Evaluation of survival outcome and prognostic factors for oral cavity cancer treated with volumetric arc therapy

This study aimed to evaluate the survival outcomes and identify prognostic factors for patients with oral cavity cancer (OCC) who underwent adjuvant treatment with volumetric arc therapy (VMAT) using simultaneous integrated boost (SIB). Data was collected for post-operated patients of carcinoma of oral cavity who received adjuvant VMAT with SIB between June 2018 and December 2022. The data was entered and analyzed using SPSS software version 20.0. Survival rates were estimated using Kaplan Meier method. To determine survival difference between the groups, log rank test was used. Multivariate analyses were performed with Cox proportional hazard model and p value < 0.05 was considered as significant. A total of 178 patients were included in the study. The median follow-up period was 26 months (range 3–56 months). The 3-year OS, DFS, and LRC rates were 78% (95% CI 77–79%), 76% (95% CI 74–77%), and 81% (95% CI 80–82%), respectively. Univariate analysis identified age ≥ 50 years, lymph node involvement, extracapsular extension (ECE), and N2–N3 disease as significant adverse prognostic factors for OS, DFS, and LRC. Multivariate analysis confirmed age ≥ 50 years and nodal involvement as independent predictors of worse OS, DFS, and LRC. Additionally, ECE independently affected OS and DFS. Adjuvant treatment with VMAT using SIBin patients with OCC is effective. Age and nodal involvement had significant impact on LRC, DFSand OS while ECE on DFSand OS.


Introduction
Head and neck cancers constitute 4.9% of all malignancies worldwide, out of which, two percent cases are those of oral cavity and lip cancers (Sung et al. 2021).
Surgery represents the primary therapeutic approach for operable oral cavity cancer (OCC).Nevertheless, in cases where patients present with locally advanced disease or exhibit unfavorable prognostic indicators in the post-operative histopathology report (HPR), the recommendation is to undergo adjuvant radiotherapy (RT).In instances where positive margin and/or extracapsular extension (ECE) are evident in the post-operative HPR, concurrent chemotherapy (CRT) is also advised to be administered alongside RT (Hashim et al. 2019;Robertson et al. 1998;Cooper et al. 2004;Bernier et al. 2004).
With the advent of novel RT techniques, such as intensitymodulated radiotherapy (IMRT) or volumetric arc therapy (VMAT), it has become feasible to reduce RT-associated toxicities as compared to three-dimensional conformal RT (3DCRT), while still delivering optimum doses to target volumes.Additionally, the utilization of simultaneous integrated boost (SIB) enables the irradiation of distinct target volumes at varying desired dose levels.The ability of IMRT with SIB to modulate radiation beams and deliver varying dose levels to different target volumes offers enhanced conformity and homogeneity compared to conventional RT techniques.This may result in better coverage of the tumor bed and involved lymph nodes, potentially leading to improved locoregional control (LRC) and reduced rates of local recurrence (Studer et al. 2007).VMAT is also a form of IMRT.
This study aims to investigate the survival outcomes and prognostic factors, in patients of post-operative squamous cell carcinoma (SCC) of the oral cavity who received adjuvant RT by VMAT with SIB.Considering the paucity of data in literature regarding this treatment approach in OCC, we analyzed a cohort of patients to provide valuable insights into the impact of VMAT with SIB as an adjuvant therapy for OCC, which can further guide clinical decision-making and improve patient care.

Patient selection
Following obtaining approval by the institute's ethical committee (Reference no.-Dean/2022/EC/5023), data were collected for post-operated patients of SCC of oral cavity, who were treated by adjuvant VMAT with SIB between June 2018 to December 2022.Patients of both gender, who underwent R0/R1 resection, received adjuvant RT with or without concurrent CT, having ECOG (Eastern Co-operative Oncology Group) performance status: 0-2, normal hematological, renal, and liver function tests were included in the study.Patients having more than one primary cancer or previous history of RT were excluded.

Pretreatment evaluation
Before starting RT, patients were evaluated by complete physical examination, complete blood test, and chest X-ray.Computed tomography scan (CT-scan) and/or magnetic resonance imaging (MRI) of the head and neck region was done in selected cases to exclude any recurrent/residual disease.Group staging was done according to AJCC 8th edition.Based on postoperative HPR, patients were planned for either adjuvant RT or CRT.Dental prophylaxis was done in all patients before RT.

