Insufficiency fractures (IFs) are defined as a type of stress fracture, which can occur if a weakened bone, due to decreased elastic resistance and demineralization, is stressed with normal and/or physiological force.
Recently, radiation therapy (RT) has been recognized as a risk factor for IFs (5) in many malignancies (6-10), ranging from 9% to 11.2% in rectal (11), 8.2% to 45.2% in cervical (12-14), and up to 6.8% (10) in prostate cancer, respectively. The risk factors for RT-induced IFs that have been identified include post-menopausal state, older age, chemotherapy and female sex (8,11,13,14).
Texture analysis (TA) is able to quantify image heterogeneities that may not be appreciated with the naked eye, and represents a method based on mathematical analysis for the evaluation of gray-level intensity and for the position of the pixels within the images, providing “texture features”, that represent a quantitative measure of various imaging techniques (15). Statistical analysis achieves and quantifies both distribution and relationships of the gray-level values of the image. Actually, many studies have considered TA in several areas of cancer imaging, showing a potential application in diagnosis, assessment of response to treatment as well as characterization of tumors (16-24). In regards of bone physiology, TA has been applied mainly for densitometry, leading to the development of the trabecular bone score (TBS), an analytical tool for gray-level texture measurements calculated on dual X-ray absorptiometry (DXA) of the lumbar spine, thus providing information related to trabecular architecture (25-27).
With these premises, we have investigated in the present study the potential role of TA based on 3D ROI, automatically contoured using the treatment planning software Raystation©. TA parameters were calculated using LifeX Software© (30), and included parameters from the gray-level histogram and from the matrix of GLCM (gray level co-occurrence matrix).
IF cohort of patients (IF-p)
From January 2009 to December 2016, 31 patients that were previously treated for pelvic malignancies developed pelvic IFs during the follow-up. We collected all the clinical data, as well as the pathological and dosimetric information, for the present study.
The IF-p series included 14 patients (46%) with endometrial or cervical cancer, 15 patients (48%) with anal or rectal cancer and 2 (6%) with prostate or bladder tumors.
A CT simulation for treatment planning calculations was done before RT. Previous fractures of the pelvic bone and any tumor recurrence were considered as a cause of exclusion.
In this regard, we have excluded twelve patients from this analysis (five patients showed evidence of IFs before the radiation treatment and seven patients developed bone tumor recurrence).
Controlled patients cohort (C-p)
The IF-p patients were compared (1:1 ratio) with the C-p series, which were similarly patients submitted to pelvic irradiation in our institution in the same time-lapse, but not developing IFs. Each IF-p patient was matched with one C-p patient, for the criteria of sex, menopausal status, age, localization of tumor, chemotherapy and RT dose. The exclusion criteria were identical.
In order to limit biases, we also considered the time-lapse of RT administration (Jan 2009 to Dec 2012 vs. Jan 2013 to Dec 2016), the RT total doses and the RT technique [intensity-modulated RT (IMRT) vs. three-dimensional conformal RT (3D-CRT)].
Radiotherapy and chemotherapy treatment
RT was given with a Linear Accelerator, with 6 or 15 MeV photon beams. 3D-CRT or IMRT techniques were chosen according to the clinician choice. Target volumes and organs at risk were identified by diagnostic CT and contoured on simulation CT.
Chemotherapy was administered concurrently with, or sequentially to, RT, employing standard association of platinum, fluoropyrimidine compounds, mitomycin and taxanes, according to international guidelines.
Specifically, patients with cervical cancer underwent chemotherapy with weekly cisplatin (40 mg/m2), patients with rectal cancer underwent chemotherapy with capecitabine (825 mg/m2, twice daily for 5 days/week) daily throughout the radiotherapy course, and patients with anal canal cancer underwent chemotherapy with 5-FU (1,000 mg/m2/day) by continuous infusion for 4 days and MMC (10 mg/m2) intravenous bolus for two cycles during the course of RT.
Authorization for the retrospective analysis was given by the Internal Institutional Review Board.
Each patient signed an informed consent both for the treatments and for the anonymous use of clinical data. All procedures were in compliance with the ethical statements of the Helsinki Declaration (1964, amended most recently in 2008).
After completion of treatment, all patients underwent scheduled follow-up visits, according to the primary tumor. In patients with gynecological, gastrointestinal and bladder malignancies, an imaging with CT and/or MRI was performed at 4–6 and 12–16 weeks after the completion of RT, then every 6 months. In patients with prostate cancer, diagnostic CT and/or MRI was obtained only if justified by a rise of the PSA value and/or by emerging symptoms or physical signs of recurrence or complications.
