METHODS
20 patients with oral cavity cancer underwent treatment for VMAT_FF. Subsequently, retrospective
VMAT_FFF treatment plans were developed using the eclipse treatment planning system. Both treatment
plans adhered to a Simultaneous Integrated Boost (SIB), delivering 60Gy to PTV60 and 54Gy to
PTV54 in 30#. The assessment encompassed biological indices (e.g., NTCP) and physical dose metrics,
including target coverage, conformity, dose homogeneity, and doses to organs at risk.
RESULTS
The dosimetric evaluation revealed negligible differences between the both techniques. The conformity
index was similar for VMAT_FF (0.975±0.017) and VMAT_FFF (0.975±0.019, p=0.813). The monitor
units required for VMAT_FFF (583±52.1) were significantly greater than VMAT_FF (530±69.9,
p=0.001). NTCP values for critical structures, including the spinal cord, brainstem, and optic chiasm,
were consistent at 0.00±0.00 for both techniques. For the parotid glands, NTCP values related to xerostomia
show insignificant variation: 17.8±8.17 (right) and 20.3±11.2 (left) for VMAT_FF compared to
17.9±8.29 (right) and 20.7±11.4 (left) for VMAT_FFF.
CONCLUSION
Both VMAT_FF and VMAT_FFF techniques exhibited comparable dosimetric and radiobiological
results for the treatment of oral cavity cancer. Although VMAT_FFF required a higher number of
monitor units, it demonstrated similar clinical effectiveness, suggesting its appropriateness for therapeutic
application.
Keywords: Dosimetric analysis; flattening filter-free; normal tissue complication probability; oral cavity cancer;radiotherapy; volumetric modulated arc therapy
Postoperative radiotherapy is a crucial treatment
modality that plays a significant role in improving
local disease management and substantially reducing
the likelihood of recurrence. In this context,
Volumetric Modulated Arc Therapy (VMAT) has
emerged as a groundbreaking radiotherapy technique,
providing exceptional accuracy in dose administration
and enhanced treatment effectiveness
when compared to traditional radiation methods.[
The role of radiobiological analysis is vital in refining
radiotherapy techniques, employing metrics such
as Normal Tissue Complication Probability (NTCP) to obtain critical insights into the risks linked to radiation-
induced complications. The Eclipse Planning
System offers comprehensive tools for evaluating biological
parameters, facilitating the development of
customized treatment plans that optimize the equilibrium
between tumor control probability (TCP) and
the protecting normal tissues.
The objectives of the current study were to explore
the therapeutic benefits of the Flattening Filter-Free
(FFF) mode in Volumetric Modulated Arc Therapy
(VMAT) in comparison to the Flattened Filter (FF)
mode for patients who have undergone surgery for oral
cavity cancer. Furthermore, the study sought to analyze
the variations in dosimetric parameters and Normal
Tissue Complication Probability (NTCP) values by utilizing
Eclipse Planning System biological plan evaluation
tools for both radiation beam types.
Patient Selection and CT Simulation
This retrospective analysis involved a cohort of 20
patients diagnosed with oral cavity cancer, sourced
from our institutional database. The study focused
on histopathologically confirmed cases of individuals
aged between 18 and 70 years, all possessing a
Karnofsky Performance Status exceeding 70. Patients
were excluded if they had residual disease, metastatic
conditions, prior radiotherapy exposure, or uncontrolled
medical issues.
CT simulation was performed using a Revolution EVO (GE Healthcare) system, with patients positioned in a supine and immobilized with a thermoplastic mask. A standard and contrast-enhanced computed tomography (CT) scan was performed with a slice thickness of 2.5 mm, encompassing the area from the top of the skull to the mid-thoracic region. The obtained CT data were then transferred to the treatment planning system for comprehensive volumetric delineation.
The contouring process meticulously defined the Gross Tumor Volume (GTV), Clinical Target Volume (CTV), and Planning Target Volume (PTV) in accordance with institutional protocols. Critical organs at risk (OARs), including the spinal cord, brainstem, parotid glands, mandible, and structures within the oral cavity, were accurately contoured to ensure precise treatment planning and minimize the risk of radiation- induced complications.
