). Results: Bladder volumes varied considerably during RT (coefficient of variation: 16–58%). The population-averaged planned and delivered DVH metrics were not significantly different at any dose level. Larger treatment bladder volumes resulted in increased absolute volume of the posterior/inferior bladder sector receiving intermediate-high doses, in both groups. The superior bladder sector received less dose with larger bladder volumes for local treatments (rs ± SD: −0.47 ± 0.32), but larger doses for pelvic treatments (rs ± SD: 0.74 ± 0.24). Conclusions: Substantial bladder volume changes during the treatment course occurred even though patients were treated under a full bladder/daily image-guided protocol. Larger bladder volumes resulted in less bladder wall spared at the posterior-inferior sector, regardless the treatment received. Contrary, larger bladder volumes meant larger delivered doses to the superior bladder sector for pelvic RT but smaller doses for local treatments. Graphical Abstract

Spatial rectal dose/volume metrics predict patient-reported gastro-intestinal symptoms after radiotherapy for prostate cancer

Abstract Background: Gastro-intestinal (GI) toxicity after radiotherapy (RT) for prostate cancer reduces patient’s quality of life. In this study, we explored associations between spatial rectal dose/volume metrics and patient-reported GI symptoms after RT for localized prostate cancer, and compared these with those of dose–surface/volume histogram (DSH/DVH) metrics. Material and methods: Dose distributions and six GI symptoms (defecation urgency/emptying difficulties/fecal leakage, ≥Grade 2, median follow-up: 3.6 y) were extracted for 200 patients treated with image-guided RT in 2005–2007. Three hundred and nine metrics assessed from 2D rectal dose maps or DSHs/DVHs were subject to 50-times iterated five-fold cross-validated univariate and multivariate logistic regression analysis (UVA, MVA). Performance of the most frequently selected MVA models was evaluated by the area under the receiving–operating characteristics curve (AUC). Results: The AUC increased for dose-map compared to DSH/DVH-based models (mean SD: 0.64 ± 0.03 vs. 0.61 ± 0.01), and significant relations were found for six versus four symptoms. Defecation urgency and faecal leakage were explained by high doses at the central/upper and central areas, respectively; while emptying difficulties were explained by longitudinal extensions of intermediate doses. Conclusions: Predictability of patient-reported GI toxicity increased using spatial metrics compared to DSH/DVH metrics. Novel associations were particularly identified for emptying difficulties using both approaches in which intermediate doses were emphasized.