Abstract
Background/Aim: This study aimed to assess whether the patient’s abdominal adiposity affects the performance of the Exactrac imaging system compared to the cone beam computed tomography (CBCT)-based setup, which was used as the reference positioning for the image-guided radiotherapy (IGRT) delivery to patients with localized prostate cancer. Patients and Methods: The daily positionings of patients with localized prostate cancer undergoing definitive or adjuvant/salvage radiotherapy (RT) were analyzed. The abdominal fat areas and pelvic incidence angle were determined on the CT simulation for each patient. A couple of ExacTrac images and a CBCT were acquired daily to verify the patient setup. We recorded every daily set of the three residual translational errors detected on the CBCT after the ExacTrac-based setup. These sets were clustered within three different thresholds (0.1 mm, 0.2 mm, and 0.3 mm), for each of which the influence of adipose tissues on Exactrac accuracy was assessed as the percentage of sub-threshold displacements as the fat parameters varied. A full bladder and empty rectum preparation protocol was adopted as much as possible. Results: From the assessment of 1,770 daily positionings in 55 patients (38 definitive RT, 17 adjuvant/salvage RT), a good agreement between ExacTrac and CBCT could be inferred, which was quite robust against slight variations in the bladder and rectal filling, and the presence or not of the prostate. The percentages of above-threshold corrections increased with increasing abdominal fat, which therefore seemed to reduce the ExacTrac accuracy. This might be influenced by any intrafraction prostate displacement, likely induced by abdominal respiratory movements, and are more pronounced among overweight men. Conclusion: Our results promote the CBCT use over ExacTrac for IGRT of overweight patients with localized prostate cancer, while calling for attention to the probable need for personalization of planning target volume margins depending on the patient’s body habitus.
- Image-guided radiotherapy
- prostate cancer
- ExacTrac
- cone beam computed tomography
- fat tissues
- personalized radiation therapy
Image-guided radiation therapy (IGRT) revolutionized the treatment of patients with localized prostate cancer allowing to safely escalate the radiation dose to the target without threatening the tolerance of neighboring organs at risk (OARs) (i.e., bladder, penile bulb, and rectum) (1). The set-up verification is typically pelvic bony structure-based or alternatively soft tissue-based. The latter, thanks to the direct visualization of volumes of interest, was proven to be superior to the first, even when this uses high-definition kV imaging rather than MV electronic portal imaging devices (EPID) (2).
Among the kV systems, ExacTrac® (Brainlab, Munich, Germany) was initially designed for stereoscopic image guidance of stereotactic radiotherapy (RT) treatments of intracranial or spine targets (3, 4). Being based on bony matching, its performance is great also for targets abutting the appendicular skeleton (5).
In prostate treatments, matching the pelvic bones as a target position surrogate implies some positional uncertainties that require a larger planning target volume (PTV) as compared to a soft tissue-based setup using cone-beam computed tomography (CBCT) (6). To bridge this accuracy gap between the two imaging methods, the bone-based one needs the implantation of fiducial markers into the prostate (7). This is especially necessary when delivering ultra-hypofractionated radiation doses through non-isocentric linear accelerators not equipped with CBCT (8). The typical low risk, further improvable by supportive care, of radiation-related toxicities in normo-fractionated or moderately hypofractionated bone-guided radiotherapy schemes does not warrant the use of locally invasive procedures like the fiducial implantation under these circumstances (9, 10).
Being aware of the overall superiority of the soft tissue-based setup over the bony one, we evaluated whether the performance of the ExacTrac system is influenced by the patient’s anatomical composition as determined from the Computed Tomography (CT) simulation. We focused our attention on patients submitted to definitive or adjuvant/salvage radiotherapy (RT) to prostate or prostate bed.