Treatment Planning
This retrospective investigation involved a thorough
treatment planning methodology for patients diagnosed
with oral cavity cancer. A total of 40 treatment
plans were formulated for 20 individuals, utilizing both
Flattened Filter (FF) and Flattening Filter Free (FFF)
photon beam techniques within the framework of Volumetric
Modulated Arc Therapy (VMAT).
Multiple dose levels were allocated to the Planning Target Volumes (PTVs) utilizing the Simultaneous Integrated Boost (SIB) methodology. The dosage for PTV60, which included the high-risk Clinical Target Volume (CTV) and the nodal CTV, was established at 60Gy in 30 fractions @ 2 Gy per fraction. In contrast, the dosage for PTV54, which addressed the low-risk CTV, was determined to be 54 Gy over 30 fractions @ 1.8 Gy per fraction.
The treatment planning process was carried out utilizing the Eclipse Treatment Planning System (version 16.1), with final dose calculations performed through the Anisotropic Analytical Algorithm (AAA). The beam characteristics were clearly specified, with a dose rate of 600 MU/min for flattened fields (FF) and 1400 MU/min for flattening filter-free (FFF) beams. All treatment plans were developed and executed using a True Beam SVC linear accelerator (Varian Medical Systems, a subsidiary of Siemens Healthineers) equipped with a 120 millennium multileaf collimator (MLC). The VMAT treatment planning approach utilized a sophisticated arc rotation configuration. Three distinct arcs of rotation were meticulously crafted, encompassing angles of 181°-179°, 179°-181°, and 181°-179°, with collimator angles precisely established at 30°, 330°, and 30°, respectively. To minimize potential bias and ensure methodological consistency, all planning and optimization parameters were uniformly applied across both FF and FFF photon beam plans. The plan optimization objective was 95% of the PTVs received the prescribed dose, while concurrently reducing exposure to the Organs at Risk (OARs) including Spinal cord: ≤45 Gy, Brainstem: Dmax≤54 Gy, Optic chiasm: Dmax≤54 Gy, Eyes: Dmax≤45 Gy, Parotid glands: Dmean≤26 Gy, D50%≤30 Gy, V30Gy≤50%, V40Gy≤30%, V50Gy≤20%.
The VMAT plans generated by VMAT_FF and
VMAT_FFF can be accessed through the integrated
dose-volume analysis tool available in the Eclipse
system. Furthermore, the Normal Tissue Complication
Probability (NTCP) value for Organs at Risk
(OARs) can be evaluated using a biological assessment
tool, which is not included as a standard feature
but is instead an additional software component
created by RaySearch Laboratories. Additionally, the
NTCP for each OAR was determined utilizing the
Poisson model, relying on the parameters and endpoints
specified in Table
Treatment Plan Evaluation
In the assessment of radiotherapy treatment plans, various
dosimetric indices play a vital role in evaluating
the quality and efficacy of dose distribution within the
target volume, as well as the protection of organs-atrisk
(OARs).
Coverage Index: It is defined as ratio of minimum
dose within target volume to prescribed dose.[
C=Dmin / PD
The prescribed dose (PD) represents the minimum
dosage required for tumor volume. A treatment
plan is deemed compliant with protocol if the target
volume is entirely encompassed by 90% of the prescribed
isodose. A minor deviation occurs when the
target is covered by 80% of the prescribed dose. Conversely, if 80% of the PD fails to fully cover the target,
it is classified as a major deviation.[
Uniformity Index: UI = D5% / D95%,
D5% and D95% denote the doses administered to
the highest and lowest 5% of the target volume, respectively.[
Homogeneity Index: HI=Dmax / PD,
Where, Dmax is the maximum dose delivered to
the target and PD is the prescribed dose.[1.5.
