Abstract
Purpose
Rib fractures are a well-described complication following thoracic stereotactic body radiation therapy (SBRT). However, there are limited data in the setting of liver-directed SBRT.
Methods
Patients who underwent liver SBRT from 2014 to 2019 were analyzed. Logistic regression models were used to identify the demographic, clinical, and dosimetric factors associated with the development of rib fractures.
Results
Three hundred and forty-three consecutive patients were reviewed with median follow-up of 9.3 months (interquartile range [IQR]: 4.7–17.4 months); 81% of patients had primary liver tumors and 19% had liver metastases. Twenty-one patients (6.2%) developed rib fractures with a median time to diagnosis of 7 months following SBRT (IQR: 5–19 months). Of those patients, 11 experienced concomitant chest wall pain, while 10 patients had an incidental finding of a rib fracture on imaging. On univariate analysis, female gender (odds ratio [OR]: 2.29; p = 0.05), V30 Gy (OR: 1.02; p < 0.001), V40 Gy (OR: 1.08; p < 0.001), maximum chest wall dose (OR: 1.1; p < 0.001), and chest wall D30 cm3 (OR: 1.09; p < 0.001) were associated with an increased probability of developing a rib fracture. On multivariate analysis, maximum chest wall dose (OR: 1.1; p < 0.001) was associated with developing a rib fracture. Receipt of more than one course of SBRT (p = 0.34), left versus right sided lesion (p = 0.69), osteoporosis (p = 0.54), age (p = 0.82), and PTV volume (p = 0.55) were not significant.
Conclusions
Rib fractures following liver SBRT were observed in 6.2% of patients with the majority being asymptomatic. To mitigate this risk, clinicians should minimize dose delivery to the chest wall. Female patients may be at increased risk.
Keywords: Hepatocellular carcinoma, liver metastases, radiation oncology
INTRODUCTION
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the second leading cause of cancer mortality.[1] The liver is also a common site for metastasis with approximately 5% of cancer patients presenting with liver metastases.[2] Stereotactic body radiation therapy (SBRT) is increasingly being used as an ablative modality for primary liver malignancies and for liver metastases in the setting of oligometastatic cancer.[3-7]
Several large series have shown excellent rates of local control for primary liver tumors, with two- and three-year local tumor control rates ranging from 68-95%, and two-year local tumor control rates ranging from 70-85% for 1-3 liver metastases.[8-20] A prospective study by Rusthoven et al. of 47 patients with oligometastatic liver cancer demonstrated local control rates > 90% at 1- and 2-years post SBRT. Therefore, given these high local control rates and favorable toxicity profile, there has been an increased interest in utilizing SBRT in these settings.
While liver SBRT is generally well-tolerated, late toxicities include radiation-induced liver disease (RILD), biliary strictures, or ascites.[21] Centrally-located tumors, defined as a 15-mm expansion of the portal vein from the splenic confluence to the first bifurcation of the left and right portal veins, are associated with an increased risk of developing these severe gastrointestinal toxicities.[7, 22-25] Peripherally located lesions near the chest wall are more commonly associated with a risk of rib fracture.
The development of chest wall toxicity including chest wall pain and the development of rib fractures has been well reported after lung SBRT with a reported incidence between 1.5% and 33% for chest wall pain and between 1.6% and 42.4% for rib fractures.[26-29] In addition, several clinical and dosimetric factors, such as female gender, tumor to chest wall distance and chest wall dose, have commonly been associated with an increased risk in the development of chest wall pain and rib fracture.[28-30] Several studies have shown that chest wall V30 Gy > 30 cm3 is significantly correlated with chest wall pain and rib fractures.[29, 31-33] A study by Andolino et al. that included 280 lung lesions and 67 liver lesions showed that 5 cm3 and 15 cm3 of chest wall receiving 40 Gy predicted a 10% and 30% risk of chest wall toxicity, respectively.[11] As such, current clinical protocols for thoracic SBRT include dose constraints such as V30 Gy < 30 cm3 and V40 < 5 cm3 to minimize chest wall toxicity.