Patients and Methods
This study was prospectively designed to compare the efficacy of a bone-based setup verification with a soft tissue-based one over a long course of RT for localized prostate cancer patients. We retrospectively reviewed the treatment records of patients definitively or adjuvantly irradiated to the prostate or prostate bed with RT schemes ranging from 70.2 Gy in 26 fractions of 2.7 Gy/day to 66-80 Gy in 33-40 fractions of 2 Gy/day from January 2019 to April 2020. Normofractionation was used for both prostate and prostate bed, while hypofractionation was only for unresected patients. We collected only patients for whom a CT-simulation extended up to the third lumbar vertebra (L3) was available. This was performed with 3mm thickness slices in the supine position and with the bladder full and the rectum empty. ProStep™ was used for daily patient immobilization. The Clinical Target Volume (CTV, prostate±seminal vesicles or prostate bed) and OARs (bowel, bladder, penile bulb, femoral heads, and rectum) were delineated according to the Radiation Therapy Oncology Group (RTOG) consensus guidelines (11, 12). The CTV-to-PTV margins were determined according to the Alonso-Arrizabalaga’s findings calculated for a daily IGRT schedule (13): the values 4.7 mm, 6.2 mm, and 1.9 mm in the anterior–posterior, superior–inferior, and right–left directions were approximated to 5 mm, 6 mm, and 2 mm, respectively, to consider any intrafraction uncertainties. All patients were treated on a Novalis TrueBeam STx (Varian, Palo Alto, CA, USA) equipped with both a Varian kV on-board-imager (OBI) performing a 125 kV CBCT and an ExacTrac X-ray system (version 6.2.3) shooting a couple of 120 kV X-ray images. Volumetric modulated arc therapy (VMAT) was planned and delivered with the couch at 0°. The verification protocol involved the daily use of two couples of “snapshots” by the ExacTrac system (the first to correct the laser-guided positioning by the treating radiation therapists, and the second to confirm and validate the first correction) followed by a CBCT. Obviously, the ExacTrac radiographs matched the pelvic bones with the corresponding digitally reconstructed (DRR) from the planning CT, allowing a 6 degree-of-freedom movement of the treatment couch; conversely, the daily CBCT was used for directly matching the CTV without the option to detect any pitch and roll (not available). The residual translational (lateral, vertical, longitudinal) shifts detected on the CBCT after the ExacTrac corrections were recorded and applied, unlike the yaw. No intrafraction motion was assessed. The patients were invited to keep the bladder full and the rectum empty as constantly as possible during each daily treatment session: moderate fluctuations in the fullness of the rectum and bladder (not exceeding 20% of the baseline volume at the planning CT, as clinically perceived by the radiation oncologist during the CBCT verification) were permitted. Otherwise, the patient was asked to adjust the filling volume of his bladder and rectum before the treatment delivery. Variations below 5% were intended as perfectly matching the reference (0 for the full bladder and empty rectum) while variations between 5% and 20% were recorded as moderate but still acceptable to treat (1 for not completely full bladder and empty rectum). Both thresholds were estimated through a clinical eye-based evaluation.
We evaluated the body composition of each patient on a planning CT slice passing through L3 according to the method in (14). We extracted the total fat area (TFA) from the total area (TA) by subtraction of the skeletal muscle area (SMA), bones and any visceral organs (i.e., bowel loops and kidneys); TFA was further divided into the subcutaneous (SFA) and visceral fat areas (VFA) depending on the location in relation to the sides of SMA (SFA on the outside, VFA on the inside). Furthermore, we determined the pelvic incidence (PI) angle on the sagittal view of each planning CT as described in (15) (Figure 1).
Segmentation of fat tissues for a thin (A) and an overweight (B) patient. (C) and (D) refer to the corresponding pelvic incidence angles. Magenta is for subcutaneous fat area, orange for skeletal muscle area, yellow for visceral fat area (cropped from bowel loops, great vessels, and kidneys), green for bones, light blue, and brown for kidneys.
The patient data collection included: the daily residual translational shifts detected through the CBCT in relation to the second correction applied by the ExacTrac system (over the full course of RT), the RT intent (definitive or adjuvant or salvage), the daily fullness/emptiness status of the bladder and rectum (0 or 1), and the body parameters (TA, TFA, SFA, VFA, and PI).
To investigate the influence of abdominal adiposity on the ExacTrac accuracy, the CBCT-detected residual errors were clustered under three different thresholds (0.1 mm, 0.2 mm, and 0.3 mm). We then considered the frequency of occurrence of the displacements in relation to the investigated body parameters for each group of values. Each group required daily displacements within the given limits for all three axes, i.e., 0.1 mm, 0.2 mm, and 0.3 mm, respectively.
Ethics approval. The local ethics committee Comitato Etico Catania 2 approved the study (protocol number 50/2018/CETC2) on 13 November 2018. The study was performed according to the Good Clinical Practice guidelines and Declaration of Helsinki. All patients provided written informed consent to participate to this study.
