Abstract
Purpose
To investigate the relationship between geometric and dosimetric characteristics of salivary glands and acute xerostomia during or shortly after radiation therapy in patients with head and neck cancer (HNC).
Methods and Materials
We used an Automated Watchdog in Adaptive Radiotherapy Environment (AWARE) program to monitor changes in tumor and organ-at-risk using weekly cone beam computed tomography (CT) images for patients with HNC. Gross tumor volume and organ-at-risk contours were propagated from the planning CT to the weekly cone beam CT using deformable registration and reviewed by clinical users. This study analyzed 165 evaluable patients with AWARE-HNC treated between 2021 and 2024. The National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 was employed to grade toxicities. Acute xerostomia was defined as grade ≥2, occurring during or within 3 months after radiation therapy completion. We compared weekly salivary (parotid and submandibular) gland shrinkage and radiation doses between patients with and without acute xerostomia.
Results
Of the 165 patients with HNC, 66 (40.0%) developed acute xerostomia. Patients with acute xerostomia exhibited significantly larger parotid gland shrinkage in the second and third weeks and submandibular gland shrinkage in the second week (15.4%, 21.0%, and 13.1%, respectively; t test P = .047, .032, and .007) during radiation therapy, compared with those without acute xerostomia (11.4%, 17.2%, and 7.7%). Compared with the nonxerostomia group, patients who developed acute xerostomia received significantly higher mean doses to the ipsilateral parotid (24.7 Gy vs 19.8 Gy; P = .003) and ipsilateral submandibular glands (60.7 Gy vs 57.4 Gy; P = .045). Lower parotid dose in the cone-down boost and subsequent adaptation mitigated the risk of acute xerostomia (P = .015).
Conclusions
Increased mean doses to the ipsilateral parotid and submandibular glands were associated with larger salivary gland shrinkage during radiation therapy and a significantly higher risk of acute xerostomia. This early signal could trigger adaptive replanning promptly. Cone-down and adaptive techniques can reduce the salivary gland dose, helping mitigate the risk of acute xerostomia.
Introduction
Head and neck cancer (HNC) is the seventh most prevalent cancer worldwide, with approximately 890,000 new cases annually (4.5% of all global cancer diagnoses).1 Radiation therapy (RT) is one of the standard treatment modalities for HNC.2 Over the past 20 years, RT for head and neck squamous cell carcinoma has advanced from 3-dimensional RT to intensity modulated RT, which reduces the radiation dose to organs-at-risk (OARs). This has led to a decrease in toxicity rates, such as xerostomia and dysphagia,3, 4, 5 without compromising loco-regional control and overall survival. Moreover, developing image guided RT, such as daily cone beam computed tomography (CBCT), can minimize uncertainties in target volumes, reduce the risk of overtreating adjacent organs, and potentially reduce radiation-related toxicity between treatment days.6
Radiation-induced xerostomia is a common acute and long-term side effect of head and neck RT that negatively affects the quality of life of long-term survivors.7, 8, 9, 10, 11 Eisbruch et al12 reported a correlation between the dose received by parotid glands and salivary flow rates following RT. The PARSPORT study confirmed the clinical validation of radiation dose reduction to parotid glands to mitigate xerostomia.5 However, despite parotid sparing, 20% to 25% of patients still develop xerostomia. A major challenge during the radiation course is that many patients experience anatomic changes due to a combination of tumor response, weight loss, and radiation effects on normal tissue.13,14 Consequently, this can result in healthy tissue receiving unintended, excessive radiation doses.
Early shrinkage of salivary glands during intensity modulated RT treatment has been shown to be associated with the risk of acute xerostomia.15,16 One approach to reducing radiation exposure to salivary glands while maintaining the target dose is adaptive radiation therapy (ART).17 ART enables radiation oncologists to adjust treatment plans in response to anatomic changes, thereby preserving salivary gland function and mitigating xerostomia. Despite the potential benefits of ART, several challenges hinder its routine and efficient implementation. It requires significant resources from both the radiation oncology and medical physics teams. The radiation oncologist must recontour all critical structures and targets, the medical dosimetrist must rapidly create a revised treatment plan, and the medical physicist must conduct quality assurance on the updated plan. To adopt ART in a streamlined workflow within clinical resource constraints, we developed an in-house software called Automated Watchdog for Adaptive Radiotherapy Environment (AWARE), which allows us to monitor longitudinal images for anatomic changes, including the target tumor and normal organs. We reported that ART resulted in greater reductions in parotid dose when parotid volume changes exceeded 7%.18 In the current study, we aim to investigate the relationship between salivary gland shrinkage during RT and acute xerostomia occurring during or shortly after a course of RT in HNC patients, evaluate the clinical benefit of adopting ART to mitigate the risk of xerostomia, and provide helpful guidance in the design of adaptive strategies.