Conformity Index: CI=Vreference volume/PTV
Volume
Where, Vreference volume is the volume receiving
the reference dose, and PTV volume is the planning
target volume. The theoretical ideal for the CI is 1.[
For the PTV: 60Gy, the minimum dose administered
to the PTV for both VMAT_FF (50.0±4.19
Gy) and VMAT_FFF (50.1±4.26 Gy) is nearly the
same, with no statistically significant difference
(p=0.710). Likewise, the average dose to the PTV is
almost identical for both methods, exhibiting minimal
variations-VMAT_FF provides 60.1±0.134 Gy
while VMAT_FFF offers 60.1±0.119 Gy. This difference
is not statistically significant (p=0.123). The
maximum dose is also comparable between the two
methods (VMAT_FF: 64.3±0.976 Gy, VMAT_FFF: 64.4±1.00 Gy), with no significant difference observed
(p=0.537). The D95% values for both VMAT_FF
(96.4±0.773%) and VMAT_FFF (96.4±0.867%) are
virtually the same, indicating no significant difference
(p=0.993). These findings, as presented in Table
The evaluation of the plan dosimetric parameters reveals that the uniformity index (UI) for VMAT_FF (1.077±0.013) and VMAT_FFF (1.070±0.016) does not exhibit a significant difference (p=0.438). This suggests that both techniques achieve comparable dose uniformity throughout the PTV. The coverage index values for the two techniques are closely aligned, with VMAT_FF measuring 0.834±0.07 and VMAT_FFF at 0.835±0.07, showing no significant difference (p=0.710). Regarding the homogeneity index (HI), both VMAT_FF (1.07±0.016) and VMAT_FFF (1.07±0.017) are nearly the same, with no significant difference (p=0.537). This finding suggests that both techniques provide comparable homogeneity in dose distribution, ensuring an even dose within the PTV. The conformity index (CI) is also very similar for both methods, with VMAT_FF at 0.975±0.017 and VMAT_ FFF at 0.975±0.019, again showing no significant difference (p=0.813). Both techniques exhibit equivalent conformity. In terms of the gradient index (GI), the values for both techniques are comparable (VMAT_ FF: 1.21±0.120, VMAT_FFF: 1.21±0.118), with no significant difference (p=0.769). This indicates that the dose fall-off outside the PTV is similarly pronounced for both techniques. Lastly, the undefined dosimetric index (UDI) for both techniques is nearly identical (VMAT_FF: 1.05±0.015, VMAT_FFF: 1.05±0.014), with no significant difference (p=0.712). This implies that both techniques possess similar dosimetric characteristics that are not reflected in the other indices, thereby maintaining equivalent treatment quality.
The monitor units (MU) were notably higher in the VMAT_FFF plans (583±52.1) compared to the VMAT_FF plans (530±69.9, p=0.001), indicating improved delivery efficiency in the VMAT_FF plans. The mean Gamma Passing Rate was significantly higher for VMAT_FF (98.8±0.359%) compared to VMAT_FFF (98.5±0.346%), p<0.001.
Table
Regarding the mandible, no significant difference was observed (p=0.694), with doses of 62.2±0.725 Gy for the VMAT_FF plan and 62.3±0.757 Gy for the VMAT_ FFF plan. For the Right Parotid Gland, the average dose delivered by VMAT_FF is 24.6±4.64 Gy, whereas VMAT_FFF provides a dose of 24.1±4.52 Gy. The observed difference is statistically significant (p=0.001), indicating that VMAT_FF delivers a marginally higher mean dose. Regarding D50, which represents the dose received by 50% of the parotid volume, VMAT_FF administers 20.6±7.93 Gy, in contrast to VMAT_FFF, which delivers 19.6±7.41 Gy. This difference is also statistically significant (p=0.003), suggesting that VMAT_ FF results in a greater dose to 50% of the parotid gland compared to VMAT_FFF. However, no substantial differences were found in specific dose-volume metrics, such as V50 (11.3±6.95% in VMAT_FF versus 11.6±7.41% in VMAT_FFF, p=0.326), V40 (24.2±10.3% in VMAT_FF versus 24.2±9.72% in VMAT_FFF, p=0.863), and V30 (36.3±12.7% in VMAT_FF versus 35.3±10.9% in VMAT_FFF, p=0.178).