Statistical analysis. We investigated whether any correlation exists between the ExacTrac system’s performance and patient’s body parameters. The statistical and graphic analysis was carried out using the R (v. 4.1.1) environment (16) and RStudio (v. 2021.09.1+372) (17) with plotly (v. 4.10.0) (18), ggridges (v. 0.5.3) (19), ggplot2 (v. 3.3.5) (20) and dplyr (v. 1.0.7) (21) packages. Data were compared using the Pearson’s correlation coefficient and the statistical significance was indicated by including a p-value (<0.05).
Results
Overall, we collected 1,770 daily positionings for 55 patients, 38 of whom received radiotherapy to the prostate and 17 to the prostate bed. Our analysis aimed to identify the relationship between the residual errors of ExacTrac and the anatomical characteristics of the patients. In these comparisons, knowledge of ExacTrac residual errors derived from subsequent CBCT adjustments (Figure 2).
Examples of residual errors detected on a treatment day at the CBCT after ExacTrac positioning for a thin and an overweight patient. For the latter, the vertical, longitudinal, and lateral displacements were 0.4 mm, 0.7 mm, and 0.8 mm, respectively, while the ones for the thinner patient were 0 mm in all three axes.
We summarized in Table I descriptive statistics for the parameters of the entire population. As observed in Figure 3, the density distribution of ExacTrac displacements varied according to the threshold value; the number of displacements ≤0.3 mm was approximately 25%, indicating an agreement with CBCT positioning with minimal error.
Descriptive statistics of variables under study.
Density distribution of residual errors for each threshold: wider displacements imply a considerable increase of corrections under threshold.
Residual displacements after ExacTrac positioning are very limited in range, as, out of the 1,770 analyzed corrections, 1,371 were ≤1 mm. These latter are highlighted in Figure 4. In the graph, the color of each dot was calculated using the maximum component of the vector [e.g., a residual error like (lateral=−1; vertical=0.2; longitudinal= 0.0) mm for a position is colored by a black dot since the lateral component requires a 1 mm adjustment]. It can be observed due to the color distribution as most of the positionings are less than ±0.7 mm and a numerical explanation can be found in Table II, where the standard deviation better explains the extremely low dispersion of the data around the mean with a small interquartile range.
Graphical representation of the residual errors ≤1 mm detected by cone beam computed tomography after the ExacTrac alignment. The axes denote a 3D spatial direction of the movements (in millimeters) and the colors show the quality of positioning (green for near 0 mm and black for near 1 mm error). There are 1371 corrections ≤1 mm, 520 of which are hidden by overlapping with others.
Descriptive statistics for residual errors (in absolute value, mm) after ExacTrac alignment.
The relationships between anatomical parameters like TA, TFA, SFA, VFA, and PI with ExacTrac positionings under a threshold of residual errors are shown in Figure 5. In these correlations the “Displacements under threshold (%)”, represented by the x-axis, describe for each patient the percentages of positionings under a fixed threshold (e.g., 0.1, 0.2 or 0.3 mm).
Correlation plots for anatomical parameters and percentage of displacements under three classes of residual errors in absolute value: A) Correlation plot for total area (TA), statistically significant for ≤0.3 mm threshold (p-value=0.021); B) Correlation plot for total fat area (TFA), statistically significant for ≤0.3 mm threshold (p-value=0.023); C) Correlation plot for subcutaneous fat area (SFA), no statistical significance for any threshold; D) Correlation plot for visceral fat area (VFA), statistically significant for ≤0.1 and ≤0.3 mm thresholds (p-value=0.046 and 0.039, respectively); E) Correlations for pelvic incidence (PI), displacements ≤0.3 mm correlate significantly with PI (p-value=0.022). All other cases follow the same trend without being statistically significant.
The data show a negative correlation for all assessments (as summarized in Table III), therefore the positioning under a certain threshold increases as the variables on the y-axis decrease. As can be observed, there is an agreement on the 0.3 mm threshold as the most correlated with each abdominal fat variable under study; as the number of cases increased, the trend strengthened. There were also no significant differences in placement under the filling state of the bladder and rectum (p-value=0.49 and 0.97, respectively).
Summary of correlation results for total area, subcutaneous fat area, and visceral fat area with different classes of residual errors.
For TA and VFA, the correlation with the 0.3 mm-threshold was statistically significant (p-value=0.021 and 0.039, respectively) but this was not the case for SFA (p-value=0.1). Both TA and VFA for 0.1 and 0.2 mm showed a good correlation; however, in most cases, they were not statistically significant except for VFA with the 0.1 mm-threshold (R=−0.27 p=0.046).