Methods and Materials
Patient selection and characteristics
This retrospective study was approved by the institutional review board (IRB #16-700). It includes 165 patients who received RT under the AWARE monitoring program, as illustrated in Fig. 1, between April 2020 and August 2024. According to the institutional ART protocol, patients were selected based on a clinical determination that they would likely benefit from ART. General guidelines focused on patients with oropharyngeal cancers and with large (>10 cm3) nodal and/or primary gross tumor volumes (GTVs), but clinicians were able to add any patient with HNC based on their clinical judgment. Physicians primarily selected patients during peer conferences, reviewing treatment volumes, or during treatment periods when the benefits of monitoring and adapting were considered. The electronic medical records and the dosimetric data for eligible patients were reviewed, including patient demographics, Karnofsky performance status, primary tumor site, tumor (T) and nodal (N) stages, p-16 status, smoking status, comorbidities, use of induction chemotherapy, and concurrent chemoradiation.
Figure 1.
Flowchart of Automatic Watchdog for Adaptive Radiotherapy Environment (AWARE).
Abbreviations: DIR = deformable image registration; OAR = organ-at-risk.
RT treatment planning
At our institution, RT for HNC is typically delivered in sequential phases. The initial phase consists of 30 Gy to the entire planning target volume (PTV), followed by a cone-down (CD) boost of 40 Gy to areas of gross disease, resulting in a total dose of 70 Gy.19 Image guided RT protocols include daily kilovoltage (kV) imaging and weekly CBCT.
Treatment plans are optimized to ensure that at least 95% of the PTV receives the prescribed dose along with the following OAR objectives: (1) parotid glands: mean dose <26 Gy (<20 if GTV not adjacent); (2) submandibular glands: mean dose <39 Gy for ipsilateral and <26 Gy contralateral; and (3) oral cavity (less PTV): mean dose <40 Gy. During planning, particular emphasis is placed on minimizing radiation exposure to OARs, especially the salivary glands, including the parotid glands, submandibular glands, and the oral cavity, and when possible, doses are reduced below the objectives listed above.
Adaptive workflow
Upon being chosen for the AWARE protocol, a patient was registered in the treatment planning system and monitored via the AWARE program.18 Each time a CBCT was acquired during the treatment course for the purpose of image guided setup and response assessment, a nightly script automatically pushed the scan as a DICOM (Digital Imaging and Communications in Medicine) to MIM software (GE HealthCare, version 7.2.8). The weekly CBCT was deformably registered to the original planning computed tomography (CT) using the MiM application programming interface. The primary and/or nodal GTV and the parotid and submandibular glands were propagated from the planning CT to the weekly CBCT. Volumes of these structures were tabulated on a weekly basis, plotted, and emailed to the AWARE clinical team the next morning. The clinical team reviewed the volume changes and determined whether they were accurate and clinically significant.
All patients were recommended for resimulation and ART at the third week of RT, but simulation was recommended earlier if clinically significant changes were observed. ART was recommended regardless of the AWARE findings, but the decision to adapt was left to the treating physician. Most of the resimulations occurred during the third week of the RT course, resulting in the adaptive plans being delivered in the fourth week of RT.
Treatment response evaluation
In this retrospective study, treatment-related acute toxicities were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0, based on subjective physician-reported evaluations documented by the treating radiation oncologist during routine clinical visits. Toxicity data were obtained through retrospective chart review. Acute toxicities were defined as radiation-related events occurring during treatment or within 3 months after completion of RT. The primary endpoint was acute xerostomia, defined as National Cancer Institute Common Terminology Criteria for Adverse Events grade ≥2, as recorded by the treating radiation oncologist based on symptoms such as moderate dryness, the need to alter oral intake, and persistent oral discomfort. No objective measurements of salivary function were performed; therefore, toxicity grading may be subject to interobserver variability and reporting bias.
Analysis
Patient characteristics between the ART and non-ART groups, and between the xerostomia and nonxerostomia groups, were compared using rank-sum and χ2 tests for continuous and categorical variables, respectively. Weekly shrinkages of parotid and submandibular glands and radiation doses were compared between patients who did and did not develop acute xerostomia using a t test. All statistical analyses were performed with Stata software (StataCorp, version 18.0) and Python scipy.stats library.
Results
This study included a total of 165 patients with HNC, among whom 66 (40.0%) developed acute xerostomia (≥grade 2) and 99 (60.0%) did not. Table 1 shows patient characteristics, comparing the xerostomia with the nonxerostomia groups. The median age was 64 years (IQR, 57-71). Only diabetes showed a statistically significant difference between the 2 groups, with a higher prevalence in the nonxerostomia group than in the xerostomia group (18% vs 5%; P = .019). Oropharynx was the most common subsite in both groups, with no significant difference (P = .792). There was no significant difference in the proportion of human papillomavirus status (human papillomavirus immunohistochemistry and/or p-16; P = .560). There was no significant difference in the distribution of T-stage, N-stage, and overall stage (P = .441, .198, and .255, respectively). No significant differences were found in induction chemotherapy (P = .830), concurrent chemoradiation (P = .771), surgical intervention (P = .812), and ART (P = .497) between the 2 groups. Acute toxicities were compared between patients receiving ART and those who did not (Table 2); no significant differences were found between the 2 groups.