A similar trend was observed for the left parotid gland, where the mean dose was significantly lower in the FFF plan (24.9±5.27 Gy) compared to the FF plan (25±5.19 Gy, p=0.003), For the Left Parotid Gland, the average dose administered by VMAT_FF is 24.9±5.16 Gy, whereas VMAT_FFF delivers an average dose of 24.5±5.27 Gy, with a statistically significant difference observed (p=0.005). Regarding D50, which represents the dose received by 50% of the parotid volume, VMAT_FF provides a dose of 20.7±7.94 Gy, in contrast to VMAT_FFF, which delivers 19.8±7.74 Gy, also showing a significant difference (p=0.037). This suggests that VMAT_FF administers a higher dose to 50% of the left parotid gland compared to VMAT_FFF. While the dose-volume parameters V50, V40, and V30 did not show significant differences.
A comparison of the maximum dose delivered to the eyes revealed no significant difference for the right eye, with values of 3.45±3.37 Gy in the VMAT_FF plan and 3.33±3.66 Gy in the VMAT_FFF plan (p=0.190). However, a significant reduction in the maximum dose to the left eye was observed in the VMAT_FFF plan, which recorded a dose of 5.64±10.5 Gy, in contrast to the VMAT_FF plan"s dose of 5.99±10.7 Gy (p=0.005).
The comparison of NTCP values between VMAT_FF and VMAT_FFF plans indicated that there were no significant differences for most organs at risk (OARs). In particular, the NTCP values for the spinal cord, brainstem and optic chiasm, eye related to myelitis necrosis, necrosis/infarction and blindness were both recorded as 0.00±0.00 for the VMAT_FF and VMAT_FFF plans. Furthermore, although the NTCP values for joint dysfunction in the mandible were slightly higher in the VMAT_ FFF plans (0.686±0.369) compared to the VMAT_FF plans (0.656±0.376), this difference did not reach statistical significance (p=0.072). Concerning the parotid glands, The NTCP values for Xerostomia, derived from the Poisson-LQ model, exhibited minimal differences between VMAT_FF and VMAT_FFF. For the right parotid, the values recorded were 17.8±8.17 and 17.9±8.29, while for the left parotid; the values were 20.3±11.2 and 20.7±11.4. These findings indicate that there is no significant difference, implying that the NTCP values remain consistent across both treatment modalities (p>0.05).
VMAT: Volumetric modulated arc therapy; FF: Flattening filter; FFF: Flattening filter free.
VMAT: Volumetric modulated arc therapy; FF: Flattening filter; FFF: Flattening filter free.
In our study, dosimetric analysis of PTV-60Gy, the
maximum and mean doses delivered to the target volume
were observed to be comparable in both VMAT_
FF and VMAT_FFF techniques. Furthermore, the conformity
index (CI) in the FFF mode demonstrated a
significant similarity to that of the FF mode, indicating
that the dose distribution conformity between the two
methods is alike. These results are consistent with earlier
research that has examined the dosimetric properties
of flattening filter-free (FFF) linear accelerators. For
instance, Zwahlen et al.[
Dosimetric indices of dose distribution, the uniformity
index (UI), homogeneity index (HI), gradient
index (GI), and undefined dosimetric index (UDI) in
our study revealed no significant differences between
the two modalities. This suggests that both VMAT_
FF and VMAT_FFF exhibit similar characteristics in
dose distribution regarding uniformity and homogeneity. These results align with the findings of earlier
studies conducted by Kim et al.[
A minor variation in the mean dose for the PTV-
54Gy was noted between the two techniques, with
VMAT_FF administering a slightly lower dose
(54.2±0.217 Gy) compared to VMAT_FFF (54.3±0.217
Gy), which was statistically significant (p=0.011). Although
this difference is minimal, it may indicate
the influence of the lower energy and the more rapid
off-axis dose reduction associated with the FFF mode,
as previously highlighted in the research conducted by
Sarma et al.[
Monitor units (MU) employed in FFF VMAT planning
were observed to be significantly higher than
those used in FF VMAT planning (583±52.1 compared
to 530±69.9, p=0.001). This observation aligns with
previous studies, such as that conducted by Zwahlen
et al.,[
Figure
The graph further illustrates that specific normal
tissues, including the Parotid Gland and Xerostomia,
exhibit two separate NTCP curves, which are
distinguished by the labels VMAT_FF and VMAT_
FFF. This indicates that the selection of the radiation
beam whether a VMAT_FF or a VMAT_FFF
beam can influence the likelihood of normal tissue
complications in these organs for the patient. The
variation between the NTCP curves for VMAT_FF
and VMAT_FFF suggests that the type of beam may
significantly affect the risk of toxicities, with the
VMAT_FFF beam potentially presenting a reduced
probability of complications for certain organs when
compared to the VMAT_FF beam at the same equivalent
dose level. These results underscore the critical
role of beam selection in radiation treatment planning
and emphasize the necessity of integrating this understanding into the optimization process to enhance
patient outcomes and quality of life.