However, the results for the relationship of VFA with ExacTrac residual errors indicate visceral fat as a good predictor of correct positioning, since by varying the threshold there were negligible differences in p-values with only one out of three with a slightly higher significance level (p=0.069). This means that the visceral fat has a better ability to describe the body composition than the subcutaneous one. In contrast, SFA correlations were not significant, emphasizing that the area outside the skeletal muscles is less specific than VFA.
To address the influence of pelvic incidence angle as a useful parameter for a correct estimation of ExacTrac positioning, we first analyzed the correlation of PI with TA, TFA, SFA and VFA, in order to demonstrate the correlation with adipose tissues, and found a significant correlation between PI and TA, p-value=0.02 (Figure 6). The correlation analysis of PI and ExacTrac residual error is presented in Figure 5E. These results show statistical significance for the 0.3 mm threshold (p=0.022), whereas 0.2 and 0.1 mm resulted in similar results but were not statistically significant.
PI correlation with the abdominal tissue areas under study: Total area (TA) (A), total fat area (B), subcutaneous fat area (C) and visceral fat area (D). Relationship between pelvic incidence PI and TA is statistically significant.
Discussion
Our study found a good agreement between the ExacTrac and CBCT setups, having reported a discrepancy not exceeding 0.7 mm in all axes for 75% of patients (third quartile), as shown in Figure 4 and Table II, with a small dispersion from the mean (0.50±0.56 mm, 0.44±0.55 mm, and 0.56±1.02 mm for lateral, longitudinal, and vertical residual errors, respectively). These values are consistent with or even lower than those reported by Sato et al. and Alonso-Arrizabalaga et al. (2, 13) who collected smaller cohorts of patients and therefore fewer verification data than ours. We reported the greatest variability along the vertical axis, the same as Sato et al. (2), who adopted a CBCT-based flowchart like ours to determine the residual errors after the ExacTrac correction. In our report, most residual shifts in all axes were within 1 mm, like in the study of Kudo et al. (22). These findings question the use of ExacTrac as an alternative safe option to CBCT for normofractionated or moderately hypofractionated IGRT of patients with localized prostate cancer. In this regard, out of 1,770 positionings, we observed only three corrections (0.0017%) greater than 1.5 mm in all axes and 211 (11.92%) in at least one. Thus, adding a 1.5-mm isotropic expansion margin would have made ExacTrac sufficient to not miss the target in 88% of setup verifications. However, the need for larger PTV when CBCT is not used must carefully be balanced against the increased risk of not meeting dose-volume constraints for surrounding OARs. Therefore, once PTV size is adjusted, we advise the use of ExacTrac over CBCT solely on the condition of pursuing as much as possible isotoxic dosimetric goals by exploiting the optimization abilities of inverse planning of intensity-modulated RT techniques.
ExacTrac presents some advantages over CBCT: 1) a lower radiation exposure of the patient for treatment verification purposes (23); 2) the “snapshot” nature implying a shorter time of each treatment session with likely improved compliance of some patients (i.e., those developing urinary urgency negatively affecting their ability to keep the bladder full for a long time during RT delivery); 3) as a consequence of the previous point, the time-saving for each patient may increase access to healthcare for a larger number of patients; 4) the possibility to verify even non-coplanar arcs immediately prior to their delivery. As regards the latter issue, some authors proved a greater rectal sparing with non-coplanar 4π intensity-modulated radiation therapy compared to VMAT plans using only two full coplanar arcs (24, 25): ExacTrac may be particularly useful in the first scenario, overcoming the spatial limits of CBCT. Finally, ExacTrac may have a lower and more affordable reimbursement than CBCT, reducing the cost burden on the national healthcare systems, like in Italy and other European countries (26). Conversely, the CBCT allows for narrower margins in determining the PTV based on a direct visualization of the target and not only of the surrounding bones as its surrogate. It is necessary to implant radiopaque fiducial markers into the prostate so they are visible by the ExacTrac system to improve its accuracy and reduce the CTV-to-PTV margins (23).
Our method failed to correct any residual rotational errors post-ExacTrac correction along the Z (roll) and X (pitch) axes since our CBCT did not implement their detection. This weakens the CBCT accuracy in favor of ExacTrac. Indeed, Graf et al. proved small but significant rotational differences when comparing the bone-based (surrogate) and the intraprostatic fiducial markers-based (reference) ExacTrac verifications, advocating the full correction with 6 coordinates rather than with 4 coordinates only (also including the yaw in addition to the three translations) for more precision (27). Anyway, other reports proved some interchangeability between a three degrees-of-freedom fiducial marker (3DOF-FM)-based setup with ExacTrac and a 3DOF-soft tissue (ST)-based setup with CBCT (28).