Treatment details
For RT, all patients were simulated in the supine position.Immobilization was done using a four-clamp thermoplastic mask attached to a carbon-fiber base plate.
Contrast-enhanced planning CT images were then obtained in the treatment position from vertex to carina.The images were obtained at 3 mm intervals.Segmentation was done on CT images slice by slice.Clinical target volume high risk (CTV-HR) was defined as primary tumor bed (HR CTV-P) and pathologically positive lymph node stations in the neck (HR CTV-N).CTV intermediate risk (CTV-IR) was defined as lymph nodal stations adjacent to HR CTV-N and CTV low risk (CTV-LR) as nodal stations that were adjacent to CTV HR-N or CTV IR-N and/or in the contralateral neck.The contralateral neck was included in CTV LR wherever the primary disease was crossing the midline or there were multiple positive ipsilateral neck nodes or single/multiple ipsilateral lymph nodes with ECE to eradicate potential metastatic foci in the cervical lymph nodes (LN) (Lin et al. 2021).All the CTVs were modified by cropping from air and anatomical barriers.
The CTVs were subsequently expanded by 5 mm to generate respective planning target volumes (PTV).Doses prescribed to PTV-HR, PTV-IR, and PTV-LR were: 60-66 Gy, 54-60 Gy, and 50-54 Gy respectively in 30-33 fractions, single fraction in a day, and 5 fractions per week.A dose of 66 Gy was prescribed to PTV-HR in patients with ECE and/or positive margins while 60 Gy was the prescription dose to PTV-HR in all other cases.Only two volumes were created (PTV-HR and PTV-LR) in patients with pathologically N0 disease or node-positive disease with no ECE and negative margins.All the patients were treated by VMAT with SIB.All treatment plans were grated in the treatment planning system and treatment was delivered using a 6 MV linear accelerator.Patients having positive margin, ECE, and/or multiple poor prognostic factors such as close margins (1 mm), presence of lymphovascular invasion (LVI), perineural invasion (PNI), or lymph nodal involvement at multiple stations received concurrent cisplatin at a dose of 40 mg/m 2 weekly.

Follow up
Patients were followed weekly during treatment.After treatment completion, follow-up was done, monthly for up to 3 months, 2-3 monthly for up to 2 years, and 4-6 monthly thereafter.

Statistical analysis
Statistical analysis was done using SPSS software version 20.0.The categorical data were presented in frequency and percentages.All continuous data were analyzed using descriptive statistics and described as median and range.LRC was defined as the time between the date of surgery to recurrence of disease at the local and or nodal site.Recurrence apart from loco-regional was considered a distant failure.Disease-free survival (DFS) was defined as the duration between the date of surgery to any failure (loco-regional or distant) or second primary and overall survival (OS) from the date of surgery to death.Kaplan Meier method was used for survival analysis.Univariate analysis was done to assess important prognostic factors affecting LRC, DFS, and OS.Log-rank test was used to determine differences in survival between the groups.All reported p-values were 2-sided and p < 0.05 was considered as statistically significant.Multivariate analyses were performed with Cox proportional hazard method to identify prognostic factors affecting survival.

Results
A total of 178 patients were included in the study.The median age of whole cohort was 45 years (range 21-73).Majority of patients were male (89%).Eighty two percent had ECOG performance status score of zero.Buccal mucosa (39%) was the most common primary site.The patient and tumor related characteristics are described in Table 1.
Post-operative HPR revealed that the majority of cases were of T3-T4 stage (69%), and around half of the patients had node negative disease (48%).Most of the patients had free margins (92%), no LVI (75%), and PNI (67%).Additionally, 55% of the patients had stage IV disease.Forty patients (23%) received two to three cycles of neo-adjuvant chemotherapy (NACT) prior to surgery in form of two-drugs (taxane and platinum-based) or three drugs (taxane, 5-flourouracil and platinum-based) regimens.High risk HPR features like positive margin and/or ECE were observed in 66 patients (37%), owing to which, they were treated with a total RT dose of 66 Gy.Table 2 shows the treatment characteristics of all patients.The median RT dose to PTV HR was 60 Gy (range 60-66 Gy).Forty two percent patients had received concurrent CT.In 89% cases, interruption in RT was ≤ 10 days.
Several prognostic factors were analyzed for their impact on OS, DFS, and LRC.Table 4 presents the results of the univariate analysis for these prognostic factors.Age ≥ 50 years, pathological lymph node involvement (pN +), ECE presence and pN2-N3 disease stage were found to be significant adverse prognostic factors for all the three outcomes (p < 0.05) whereas LVI was found to be significant adverse factor for LRC and DFS (p < 0.05).Other factors such as gender, overall TNM stage, depth of invasion (DOI), PNI, grade, margin status and RT interruption did not reach statistical significance for these three outcomes.Factors found to be significant in univariate analysis were subjected to multivariate analysis using Cox regression and factors which were significant are shown in Table 5.After adjusting for other factors, age ≥ 50 years remained a significant prognostic factor for OS, DFS, and LRC (p < 0.001).
Nodal involvement was also a significant predictor of OS, DFS, and LRC (p < 0.05).Additionally, ECE showed significance for OS and DFS (p < 0.05).The factors found to be significantly affecting the survival outcomes on multivariate analysis are depicted in Figs. 2, 3 and 4.