Organ-specific Finding
Mandibular dysfunction, which encompasses
conditions such as trismus and osteoradionecrosis,
exhibits a strong association with the maximum radiation
dose absorbed by the mandible. Previous studies
have indicated that doses surpassing 60-65 Gy significantly elevate the likelihood of these complications.[
Kirkpatrick et al.[
The brainstem, similar to the spinal cord, exhibits
a restricted tolerance to radiation owing to its essential
neurological roles. Doses surpassing 54 Gy markedly
elevate the likelihood of necrosis and vascular
injury.[
The optic chiasm exhibits a significant sensitivity
to radiation, with a tolerance dose estimated at around
55 Gy when utilizing conventional fractionation (2 Gy
per fraction) to reduce the likelihood of complications
such as blindness. Clinical research, including the work
of Emami etal.,[
Radiation exposure has the potential to cause
ocular complications, including cataracts, retinopathy,
and optic neuropathy. Cataracts are generally
observed at radiation doses exceeding 2 Gy, while
optic neuropathy is associated with doses greater
than 45 Gy. To mitigate these risks, radiotherapy protocols are designed to keep the maximum dose to
the eyes below 45 Gy. In our investigation, the maximum
doses administered to both the right and left
eyes remained within these established limits, suggesting
a minimal risk of clinically significant visual
impairment. This finding is consistent with guidelines
that advocate for rigorous dosimetric control to
safeguard ocular structures while delivering effective
treatment. Research conducted by Mayo et al.[
Figure
Limitation of the Study
DVH: Dose volume histogram; OAR: Organ at risks; NTCP: Normal tissue complication probability.
The mean dose and D50 for the left parotid gland were
decreased by 1.61% and 4.35%, respectively, in the
VMAT_FFF technique when compared to VMAT_FF.
However, the NTCP Poisson-LQ (Xerostomia) exhibited
a slight increase of 1.93%, which was not statistically
significant. In a similar manner, the right parotid
gland experienced reductions of 2.03% in mean dose
and 4.85% in D50, accompanied by a non-significant
increase of 0.56% in NTCP. In alignment with previous
research, doses to the parotid glands that exceed
25-30 Gy significantly elevate the risk of xerostomia.
[
VMAT: Volumetric modulated arc therapy; FF: Flattening filter; FFF: Flattening filter free.
The retrospective nature of the study, along with its
restricted sample size, limits both its statistical power
and the ability to generalize the findings. Although
the Normal Tissue Complication Probability (NTCP)
analysis employing the Poisson Linear Quadratic (LQ)
model offers important insights, it may not fully encompass
the intricate nature of clinical toxicity.
Ethics Committee Approval: The study was approved by the Indira Gandhi Institute of Medical Science Office Ethics Committee (no: 35/IEC/IGIMS/2024, date: 17/05/2024).
Conflict of Interest: The authors have no conflicts of interest to declare.
Financial Support: The authors declared that this study received no financial support.
Use of AI for Writing Assistance: No AI technologies utilized.
Authorship Contributions: Concept - M.Z., D.P.; Design - D.P., M.Z.; Supervision - M.Z., D.P.; Data collection and/or processing - D.P., M.Z.; Data analysis and/or interpretation - D.P., M.Z.; Literature search - D.P., M.Z.; Writing - D.P., M.Z.; Critical review - M.Z., D.P., D.S.
Peer-review: Externally peer-reviewed.