Given the increasing utilization of liver-directed SBRT, this study aimed to characterize the incidence and predictors for chest wall toxicity after liver SBRT. Awareness of the clinical, demographic and dosimetric parameters associated with the development of chest wall rib fractures may help in further optimizing treatment delivery and improve patient-reported outcomes.
MATERIALS AND METHODS
This study was approved by the Institutional Review Board of the Mount Sinai Health System (IRB #: IF2611938). Clinical, demographic, and dosimetric data were collected, as shown in Table 1. Follow-up imaging with CT and/or MR was required after completion of SBRT.
Table 1.
Patient characteristics
| Characteristic | Number/Percent (IQR) | |
|---|---|---|
| Total Number of Patients: | 343 | |
| Gender | Male | 72.1% |
| Female | 27.9% | |
| Ethnicity | Caucasian | 39.6% |
| Black | 5.7% | |
| Hispanic | 14.4% | |
| Asian | 15.6% | |
| Other | 24.6% | |
| Diabetes | 57.4% | |
| Osteoporosis | 5.5% | |
| Obesity | 15.1% | |
| Smoking | 61.4% | |
| Tumor Location | Right | 46.3% |
| Left | 38.1% | |
| Both | 15.6% | |
| Total Number of SBRT Courses: | 382 | |
| Median Age (years): | 65 (59-72) | |
| Median Follow-up (months): | 9.3 (4.7-17.4) | |
| Primary Liver Tumors | 81% | |
| Metastases | 19% | |
| 40 Gy/5 fractions | 29% | |
| 45 Gy/5 fractions | 23% | |
| 50 Gy in 5 fractions | 18% | |
| 35 Gy in 5 fractions | 9% | |
| 48 Gy in 3 fractions | 8% | |
| 30 Gy in 5 fractions | 5% | |
| Median PTV volume (cm3) | 69.1 (40.8–158.6) | |
| Median Chest Wall V10 Gy (cm3) | 108 (58-190) | |
| Median Chest Wall V20 Gy (cm3) | 20 (0-56.6) | |
| Median Chest Wall V30 Gy (cm3) | 0 (0-11) | |
| Median Chest Wall V40 Gy (cm3) | 0 (0-0) | |
| Mean Chest Wall Dose (Gy) | 7.2 (5.4–9.9) | |
| Median Chest Wall Maximum Dose (Gy) | 29.4 (21.9-38.8) | |
| Median D30 cm3 Gy | 17.9 (13.1-24.3) | |
| Median distance from tumor to chest wall (cm) | 2.2 (0–3.8) | |
| Incidence of post-SBRT rib fracture: | 6.1% | |
| Median time to diagnosis of rib fracture (months) | 7 (5–19) | |
Abbreviations: IQR: interquartile range; SBRT: stereotactic body radiation therapy
Stereotactic Body Radiation Therapy
Our institutional SBRT delivery practice has been discussed previously.[7] SBRT was defined as delivery of at least 5 Gy per fraction in ≤ 5 fractions and was prescribed to the 100% isodose line. The chest wall was contoured using a 2cm brush and extended from the right vertebral transverse process in an ellipse pattern to include all ribs and intercostal muscles. It was extended 1.5 cm above and below the most cranial and caudal extent of the planning target volume. The normal tissue constraints mandated that at least 700 cm3 of normal liver (minus GTV) not receive ≥ 15 Gy. Additionally, maximum doses to the stomach, small bowel, and large bowel were 27.5 Gy in 5 fractions, and maximum dose to the spinal cord was 30 Gy in 5 fractions. The typical chest wall dose constraint employed was V30 Gy ≤ 30 cm3. In cases where this constrains could not be met, V30 Gy ≤ 70 cm3 was allowed. It was mandated that at least 95% of the PTV receive 100% of the prescription dose. This was prioritized over meeting chest wall constraints.
Data Collection
Gender, age, ethnicity, tumor laterality, diabetes, osteoporosis, obesity and chest wall pain, and symptom data were recorded. Rib fractures were graded using the Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE 5.0).[34] Follow-up CT/MR images were reviewed by a radiologist and a radiation oncologist, and a consensus was met to diagnose a rib fracture. Chronic rib fractures which developed prior to radiation treatment were not included. The time of rib fracture development was recorded based on the first imaging study that noted the presence of a fracture at least 3-months after completing liver SBRT. Dosimetric variables were extracted from dose volume histograms and consisted of chest wall maximum dose, mean dose, chest wall V10 Gy, V20 Gy, V30 Gy, V40 Gy, and chest was D30 Gy; where Vx was defined as the volume of chest wall receiving at least X Gy of radiation. The D30 Gy was defined the maximum dose delivered to the hottest 30 cm3 of chest wall.