Discussion
The study evaluated survival rates and prognostic factors in patients of OCC, who received adjuvant RT by advanced VMAT with SIB.At 3 years, the OS was 78%.While evaluating adjuvant IMRT in OCC, Gomez et al. reported a similar 3-year OS of 74% (Gomez et al. 2009).However, at 3 years, Dragan et al. had observed comparatively inferior OS rate of 57% (Dragan et al. 2019).In that study, 90% of the patients were having locally advanced disease and among all post-operative cases, only 47% were of the oral cavity.About similar, 86% of patients in our study had stage III and IV disease, but all patients were of OCC.The studies which have examined IMRT after surgery in OCC, have reported 3-year OS varying from 57 to 75% (Dragan et al. 2019;Daly et al. 2011;Chen et al. 2009;Yao et al. 2007;Collan et al 2011;Ooshi et al. 2016;Geretschlager et al. 2012).The survival variation in studies as compared to the present study could be because of variability in the distribution of prognostic factors and comorbidities.The 3-year DFS in the present study was 76%.Gomez et al., comparatively on a smaller sample size, have reported a DFS rate of 64% at 3 years (Gomez et al. 2009).
We observed a 3-year LRC of 81%.Studer et al. evaluated IMRT in OCC patients, who underwent R0-R1 resection and reported about similar 3-year LRC of 84% (Studer et al. 2012).The studies by Dragan et al. and Yao et al. had   1 3 shown 3-year LRC of 78% and 85% respectively, with adjuvant IMRT in a similar subgroup of patients (Dragan et al. 2019;Yao et al. 2007).However, there are some studies that have demonstrated inferior LRC rates at 3 years, compared to our study (Daly et al. 2011;Chen et al. 2009).Chen et al. revealed a 3-year LRC of 64% but their study consisted of all patients with stage III and IV disease and that could be the reason for inferior LRC (Chen et al. 2009).We observed that loco-regional recurrence (LRR) was in 19%of patients.Dragan et al. have also reported about similar LRR rate of 20% (Dragan et al. 2019).Eighty percent of loco-regional recurrences in the present study were in the high-risk volume.
The result in the study by Dragan et al. was quite the same, as the authors had reported 89% recurrences in the area of high-risk dose (Dragan et al. 2019).Many other studies have also identified high-risk regions as the commonest site of loco-regional failure (Chao et al. 2003;Dawson et al. 2000).
In our study, the median age of presentation was 45 years.We observed age of 50 years or more was a poor prognostic indicator for OS, DFS, and LRC in univariate analysis (p = 0.00) and the result was consistent in multivariate analysis (p = 0.000, 0.000, 0.001 respectively).Zanoni et al. in their study have also demonstrated elderly age as an independent prognostic factor adversely affecting OS in patients of SCC of the oral cavity (Zanoni et al. 2019).The median age of patients in this study was 62 years.Studies by Pant et al. and Thiagarajan et al. have reported median ages of 45 and 48 years respectively and both demonstrated favorable survival outcomes in the younger population as compared to the elderly (Pant et al. 2021;Thiagarajan et al. 2014).Suresh et al. demonstrated that elderly age has a negative impact on DFS and OS (Suresh et al. 2019).The poorer outcome in elderly patients could be because of co-morbidities that affect both treatment tolerance and response to treatment.It may not be entirely because of the biology of disease (Habbous et al. 2014).Besides, young patients do not present with more advanced stages and are more likely to receive adjuvant RT/CT (Chen et al. 2020).
