Comparative Analysis of Parotid Doses in Tomotherapy Versus Volumetric Modulated Arc Therapy for Head and Neck Cancer Patients Undergoing Bilateral Neck Irradiation: A Non-Randomized, Prospective, Dosimetric and Clinical Study

: Background and Objectives: Xerostomia, a common side effect of head and neck radiation therapy, significantly impacts subjective well-being and quality of life. Its severity depends on the radiation dosage received by the parotids. Advanced techniques like Volumetric Modulated Arc Therapy (VMAT) and Tomotherapy offer improved parotid sparing. This prospective, non-randomized, double arm, dosimetric, and clinical study aims to compare parotid dosages between Tomotherapy and VMAT (Rapid Arc) in head and neck cancer patients undergoing bilateral neck irradiation. Methods: Fifty-two eligible patients were included, with 26 treated by Tomotherapy and 26 by VMAT. Plans were cross planned between the two techniques while maintaining similar Planning Target Volume (PTV) coverage. Bilateral parotid dosages were evaluated, and clinical xerostomia assessment utilized the Xerostomia Questionnaire (XQ) and Radiation Therapy Oncology Group (RTOG) scoring criteria. Statistical analysis employed the paired t-test. Results: Both right and left parotids received significantly lower mean doses on Tomotherapy (21.23Gy ± 4.429) compared to VMAT (23.

employed, with iterative optimization for Tomotherapy plans.Dosimetric parameters were compared, ensuring PTV coverage and dose constraints.Parotid Dosimetry Comparison: Parotid dosages were compared for both techniques, encompassing D mean, D median, V15, V30, and V50 for right and left parotids, as well as combined parotids' V20.Concurrent Chemotherapy Plan: Patients undergoing radical intent received weekly cisplatin at a dose of 40 mg/m² or 3-weekly cisplatin at a dose of 100 mg/m².In the adjuvant setting, chemoradiation was administered selectively to patients with positive margins and extra nodal extension.A few patients did not receive any chemotherapy, a decision based on individual patient considerations.Clinical Evaluation of Patients on Follow-ups: Patients treated with Tomotherapy and VMAT were clinically evaluated at the first and second follow-ups.Evaluation included both patient-reported xerostomia questionnaire (XQ) and observer-reported Radiation Therapy Oncology Group (RTOG) scoring criteria (3).Xerostomia Questionnaire (XQ): A literature search informed the selection of questions for the XQ, incorporating xerostomia-specific and general head and neck cancer quality of life instruments.The questionnaire, adapted from the Eisbruch xerostomia questionnaire (4), consisted of 8 items assessing dryness while eating or chewing and dryness while not eating or chewing.Patients rated each symptom on an 11-point Likert scale, with scores transformed linearly to produce a final summary score between 0 and 100.Questionnaires were administered at 1st and 2nd follow-ups, 2-3 months, and 5-6 months postradiotherapy completion for Tomotherapy and VMAT patients, respectively.Clinical Observations and Toxicity Grading: Patients' medications were recorded at each visit, with restrictions on salivary stimulating or protecting agents during the study.Observer-defined toxicity grading, specifically the RTOG scoring criteria for acute salivary gland morbidities, was employed.This subjective assessment correlated XQ scores and RTOG scores with the treatment technique received.

RESULTS:
Study Evaluation: Patient Characteristics: Total Enrolment: A total of 52 patients participated in the study, comprising 12 females and 40 males.
In the Tomotherapy arm, there were 25 males and 1 female, while the Rapid Arc arm included 11 females and 15 males (refer to Figure 1).Age Distribution: Among patients treated with Tomotherapy, 10 were aged between 60-70 years, 8 were under 60 years, and 8 were over 70 years.In the Rapid Arc arm, 14 patients were under 60 years, 8 were between 60-70 years, and 4 were over 70 years old (refer to Figure 2).Treatment Intent: Most patients underwent treatment with radical intent, with 19 in the Tomotherapy arm and 20 in the Rapid Arc arm.Adjuvant intent was observed in 7 patients in the Tomotherapy arm and 6 in the Rapid Arc arm.Treatment modalities included both simultaneous integrated boost and sequential phases, determined by physician preference (refer to Figure 3).Diagnosis Distribution: Within the Tomotherapy arm, the predominant diagnoses were oral cavity cancers (7), followed by hypopharynx, oropharynx (6 each), larynx (5), and nasopharynx (2).In the Rapid Arc arm, the majority had hypopharyngeal cancers (8), followed by oral cavity, larynx (7 each), oropharynx (3), and nasopharynx (1) (refer to Figure 4).