Statistical Analysis
Statistical analyses were conducted in R Studio Version 1.1.383 (Boston, MA).[35] Univariate and multivariate logistic regression was performed to calculate odds ratios (OR) and characterize predictors of developing a rib fracture, where the null hypothesis was rejected for p < 0.05. Variable selection for the multivariate model was conducted using forward selection, where minimization of the Akaike Information Criterion was used to determine the model of best fit. The Fine and Gray model was utilized to model the cumulative incidence of rib fracture over time while accounting for the competing risk of death.[36] The “Drawing Survival Curves using “ggplot 2” and “Subdistribution Analysis of Competing Risks” packages were used to perform the analyses and generate the cumulative incidence plot.[37] The impact of SBRT dose was evaluated as both a categorical and continuous variable. For the latter, biologically effective doses were calculated with α/β ratios of 3 Gy and 10 Gy. An additional exploratory analysis was conducted for each dosimetric variable, where dose cutoffs were generated by calculating the largest value that associated with a fracture probability of <5%.
RESULTS
Between 2014 and 2019, 343 patients were identified who received liver-directed SBRT, as shown in Table 1. Median follow up was 9.3 months (interquartile range [IQR]: 4.7-17.4 months). With respect to primary site, 81% were primary liver tumors and 19% metastases. With respect to radiation dose, 5% of patients received 30 Gy in 5 fractions, 9% received 35 Gy in 5 fractions, 29% received 40 Gy in 5 fractions, 23% received 45 Gy in 5 fractions, 18% received 50 Gy in 5 fractions and 8% received 48 Gy in 3 fractions. Dosing and fractionation was chosen based on tumor histology as well as dosimetric considerations. Total doses for patients who received 3 fractions ranged from 36 Gy to 54 Gy, and for 5 fractions ranged from 30 Gy to 60 Gy. The median PTV volume was 69.1 cm3 (IQR: 40.8–158.6 cm3). Median distance from PTV to chest wall was 2.2 cm (IQR: 0–3.8 cm). The median chest wall maximum dose was 29.4 Gy (IQR: 21.9-38.8 Gy).
Chest Wall Toxicity
A total of 21 patients (6.1%) experienced rib fractures after undergoing liver-directed SBRT. Of these patients, three (17.6%) and one (6%) underwent two and three liver SBRT courses, respectively. Eleven patients experienced rib fractures with concomitant chest wall pain while ten patients had an incidental finding of a rib fracture on imaging (CTCAE Grade 1). Of the eleven patients who experienced chest wall pain, five of them had onset of pain prior to obtaining follow-up radiographic imaging and the remaining six had onset of pain after radiographic diagnosis of rib fracture. All of the patients who developed rib fractures were CTCAE Grade 2 with no Grade 3-5 events reported. The median time to diagnosis of rib fracture was 7 months (IQR: 5–19 months). There were 324 patients with adequate data for the competing risks analysis, as shown in Figure 2. The cumulative incidence of rib fracture, while accounting for the competing risk of death, was 5.9% at 2-years post SBRT.
Figure 2.
Cumulative Incidence of Rib Fracture.