In our study, we observed pathological positive LN status (pN +) as an independent prognostic indicator for OS (p = 0.05), DFS(p = 0.021), and LRC(p = 0.19).A study by Chen et al. also demonstrated pN + ve as a significant Fig. 1 a-c Kaplan-Meier graph for overall survival, disease free survival and loco-regional control of the study population, respectively prognostic factor affecting OS, DFS, and LRC (Chen et al. 2016).Various studies have reported pN + ve status as a significant predictor in determining OS and LRC (Zanoni et al. 2019;Thiagarajan et al. 2014;Goldstein et al. 2013;Nair et al. 2018;Garzino-Demo et al. 2016).Like positive LN, the presence of ECE is also a poor prognostic indicator for OS and DFS (Chen et al. 2016).In the present study also, ECE was significantly associated with inferior survival rates in both univariate and multivariate analysis.Regarding LRC, we observed ECE had a significant effect in univariate (p = 0.00) but not in multivariate analysis (p = 0.135).However, in a retrospective study, Lai et al. revealed ECE as a significant predictor of LRC in both univariate and multivariate analysis (Lai et al. 2017).We evaluated, separately, the impact of pathologically positive N2 or N3 status and found that it was significantly associated with inferior LRC (p = 0.00), DFS (p = 0.00), and OS (p = 0.00) in univariate analysis.The study by Lai et al. also reported inferior LRC with N2 or N3 disease in univariate analysis, but, like our study, the result was not significant in multivariate analysis (Lai et al. 2017).Lymphovascular invasion is an important prognostic factor that affects survival (Pant et al. 2021;Dolens et al. 2021).In our study, we observed inferior LRC (p = 0.03) and DFS (p = 0.03) rates with positive LVI in univariate analysis, but the result was not consistent in multivariate analysis (p = 0.65 and 0.75, respectively).Many studies have demonstrated PNI, stage, DOI, positive margin, tumor grade and treatment interruptions as significant prognostic factors in multivariate analysis (Chen et al. 2016;Nair et al. 2018;Garzino-Demo et al. 2016;Dolens et al. 2021).However, in the present study, we didn't find any significant influence of these parameters on survival outcomes.
Being retrospective in design, missing data was the study's major limitation.There was selection bias because of variation in NACT practice.The heterogeneity regarding NACT practice was because many patients were referred from outside the institution.Few comparisons could not be done because of a disproportionate number of patients.With a longer duration of follow-up, more mature data with adjuvant VMAT in OCC could be obtained.However, in patients of OCC, the majority of failures occur within 2 years after treatment completion and we have presented LRC and survival rates at 3 years, so it is worth reporting (Boysen et al. 1992).The observed LRC, DFS and OS rates of the study were in concordance with the results of the previously published studies which had evaluated IMRT in SCC of the oral cavity, after surgery.
To minimize selection bias, we included only patients of post-operated SCC of the oral cavity.Also, it was possible to know the exact pathological stage and other features of the disease for prognostication.The results of the study substantiate the role of well-proven traditional prognostic factors like pN status and ECE.In the present study, age was  Effect of age and nodal involvement on loco-regional control a significant factor adversely affecting OS.Furthermore, we also observed, age as a significant indicator of inferior DFS and LRC which have been reported by only a few studies as per our best knowledge in the literature.In the future, prospective studies evaluating adjuvant VMAT in SCC of the oral cavity with a larger number of patients and over a longer duration of follow-up could provide more robust results on its efficacy.Besides, considering the results of the present study, we suggest, more studies are required to evaluate the role of factors like pN2, N3, and age in determining treatment outcomes, especially age in DFS and LRC.

Conclusion
In patients of SCC of oral cavity VMAT with SIB is effective in adjuvant setting.Age and pathological nodal status are significant prognostic factors for LRC, DFS and OS while ECE had significant impact on DFS and OS.

Fig. 3
Fig. 3 a-c Effect of age, nodal involvement and ECE on disease-free survival

Fig
Fig. 4 a, b Effect of age and nodal involvement on loco-regional control

Table 2
Treatment characteristics

Table 3
Recurrence pattern

Table 5
Multivariate analysis *p-Value is < 0.05, i.e., significant Fig. 2 a-c Effect of age, nodal involvement and ECE on overall survival