Total Dose and Number of Fractions:
The mean total dose for patients treated with Tomotherapy was 67.26Gy (ranging from 60Gy to 70Gy) with a standard deviation (SD) of 4.09.In the Rapid Arc arm, the mean total dose was 67.345Gy (ranging from 60Gy to 70Gy) with an SD of 3.66.Regarding the number of fractions delivered, the mean in the Tomotherapy arm was 32.04 (ranging from 30 to 35) with an SD of 1.562, and in the Rapid Arc arm, it was 31.88 (ranging from 29 to 35) with an SD of 1.657.

PTV Coverage:
For patients treated with Tomotherapy, the mean PTV coverage, representing the dose received by 95% of target volumes, was 65.07Gy (ranging from 57.37Gy to 69.65Gy) with an SD of 4.13 and a standard error (SE) of the mean of 0.81.In the Rapid Arc arm, the mean dose was 65.37Gy (ranging from 57.53Gy to 69.6Gy) with an SD of 3.8.The mean PTV coverage for Rapid Arc plans executed for patients treated with Tomotherapy was 65.71Gy (ranging from 58.24Gy to 69.45Gy) with an SD of 4.22 and an SE of the mean of 0.82.In Tomotherapy plans executed for patients treated with Rapid Arc, the mean PTV dose was 64.96Gy (ranging from 56.34Gy to 69.06Gy) with an SD of 3.79.Graphical Representation: The statistical significance is visually depicted in a graphical representation in Figure 5.This figure serves as a powerful visualization tool, illustrating the distinct and statistically significant differences in parotid parameters between Tomotherapy and Rapid Arc plans.

Fig 5 shows a graphical representation of various dose parameters for right parotids, left parotids, and combined parotids among both techniques. "Clinical Evaluation of Xerostomia on Follow-up":
Grading Xerostomia (XQ): On the first follow-up, the mean XQ was 41.35 (range, 32 to 54) + SD of 6.331 for patients treated with Tomotherapy and 41.5 (range 32 to 56) + SD 7.77 for patients treated with Rapid Arc.The p-value was 1, indicating no statistically significant difference between the two techniques.
On the second follow-up, the mean XQ was 32.65 (range, 26 to 42) + SD of 5.344 for patients treated with Tomotherapy, which was slightly lower than the mean XQ for patients treated with Rapid Arc, 33.42 (range, 24 to 44) + SD 6.357.However, the p-value was 0.639, suggesting that this difference was statistically insignificant.Notably, XQ scores were observed to be lower in the second follow-up compared to the first follow-up for both treatment techniques, as tabulated in Table 5.At the second follow-up, the mean RTOG scores were 1.08 ± 0.272 for Tomotherapy and 1.04 ± 0.196 for Rapid Arc.Although the p-value remained less than 0.05, indicating statistical significance, the scores were relatively lower at the second follow-up compared to the first, aligning with the trend observed in XQ scores.The detailed statistical analysis is presented in Table 6.2001) proposed a mean dose threshold of 24-26Gy for severe parotid injury, emphasizing the exponential relationship between mean dose and saliva output (6).
Comparative Analysis: In our study, we compared dose parameters between helical tomotherapy and rapid arc, showcasing their ability to outperform intensity-modulated radiation therapy (IMRT) in terms of target coverage.Wiezorek et al. demonstrated that helical tomotherapy (HT) and volumetric-modulated arc therapy (VMAT), such as rapid arc, provided superior target dose homogeneity and organ-at-risk protection (7).Van  Limitations and Future Considerations: While our study provides valuable insights, limitations exist.The subjective nature of patient-reported outcomes and the exclusion of submandibular glands as an organ-at-risk (OAR) are acknowledged.Future studies could explore submandibular gland sparing and extend the follow-up period for a more comprehensive assessment of xerostomia recovery.

CONCLUSION:
In conclusion, our study delves into the intricate interplay of dosimetric precision and clinical outcomes in head and neck cancer treatment, specifically focusing on helical tomotherapy and volumetric modulated arc therapy (VMAT).Both modalities effectively safeguard parotid glands during bilateral neck irradiation, yet helical tomotherapy demonstrates superior dosimetric outcomes by delivering lower dosages to parotids.Interestingly, the observed dosimetric advantages did not uniformly correlate with the incidence of xerostomia, prompting a nuanced understanding of clinical outcomes.Our findings underscore the ongoing advancements in radiation therapy, particularly with helical tomotherapy, and emphasize the need for standardized evaluation metrics for xerostomia.Radiation-induced xerostomia, a significant concern in head and neck cancer treatment, continues to be mitigated by evolving radiation delivery techniques.This study contributes valuable insights to the optimization of radiation therapy, positioning helical tomotherapy as a promising avenue for refining patient outcomes and minimizing treatment-related morbidities.