Cumulative incidence plot of development of rib fractures and competing risk of death after undergoing liver directed SBRT. The cumulative incidence of rib fractures was 5.9% at 2-years post SBRT
On univariate analysis, female gender (OR: 2.29; 95% CI: 0.98-5.21; p=0.05) was the only demographic characteristic associated with an increased probability of developing rib fractures (Table 2). Increasing BED 3 Gy (1.01; 95% CI: 1.00-1.01; p=0.02), BED 10 Gy (1.02; 95% CI: 1.01-1.04; p=0.01), D30 cm3 (OR: 1.09; 95% CI: 1.05-1.15; p=0.0001), maximum chest wall dose (OR: 1.1; 95% CI: 1.06-1.15; p<0.0001), V40 Gy (OR: 1.08; 95% CI: 1.04-1.14; p=0.0005), V30 Gy (OR: 1.02; 95% CI: 1.02-1.03; p=0.0007), V20 Gy (1.003; 95% CI: 1.000-1.006; p=0.02), and V10 Gy (1.002; 95% CI: 1.000-1.004; p=0.05) were associated with an increased probability of developing rib fractures (Table 2). Increasing distance from the PTV to the chest wall was associated with a lower probability of developing rib fractures (OR: 0.69; 95% CI: 0.52-0.88; p=0.007). The mean chest wall dose was not statistically significant.
Table 2.
Univariate analysis
| Variable | OR | 95% CI | p-value | |
|---|---|---|---|---|
| Number of Fractions | 5 | Ref | Ref | Ref |
| 2 | Inf | Inf | 1 | |
| 3 | 1.32 | 0.30-4.09 | 0.67 | |
| 4 | 2.56 | 0.38-10.25 | 0.24 | |
| Number of RT Courses Stratified | 1 | Ref | Ref | Ref |
| More than 1 | 1.56 | 0.59-3.74 | 0.34 | |
| Gender | Male | Ref | Ref | Ref |
| Female | 2.29 | 0.98-5.21 | 0.05 | |
| Ethnicity | White/Caucasian | Ref | Ref | Ref |
| Hispanic | 1.07 | 0.16-4.36 | 0.93 | |
| Black/African American | 0.62 | 0.14-2.04 | 0.48 | |
| Asian | 0.37 | 0.06-1.39 | 0.2 | |
| Other | 0.59 | 0.18-1.64 | 0.34 | |
| Laterality | Right | Ref | Ref | Ref |
| Left | 0.84 | 0.34-2.00 | 0.69 | |
| Bilateral | 0.44 | 0.07-1.66 | 0.29 | |
| Osteoporosis | No | Ref | Ref | Ref |
| Yes | 1.62 | 0.25-6.16 | 0.54 | |
| Diabetes | No | Ref | Ref | Ref |
| Yes | 1.26 | 0.03-0.12 | 0.59 | |
| Obesity | No | Ref | Ref | Ref |
| Yes | 0.51 | 0.08-1.78 | 0.36 | |
| Age | 0.99 | 0.96-1.04 | 0.82 | |
| BED 3 Gy | 1.01 | 1.00-1.01 | 0.02 | |
| BED 10 Gy | 1.02 | 1.01-1.04 | 0.01 | |
| Age-Gender Interaction | 1.01 | 1.00-1.02 | 0.1 | |
| PTV Volume (cm3) | 1 | 1.00-1.01 | 0.55 | |
| Chest Wall to PTV Distance (cm3) | 0.69 | 0.52-0.88 | 0.007 | |
| Chest Wall V10 Gy (cm3) | 1 | 0.99-1.00 | 0.05 | |
| Chest Wall V20 Gy (cm3) | 1.003 | 1.004-1.007 | 0.02 | |
| Chest Wall V30 Gy (cm3) | 1.02 | 1.01-1.03 | 0.0007 | |
| Chest Wall V40 Gy (cm3) | 1.08 | 1.04-1.14 | 0.0005 | |
| Mean Chest Wall Dose (Gy) | 1 | 1.00-1.01 | 0.94 | |
| Maximum Chest Wall Dose (Gy) | 1.1 | 1.06-1.15 | <0.0001 | |
| Chest Wall D30 cm3 (Gy) | 1.09 | 1.05-1.15 | 0.0001 | |
Abbreviations: CI: confidence interval; OR: odds ratio; Ref: reference
Figure 1.
Patient with post-SBRT Rib Fracture.
(Left Pane) Simulation CT scan with overlaid isodoses (100% isodose line = yellow) (Right Pane) CT scan taken in follow-up approximately 27 months after treatment with a fracture in the right posterior 10th rib (yellow arrow). The patient is a 55 year old female with a history of metastatic squamous cell carcinoma of the anus. Imaging demonstrated two lesions consistent with metastatic disease in segments II and VI. She was treated to a dose of 48 Gy in 3 fractions to each site. Approximately 27 months later she developed pain in the right lower posterior chest wall and was diagnosed with a rib fracture.