Slight variations (<20%) in the fullness status of the bladder and rectum did not significantly interfere with the ExacTrac accuracy: the CBCT isocenter did not shift from the ExacTrac one based on that parameter. This confirms that high patient compliance to medical instructions improves the prostate stability (29). Similarly, no significant difference between patients irradiated to the prostate or prostate bed was detected: the presence of the prostate was not a factor for which the CBCT worked better than ExacTrac.
To our knowledge, the present study is the first to evaluate the influence of abdominal adiposity on the ExacTrac accuracy in comparison to the CBCT for setup verification of patients with localized prostate cancer. We demonstrated that the agreement between ExacTrac and CBCT is reduced with increased abdominal fat: the proportion of subthreshold corrections applied by CBCT starting from the ExacTrac positioning increases for each considered cut-off (i.e., residual errors ≤0.1 mm, 0.2 mm, 0.3 mm) as the TA or the abdominal adiposity (i.e., TFA, SFA, VFA) decreases (Figure 5A-D and Table III).
These findings likely reflect a greater mobility, during the respiratory cycle, of the prostate with increasing patient’s weight, as reported by Bodusz et al. (30). Taking as reference the CBCT isocenter, its shift from the ExacTrac position may result not only from an actual interfraction setup error arising from a different structure matching (bones vs. soft tissues) but also from a respiratory-induced intrafraction motion of the prostate. The intrafraction prostate shifts were assessed by Sato et al. (2) by measuring the displacements between the CBCTs before and after the daily fraction delivery. As this comparison was guided by matching soft tissues from two consecutive moments, any positional variation was due to intrafraction motion, likely respiratory-induced (31). According to what Brown et al. claimed (32), the latter movement, especially in the lateral direction, could be more marked in obese patients due to an alteration of respiratory mechanics with more intra-abdominal pressure.
Several studies agree on a greater variability of the interfraction setup error among obese men due to excessive mobility of skin marks in relation to the bony or soft tissue landmarks used for IGRT verification (33-35). Not accurately hitting the target as planned without using a daily IGRT could contribute to an increased risk of biochemical failure in obese patients, additionally to a hormonal environment prone to cancer progression (36-38). A greater positional uncertainty could be also the basis of an increased risk of radiation-related adverse events (39-42).
We support a daily verification schedule in agreement with the findings of de Crevoisier et al. (43) who found significantly better cancer-specific outcomes (biochemical progression-free and clinical progression-free interval), and rectal toxicity rates with a daily IGRT compared to a weekly control among patients with localized prostate cancer submitted to definitive normofractionated RT. These results probably stem from the fact that a daily treatment verification ensures better target coverage and rectal sparing by avoiding the risk of target missing and allowing for tighter PTV margins in comparison to a weekly schedule (44).
Regarding the effect of adipose tissue on the positioning accuracy (Figure 5A-D), our results are counterposed to those of Thompson et al. who adduced a stabilizing effect of the abdominal adiposity on the prostate based on their findings demonstrating lower intrafraction displacements for every unit increase in body mass index (BMI) (45). Yet, these authors assessed the intrafraction prostate displacements by recording the differences between the pre- and post-treatment daily orthogonal kilovoltage images. Conversely, we did not directly collect any intrafraction prostate motion since we compared only two sets of pre-treatment images, enabling CBCT to estimate any residual interfraction setup error after applying the ExacTrac correction. However, we believe that at least a proportion of these residual deviations is affected by respiratory movements featuring the intrafraction prostate mobility. An inter-method comparison (ExacTrac vs. CBCT) could be more reliable than an intra-method CBCT-based one for the determination of intrafraction prostate motion. The reason would lie in the fact that the acquisition of CBCT (and hence of its isocenter position) is averaged over about a two-minute interval capturing more respiratory phases than the few seconds-quick CT-simulation, from which the DRRs to be matched with the ExacTrac images are reconstructed. Similarly, an intra-comparison between instant kV images (including the ExacTrac ones) supported by fiducial markers could detect a potentially more representative range of translational shifts than one based on CBCT as in (2). The discrepancy between our findings and those in (45) could be partially explained by the different methods of assessing patients’ adiposity: accurate segmentation of abdominal adipose tissues vs. BMI, which is criticized as a representative indicator of obesity. However, it is necessary to emphasize that, unlike Thompson et al., we are unable to quantify the intrafraction prostate motion, of which we have only indirect evidence. Indeed, if the divergence between ExacTrac and CBCT had been attributable solely to a residual interfraction setup error deriving from the different tissue matching (bone vs. soft tissue), it should have been constant without being more frequent in a specific subpopulation, i.e., the overweight.