Fig 1 showing graphical representation of distribution of gender among techniques.Fig 2 Fig 3
Fig 1 showing graphical representation of distribution of gender among techniques.

Left Parotids:
In Tomotherapy plans, the mean dose of left parotids was 22.45Gy with an SD of 7.052, while in Rapid Arc plans, it was 24.75Gy with an SD of 7.642.The observed p-value of < 0.001 suggests that Tomotherapy plans are associated with a significantly lower mean dose (D mean) to the left parotids compared to Rapid Arc plans.Combined Parotids:The mean average of doses received by 20% of both right and left parotids in Tomotherapy plans was 43.42Gy with an SD of 11.816, whereas in Rapid Arc plans, it was 46.93Gy with an SD of 11.188.The calculated p-value of 0.001 further reinforces that Tomotherapy outperforms Rapid Arc plans in delivering significantly lower doses to the combined parotids.Table4provides a comprehensive statistical analysis of dose parameters for left, right, and combined parotids, highlighting the superiority of Tomotherapy over Rapid Arc in minimizing radiation doses to these critical structures.

Table 1 : Xerostomia Questionnaire (Adapted from Eisbruch et al) 1
. Assess the difficulty you experience in speaking due to dryness.2.Evaluate the challenge you face in chewing due to dryness.3.Rate the difficulty you encounter in swallowing solid food because of dryness.4.Indicate the frequency of sleeping problems attributed to dryness. 5. Evaluate the dryness in your mouth or throat while consuming food.6.Assess the dryness in your mouth or throat during periods of not eating.7.Indicate how often you sip liquids to aid in swallowing food.8. Rate the frequency of sipping liquids for oral comfort during times of not eating.

Table 2 : RTOG scoring criteria for acute salivary gland morbidities
Grade 0: No change over baseline Grade 1: Mild dryness of mouth, slightly thickened saliva, slightly altered or metallic taste.Grade 2: Moderate to complete dryness, thick sticky saliva, and markedly altered taste.Grade 3: Not defined for acute xerostomia.Grade 4: Acute salivary gland necrosis.
• Email: editor@ijfmr.comIJFMR230611097 Volume 5, Issue 6, November-December 2023 4 D98) for Rapid Arc plans executed for Tomotherapy-treated patients ranged from 55.14Gy to 68.74Gy (mean 64.41Gy, SD 4.67), and for Tomotherapy plans executed for Rapid Arc-treated patients, it ranged from 55.18Gy to 68.66Gy (mean 61.4Gy, SD 4.15).In this study, paired t-tests were employed for statistical analysis, considering the dependent nature of the parameters and their normal distribution.The chosen reference p-value (α) was 0.05, with values less than 0.05 considered statistically significant.
Dose Distribution:The near-maximum dose (D2) ranged from 61.44Gy to 73.3Gy in the Tomotherapy arm (mean 69.11Gy, SD 4.3) and from 61.01Gy to 73.63Gy in the Rapid Arc arm (mean 69.37Gy, SD 3.79).The near-maximum dose (D2) for Rapid Arc plans executed for Tomotherapy-treated patients ranged from 61.22Gy to 75.96Gy (mean 69.17Gy, SD 4.36), and for Tomotherapy plans executed for Rapid Arc-treated patients, it ranged from 61.37Gy to 72.54Gy (mean 69.03Gy, SD 3.57).The near-minimum dose (D98) ranged from 54.31Gy to 68.9Gy in the Tomotherapy arm (mean 63.94Gy, SD 4.7) and from 51.55Gy to 69.01Gy in the Rapid Arc arm (mean 64.23Gy, SD 4.48).The near-minimum dose ("Comparative Analysis of Parotid Dosages": In assessing parotid dosages, both Tomotherapy and Rapid Arc plans achieved comparable PTV coverages.The key parameters for parotid dosages are detailed below, emphasizing the mean values and their associated standard deviations (SD): For Tomotherapy Plans: Mean dose received by 95% of the PTV volume: 65.02Gy +/-SD of 3.929 Mean dose received by 2% of the volume (D2): 69.07Gy + SD of 3.92 Mean dose received by 98% of the volume: 63.83Gy + SD of 4.892 For Rapid Arc Plans: Mean dose received by 95% of PTV volume: 65.55Gy + SD of 3.98 Mean dose received by 2% of the volume (D2): 69.27Gy + SD of 4.05 Mean dose received by 98% of the volume: 64.32Gy + SD of 4.53 Table3provides a comprehensive overview of the mean and SD values for PTV, D2, and D98 across all sites for both Tomotherapy and Rapid Arc techniques.