Variables selected for the multivariate analysis are shown in Table 3. Increasing maximum chest wall dose (OR: 1.10; 95% CI: 1.05-1.16; p<0.001) was noted to be associated with an increased probability of developing a rib fracture. The V40 Gy and maximum chest wall dose were not statistically significant.
Table 3.
Multivariate analysis
| Variable | OR | 95% CI | p-value |
|---|---|---|---|
| Chest Wall V40 Gy (cm3) | 1.05 | 1.00-1.11 | 0.07 |
| Mean Chest Wall (Gy) | 0.90 | 0.79-1.01 | 0.14 |
| Maximum Chest Wall Dose (Gy) | 1.10 | 1.05-1.15 | <0.001 |
The exploratory analysis evaluating dose cutoffs for each dosimetric variable are shown in Table 4. As shown, V10 Gy, V20 Gy, V30 Gy, and V40 Gy of 148 cm3, 46cm3, 27cm3, and 11cm3, respectively; as well as D30 cm3, maximum chest wall dose, and mean chest wall dose of 26.2 Gy, 52.2 Gy, and 5.9 Gy, respectively were each associated with a 5% risk of developing a rib fracture post-SBRT. These dose thresholds are applicable to the 3 and 5 fraction SBRT regimens.
Table 4.
Chest Wall Dose Cutoffs by Dosimetric Variable with 5% Risk of Developing a Rib Fracture
| Dosimetric Variable | 5% Risk Cutoff |
|---|---|
| V10 Gy | 148 cm3 |
| V20 Gy | 46 cm3 |
| V30 Gy | 27 cm3 |
| V40 Gy | 11 cm3 |
| D30 cm3 | 26.2 Gy |
| Maximum Dose | 52.2 Gy |
| Mean Dose | 5.9 Gy |
DISCUSSION
As one of the largest series of liver SBRT with a total of 343 patients, our study shows that the development of rib fractures after liver SBRT is a relatively rare event with an incidence of 6.1%. Our rate is comparable to the incidence rate of 7% reported in the study by Andolino et al., which only included liver lesions in which at least the 50% isodose line or greater abutted any aspect of the adjacent chest wall.[11] Compared to thoracic SBRT, a recent meta-analysis of 5,985 cases of chest wall toxicity after lung SBRT by Ma et al. showed an overall rib fracture rate of 6.3%.[3] However, there is great variation in the literature with some studies reporting a rib fracture incidence rate as high as 41% and others reporting an incidence rate as low as 0%.[3, 26-30, 38, 39] In the largest study by Bongers et al., which included 500 patients with a median follow up of 33 months, the rib fracture incidence was 1.6%.[28]
Time to onset of chest wall rib fracture is also variable and can occur late. Our study showed a median time to the diagnosis of rib fracture of 7 months (interquartile range: 5-19 months) with a median follow up of 9.3 months (interquartile range 4.7-17.4 months). A study by Chipko et al. reported a longer median time to rib fracture of 22 months (3-46 months) with a median follow up of 49 months (24-106 months).
In patients receiving lung SBRT, female gender has previously been associated with an increased risk in the development of rib fractures.[27, 30, 40] Chipko et al. reported OR = 11.2 (p = 0.005) when comparing the increased risk in females vs males after thoracic SBRT.[30] Similarly, our study found that women were at a higher risk of rib fracture with OR: 2.29 (p = 0.05). The increased risk of rib fractures in females may be due to increased risk of osteoporosis which increases with age. Chipko et al. defined bone mineral density (BMD) as the average Hounsfield units in 1 cm diameter circle of the T12 vertebral body excluding cortex. The study reported a statistically significant increase in rib fracture incidence in patients with lower BMD. Our study did not find a statistically significant association between patients with known osteoporosis, patient age and the incidence of rib fractures. Age-gender interaction was also not associated with increased risk of rib fractures further challenging the association between the incidence of osteoporosis, which occurs more frequently in older females, and the incidence of rib fractures. Furthermore, a pooled analysis of 57 studies showed that female patients had a greater risk of rib fractures than male patients though age was not significant.[3] These findings highlight the need for further characterization of clinical predictors of rib fractures after SBRT.