The MRI examination was obtained with a 1.5-T system, Signa Excite HD, GE Healthcare, Milwaukee, WI, USA, whereas the CT was performed with a 64-detector row CT scanner (Discovery 750 HD, GE Healthcare, Milwaukee, WI, USA).
All the patients underwent a physical examination, chemistry and blood counts every 3 months.
Assessment of IFs
IFs development was confirmed at CT or MR imaging, by an expert radiologist (Salvatore Francesco Carbone), with 15 years’ experience in the oncologic field. CT ﬁndings of IF included sclerotic linear changes or fracture lines, whereas MRI ﬁndings included both on T1 and T2-weighted images the presence of signal intensity changes in the bones of >5 mm (8).
In all the patients with IFs the simulation CT scan was reviewed, in order to exclude the patients that showed pre-existent fractures.
CT simulation was performed before RT, with a 16 slice CT-scanner (slice thickness 2.5 mm, beam pitch of 1.375, reconstruction interval 2.5 mm, tube voltage of 120 kVp and reference mAs ranging from 100 to 440 mA, Index Noise 10).
We analyzed three regions of interest (ROI) on CT simulation: the vertebral body of L5, the sacrum (S1–S3) and the femoral heads (Figure 1). Each ROI was automatically contoured using a treatment planning contouring workstation (RayStation©) and validated by a radiation oncologist (Valerio Nardone).
The TA was performed using a LifeX© (30), and included features of gray-level co-occurrence matrix (GLCM), sphericity and indices from the gray-level histogram. For the femoral heads ROI we calculated the mean of the two ROI.
The TA parameters, as described above, were correlated with the development of IFs by univariate (Pearson correlation). We analyzed the correlation between the significant TA parameters and, if a correlation larger than 0.80 was observed, then the variable with the lowest univariable correlation with the endpoint was omitted, to avoid the risk of overfitting the model and of multicollinearity (31) in the multivariate analysis (binary logistic regression). After performing the multivariate analysis the ROC Curves with these parameters were also carried out. The statistical analysis was performed using the SPSS software 23.0.
The characteristics of both the cohorts of IF-p and C-p, with the localizations of the IFs are reported in Table 1. IFs occurred in different pelvic bones, with 17 patients (55%) developed multiple IFs.
The median follow-up period was equal to 43.46 months (mean 47.21 months, SD 24.26 months, range 12–84 months).
Regarding the enrollment time-lapse, 15 out of 31 patients (48%) in IF-p series and 16 out of 31 patients (52%) in C-p series were enrolled from Jan 2009 to Dec 2012, whereas 16 out of 31 patients (52%) in IF-p series and 15 out of 31 patients (48%) in C-p series were enrolled from Jan 2013 to Dec 2016 (P>0.05). Regarding the RT technique 16 out of 31 patients (52%) in IF-p series and 17 out of 31 patients (55%) in C-p series underwent intensity modulated radiation therapy (IMRT), whereas 15 out of 31 patients (48%) in IF-p series and 14 out of 31 patients (45%) in C-p series underwent 3D-conformal RT, 3D-CRT (P>0.05). The period of enrollment, as well as the radiation doses between IF-p and C-p were well balanced between the groups (see the results reported in Table 1).
We performed a Pearson correlation analysis between the TA parameters and the development of IFs.
Significant TA parameters included: L5-kurtosis (P=0.049), L5-energy (P=0.007), L5-GLCM-energy (P=0.023), sacrum-kurtosis (P=0.034), sacrum-compacity (P=0.039, this parameters is a measure of compactness of the volume), FH-kurtosis (P=0.005), FH-skewness (P=0.001), FH-energy (P=0.005), FH-GLCM-homogeneity (P=0.006), FH-GLCM-energy (P=0.020) (Tables 2,3 and Figure 2).
The TA parameters that resulted significantly at univariate analysis were normalized and tested for co-correlation. The parameters L5-GLCM-energy, FH-kurtosis, FH-energy were omitted, to avoid the risk of overfitting the model and of multicollinearity (31) in the multivariate analysis.
We performed a logistic regression analysis with the group as the dependent variable and all the normalized texture parameters, plus all relevant confounding variables (sex, radiation doses, and chemotherapy).