Table 3 : Mean and Standard Deviation of PTV, D2, and D98 for All Sites in Both
"Dosimetric Analysis of Parotids: Tomotherapy vs. Rapid Arc": Right Parotids: The mean dose of right parotids in Tomotherapy plans was found to be 21.23Gy with a standard deviation (SD) of 4.429, whereas in Rapid Arc plans, it was 23.26Gy with an SD of 4.531.The statistically significant p-value of < 0.001 indicates that Tomotherapy plans deliver a significantly lower mean dose (D mean) to the right parotids compared to Rapid Arc plans.

Table 5 : Statistical Analysis of XQ at First and Second Follow-ups Among Both Techniques Treated
5 ± 0.51 in the Rapid Arc arm, with an insignificant p-value.

Table 6 : Statistical Analysis of RTOG Scores at First and Second Follow-ups Among Both Techniques Treated
(5) Utilization in Clinical Practice: Dose-volume histograms (DVH) emerged as a valuable tool in radiotherapy, offering a comprehensive assessment of delivered dose distribution.Unlike reference point reporting, DVH, as recommended by the International Commission on Radiation Units and Measurements (ICRU) in Report 83, focuses on organ-at-risk (OAR) sparing and target volume coverage(5).Our study adhered to ICRU guidelines, reporting parameters such as D95, D2, and D98 for target volumes.Parotid Dose Considerations: The significance of sparing salivary glands, particularly the parotids, is wellestablished in radiotherapy.Literature supports the notion that minimizing the mean dose to parotids is crucial in reducing the risk of xerostomia.Eisbruch et al. ( (12)0) et al. conducted a dosimetric study emphasizing the favourable outcomes of HT in oropharyngeal carcinoma cases(8).Parotid Dose-Volume Relationships: Salivary glands, acting as parallel-responding tissues, exhibit dosevolume-response relationships.QUANTEC (Quantitative Analyses of Normal Tissue Effects in the Clinic) and Milano et al. recommended controlling the parotid D mean below 25Gy or 26Gy, respectively, to mitigate xerostomia risk(9,10).Our study maintained parotid dosages below these thresholds in both techniques, aligning with the literature suggesting that sparing at least 20 ccs of parotid tissue from doses exceeding 20Gy is crucial for retaining significant saliva production.Clinical Implications: Our findings not only corroborate existing literature but also extend support for the importance of dose-volume relationships in salivary glands.The optimization of radiation techniques, exemplified by our study's emphasis on DVH and dose thresholds, holds promise in significantly enhancing post-radiation saliva production, reducing xerostomia, and ultimately improving patients' quality of life.Clinical Correlation of Dosimetric Analysis: Our study extends beyond a mere dosimetric analysis, encompassing a clinical evaluation of xerostomia, aiming to discern the advantages of one technique over another in mitigating salivary gland morbidity.The attempt to correlate dosimetric parameters with clinical outcomes represents a holistic approach to treatment assessment.Comparative Clinical Outcomes: Boning Cai et al(11)noted a lower incidence of Grade 2 xerostomia with helical tomotherapy (HT) compared to Rapid Arc (RA).Our findings align with the literature, revealing a milder score at the 2nd follow-up in tomotherapy-treated patients.Despite the lack of statistical significance, both techniques exhibited reduced xerostomia at the second follow-up, suggesting an overall improvement in salivation.Smet et al.(12)reported superior target coverage and lower acute toxicity with rapid arc compared to sliding window IMRT.Our study, while not directly comparing these techniques, contributes to the broader understanding of treatment outcomes by incorporating both dosimetric and clinical perspectives.Xerostomia Assessment Methods: Accurate measurement of xerostomia is imperative for comprehensive evaluation.We utilized a combination of functional imaging, salivary output measurements, observerassessed toxicity grading, and patient-reported evaluations.This multifaceted approach enhances the reliability and validity of our findings.Short-Term Evaluation and Recovery Considerations: Our study evaluated only the first two follow-ups, acknowledging the limited timeframe to comment on xerostomia recovery.Literature supports the notion that the degree of recovery is dose-dependent, with minimal improvement observed at doses exceeding 50-60Gy.Roesink et al.
(6))and Eisbruch et al.(6)reported recovery trends in irradiated parotid glands, underscoring the importance of prolonged monitoring.Treatment Technique Selection: Our anticipation, drawn from the study, suggests that the recent advancements in intensity-modulated radiotherapy (IMRT) techniques, such as helical tomotherapy, offer a feasible strategy for minimizing salivary gland doses in bilateral neck irradiation.Tomotherapy, with demonstrated advantages in delivering lower dosages to parotids, emerges as a favourable choice for head and neck cancer patients undergoing bilateral neck radiation.