Given the weakness of this interpretation of our findings, some caution is warranted in attributing them to the respiratory movements of the RT target.
For the same reasons, we cannot provide any definitive indication for PTV margins, whose calculation requires the estimation of the intrafraction error in addition to the interfraction one according to the Van Herk equation (46). Unlike Sato et al. and Alonso-Arrizabalaga et al. (2, 13) who obtained another set of images after the treatment session delivery, our protocol did not involve any post-treatment imaging acquisition. This impeded us from recording the intrafraction prostate motion alone. Nevertheless, both estimations by the authors above are to be considered as an approximation compared to an intrafraction evaluation through a continuous tracking device (47).
Despite the above weaknesses, our findings have the merit of shedding light on the need for personalization of PTV margins depending on the patient’s abdominal adiposity. Finally, as Uysal et al. (15) described a positive correlation between the pelvic incidence angle and BMI, we investigated whether this angle correlates with any of abdominal adipose tissue areas so that it can be used as a substitute of them (Figure 6). Having proved this, we also demonstrated a negative correlation between the proportion of positionings under thresholds by ExacTrac and PI, as reported in Figure 5E. Therefore, PI is a good predictor of the ExacTrac accuracy, having the advantage over the other abdominal adiposity indices of being less cumbersome to be determined. Anyway, the segmentation of abdominal adipose tissues can be automated using deep learning approaches, where available (48).
Relative to CBCT, an ExacTrac-based protocol would reduce patient treatment times and consequently may increase patient throughput, against a less frequent precision in cases with greater abdominal adiposity. These should be selected upfront for a CBCT-based setup while patients with lower adiposity might be adequately treated under ExacTrac guidance, given its better performance under these conditions. This assumption needs further validation in larger cohort studies. CBCT is irreplaceable in morbidly obese patients with an irreproducible pannus whose positional uncertainty can alter the dose distribution to the prostatic target. However, in such cases, some planning tricks like avoiding beam entrances through the irreproducible pannus should be considered (49).
Finally, our study advocates an overall good accuracy of ExacTrac-based positioning (when the bladder fullness and rectum emptiness do not deviate excessively from the planned one) and a personalization of PTV margins depending on the patient’s abdominal adiposity rather than a one-size-fits-all approach. Given the limits of our study, we devolve the calculation of personalized PTV margins to further investigations.
Conclusion
ExacTrac exhibited an overall good positioning accuracy in patients with localized prostate cancer submitted to definitive or adjuvant/salvage radiotherapy. This seems to cautiously promote its judicious use as an alternative to CBCT for normo- or moderately hypo-fractionated IGRT. ExacTrac performance is altered neither by slight variations in the fullness status of the bladder and rectum nor by the presence or absence of the prostate. An increase of abdominal adiposity, and of indirect parameters like the pelvic incidence angle, worsens the proportions of ExacTrac correct positionings, probably as a result of respiratory movements more pronounced than in thin patients. This finding seems to suggest a need for personalization of PTV margins depending on the patient body habitus: the greater the abdominal adiposity, the larger the PTV margins likely needed. Larger studies are needed to further validate the present findings and to confirm the above hypotheses.
Footnotes
Authors’ Contributions
Gianluca Ferini: Conceptualization, Methodology, Supervision, Data Interpretation, Writing – Original draft preparation; Valentina Zagardo: Resources, Writing – Reviewing and Editing; Vito Valenti: Data Collection, Resources, Writing – Reviewing and Editing; Dario Aiello: Resources, Writing – Reviewing and Editing; Manuela Federico: Resources, Writing – Reviewing and Editing; Ivan Fazio: Resources, Writing – Reviewing and Editing; Mandara Muralidhar Harikar: Resources, Writing – Reviewing and Editing; Valentina Anna Marchese: Data Collection, Resources, Writing – Reviewing and Editing; Salvatore Ivan Illari: Resources, Writing – Reviewing and Editing; Anna Viola: Resources, Writing – Reviewing and Editing; Emanuele Martorana: Methodology, Data Analysis, Resources, Writing – Reviewing and Editing.
Conflicts of Interest
The Authors have no conflicts of interest to declare in relation to this study.
- Received June 13, 2023.
- Revision received July 17, 2023.
- Accepted July 21, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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