The variables that resulted significant were L5-energy [P=0.033, odds ratio (OR): 1.997, 95% CI: 1.059–3.767] and FH-skewness (P=0.014, OR: 2.338, 95% CI: 1.191–4.591), with a R2: 0.268 (Tables 2,3).
A ROC curve was generated from the binary logistic regression, the AUC was 0.741 (95% CI: 0.627–0.855, P=0.001, S.E.: 0.058) (Figure 3).
We have previously studied (28,29) the role of bone TA, with an in-house 2D software, and we have decided to explore the potential role of 3D Bone TA. Moreover, we tested the possibility of automatically obtain 3D ROI with the treatment planning contouring workstation (Raystation©).
Although the LifeX Software© (30) is able to calculate parameters of gray-level co-occurrence matrix (GLCM), neighbourhood gray-level dependence matrix (NGLDM), gray-level run length matrix (GLRLM), gray-level zone length matrix (GLZLM), sphericity and indices from the gray-level histogram, we decided to use only parameters from gray-level histogram, sphericity and GLCM matrix, to reduce the number of TA variables, including TA indices that were already used in the imaging of trabecular bone structure (32).
At this regard, the major novelties of this paper, in comparison to our previous work (28), are the 3D TA, the automatic contouring of the ROI and the higher number of texture parameters analysed.
Our results showed a co-correlation between many variables, as well as the significance of the same TA variables between the different ROI (energy, kurtosis), and this aspect increases the validity of our results.
The TA variables that resulted significant at binary logistic regression were L5-energy and FH-skewness.
Energy represents a measure of the uniformity of the distribution, and is significantly higher in IF-p than C-p. This parameter is inversely correlated to the entropy, in accordance with previous works (28,33,34). This might be explained by the fibers being more marked in the control group, with an increase in the randomness of the pixel values, and eventually an increase in the entropy and a decrease in energy.
Skewness, on the other hand, measures the asymmetry of the gray-level distribution in the histogram, and this parameter was higher in IF-p than C-p. This result could be correlated to a lower density (35) and mineralization of the bone, thus reflecting a higher asymmetry in the histogram.
We have summarized the various studies of bone TA in Table 4.
However, the interpretation of TA parameters on the grounds of bone pathophysiology is incomplete, thus our study is still awaiting an exhaustive scientific background.
In fact, radiation-induced bone damage has been described since the early years of the twentieth century, but the pathophysiology is still unclear. Irradiation seems to reduce osteoblast number, arrest osteoblast cell cycle progression and promote apoptosis, leading to a reduced bone formation (36-38). Data for osteoclasts effect are in some way contradictory (39,40), whereas the damages on bone matrix and on the vascular supply are established (41,42). The combination of these effects results in a reduction in the bone mineral density (BMD) in patients undergoing pelvic RT (43).
The incidence of IF seems to be higher than expected, although there are many discrepancies in the various study (5,10-14,44-46), probably due to the differences in the follow-up, as the choice of imaging may increase the detection of asymptomatic IFs. One study reported 89% of patients had findings compatible with IF after pelvic RT using magnetic resonance imaging (47), while another study reported 34% using bone scintigraphy (48).
It is noteworthy that currently there is no recommendation for the diagnosis and the management of radiation-related IF in patients undergoing pelvic radiotherapy.
Very recently (25-27), the TBS measurement of gray level texture on DXA images has provided some information on microarchitecture of the trabecular bone, and these parameters seem associated with an increase in both prevalent and incident fractures. These information, also, seem to be independent from the clinical risk factors and BMD.
Limitations of the study
Although our method of TA has improved with the use of automatically contoured ROI, 3D TA and a higher number of TA parameters, our results still need methodological and technical refinements, as wells as a validation in larger series and prospective trials.
The low number of patients enrolled, as well as the matched analysis comparison, also represent a limit of our study.
Insufﬁciency fractures represent an important cause of morbidity for cancer survivors undergone pelvic radiotherapy and there is a need to develop robust clinical interventions that are evidence-based.
Our results appear to be promising since the knowledge of the predictive factors of this kind of RT toxicity could drive the selection of the best appropriate preventions in the population at risk.
We’re planning to start a prospective trial, integrating bone mineralometry and serum markers, to further substantiate this field of investigation.
Conflicts of Interest: The authors have no conflicts of interest to declare.
Ethical Statement: Authorization for the retrospective analysis was given by the Internal Institutional Review Board. Each patient signed an informed consent both for the treatments and for the anonymous use of clinical data. All procedures were in compliance with the ethical statements of the Helsinki Declaration (1964, amended most recently in 2008).
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