Our study further showed that decreasing tumor distance from the chest wall was also a significant risk factor in the development of rib fractures in patients receiving liver SBRT (OR: 1.45). Five studies have previously found an association between tumor distance to the chest wall and the incidence of rib fractures in patients receiving lung SBRT. A study by Chipko et al showed that a smaller PTV to chest wall distance was associated with an increased incidence in rib fractures (OR = 0.1; p =0.01). A study by Asia et al. showed that tumor chest wall distance (TCD) < 20 mm was the only significant risk factor in the development of rib fractures, with an incidence rate of 58.1% in patients with a TCD < 20 mm vs 24.4% in patients with a TCD ≥ 20 mm.[26] Bongers et al. reported that rib fractures only occurred in patients with a TCD tumor to chest wall distance < 5 mm.[28] Nambu et al showed a rib fracture incidence rate of 31% in patients whose TCD < 16 mm vs a rate of 36% in patients whose TCD = 0 mm.[40] Andolino el al. showed a rib fracture incidence rate of 21% in patients whose TCD = 0 mm vs a rate of 4% in patients whose TCD > 0 cm.[11] Despite different tumor chest wall distance cutoffs, all showed a statistically significant association between TCD and the development of rib fractures.
Similar to prior reports, our study showed that increasing V40 Gy, V30 Gy, mean chest wall dose and maximum chest wall dose were significant predictors of rib fractures. Dunlap et al showed that the best predictor of severe chest wall pain and/or rib fracture was the V30 Gy with V30 Gy ≥ 35 cm3 correlating with a 30% risk of severe chest wall toxicity.[29] Welsh et al. showed that patients with a V30 Gy above 30 cm3 developed chest wall pain at a rate of 18% vs. 2.7% in patients with a V30 Gy below 30 cm3 (OR:= 8.19, p = 0.04).[32] Our study found that V30 > 27 cm3 correlated with > 5% risk of developing a rib fracture. As shown in Table 4, clinicians may consider these dose parameters in addition to well-established chest wall dose constraints.
Our study has multiple limitations. First, the retrospective nature of our study may result in unintended selection bias. A prospective design would be more optimal, as toxicities and other patient reported events would be expected to be captured with a greater deal of precision. Second, while we did have a large cohort of patients, the limited number of events made it infeasible to perform a multivariate analysis with more than 3 covariates. Third, our median follow-up of 9.3 months may not have been adequate to fully capture all rib fracture events. Fourth, location of each liver lesion was analyzed as a categorical variable with three levels (right, left, or bilateral). Due to the limited number of events, it was not possible to perform this analysis by liver segment, which would be expected to provide a more detailed description of the anatomic location of each liver lesion.
CONCLUSION
In this large cohort of patients, the rate of rib fractures in patients following liver-directed SBRT was 6.1%. Female gender and increased dose delivery to the chest wall appear to further increase this risk. Given the similarities between dosimetric and demographic factors associated with this risk in the thoracic SBRT population, we advise clinicians to contour the chest wall for all liver SBRT cases and to minimize dose delivery to the chest wall. Larger studies will help to further characterize this risk.
ACKNOWLEDGMENTS
Authors’ disclosure of potential conflicts of interest
The authors have nothing to disclose.
Footnotes
Author contributions
Conceptualization: Eric J. Lehrer, Michael Buckstein
Data Curation: Camille Hardy-Abeloos, Eric J. Lehrer, Anthony D. Nehlsen, Kunal K. Sindhu, Rendi Sheu
Formal Analysis: Camille Hardy-Abeloos, Eric J. Lehrer, Jared P. Rowley
Investigation: Camille Hardy-Abeloos, Eric J. Lehrer, Jared P. Rowley
Methodology: Eric J. Lehrer, Michael Buckstein
Project Administration, Resources, Supervision: Michael Buckstein
Software: Camille Hardy-Abeloos, Eric J. Lehrer
Visualization: Eric J. Lehrer
Writing – original draft: Camille Hardy-Abeloos, Eric J. Lehrer, Michael Buckstein
Writing – review and editing: All authors
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