Table 1.
Patient characteristics
| Characteristic | Total N = 165 |
||
|---|---|---|---|
| No xerostomia (n = 99) | Xerostomia (n = 66) | P value | |
| Age (y); median (IQR) | 62 (55-70) | 65 (58-72) | .183 |
| Sex, n (%) | .486 | ||
| Female | 10 (10) | 9 (14) | |
| Male | 89 (90) | 57 (86) | |
| KPS, n (%) | .875 | ||
| ≤80 | 4 (4) | 3 (5) | |
| <80 | 95 (96) | 63 (95) | |
| Subsite, n (%) | |||
| Oropharynx | 90 (91) | 61 (92) | .792 |
| Larynx | 2 (2) | 1 (2) | |
| Unknown primary | 4 (4) | 2 (3) | |
| Other | 3 (3) | 2 (3) | |
| IHC and p-16 status, n (%) | .560 | ||
| Positive | 86 (87) | 54 (82) | |
| Negative | 11 (11) | 9 (14) | |
| Other/unknown | 2 (2) | 3 (4) | |
| Overall stage, n (%) | .255 | ||
| 1 | 12 (12) | 10 (16) | |
| 2 | 38 (38) | 17 (26) | |
| 3 | 34 (34) | 31 (47) | |
| 4 | 15 (15) | 8 (12) | |
| T-stage, n (%) | |||
| 0 | 4 (4) | 2 (3) | .441 |
| 1 | 12 (12) | 9 (14) | |
| 2 | 31 (31) | 17 (26) | |
| 3 | 30 (21) | 15 (23) | |
| 4 | 22 (22) | 23 (35) | |
| N-stage, n (%) | .198 | ||
| 0 | 4 (4) | 4 (6) | |
| 1 | 31 (31) | 20 (30) | |
| 2 | 52 (53) | 40 (61) | |
| 3 | 12 (12) | 2 (3) | |
| Hypertension, n (%) | .680 | ||
| No | 52 (52) | 36 (55) | |
| Yes | 47 (48) | 30 (45) | |
| Diabetes, n (%) | .019 | ||
| No | 81 (82) | 63 (95) | |
| Yes | 18 (18) | 3 (5) | |
| Smoking history, n (%) | |||
| None | 51 (53) | 31 (47) | .809 |
| <10 packs/y | 16 (16) | 9 (14) | |
| ≥10 packs/y | 29 (29) | 23 (35) | |
| Smoking but unknown pack/y | 3 (3) | 3 (5) | |
| Induction chemotherapy, n (%) | .830 | ||
| Yes | 10 (10) | 6 (9) | |
| No | 89 (90) | 60 (91) | |
| Concurrent ChemoRT, n (%) | .771 | ||
| Concurrent chemoradiation | 98 (99) | 65 (98) | |
| RT alone | 1 (1) | 1 (2) | |
| Postoperative, n (%) | .812 | ||
| Yes | 2 (2) | 1 (2) | |
| No | 97 (98) | 65 (98) | |
| Adaptive RT, n (%) | |||
| Yes | 78 (79) | 49 (74) | .497 |
| No | 21 (21) | 17 (26) | |
Rank-sum and χ2 tests were performed for continuous and categorical variables, respectively.
Abbreviations: IHC = immunohistochemistry; KPS = Karnofsky performance status; N = nodal; RT = radiation therapy; T = tumor.
Table 2.
Comparison of acute toxicities between patients with and without adaptive radiation therapy
| Nonadaptive No. (%) (n = 38) |
Adaptive No. (%) (n = 127) |
||||||
|---|---|---|---|---|---|---|---|
| Toxicity | Grade 1 | Grade 2 | Grade 3 | Grade 1 | Grade 2 | Grade 3 | P value for grade ≥2 |
| Acute toxicity | No. of patients with event (%) | ||||||
| Dermatitis | 19 (50) | 9 (23.7) | 1 (2.6) | 51 (41.1) | 52 (41.9) | 7 (4.8) | .852 |
| Nausea | 13 (34.2) | 5 (13.2) | 1 (2.6) | 39 (30.7) | 12 (9.4) | 0 (0) | .271 |
| Vomiting | 6 (15.8) | 0 (0) | 0 (0) | 8 (6.3) | 2 (1.6) | 0 (0) | .436 |
| Mucositis | 4 (10.5) | 22 (57.9) | 5 (13.2) | 23 (18.1) | 71 (55.9) | 16 (12.6) | .765 |
| Xerostomia | 17 (44.7) | 16 (42.1) | 1 (2.6) | 67 (52.8) | 49 (38.6) | 0 (0) | .497 |
| Dysphagia | 2 (5.3) | 20 (52.6) | 7 (18.4) | 11 (8.7) | 77 (60.6) | 24 (18.9) | .272 |
| Hoarseness | 10 (26.3) | 1 (2.6) | 0 (0) | 43 (33.9) | 4 (3.1) | 2 (1.6) | .574 |
| Dysgeusia | 5 (13.2) | 29 (76.3) | 0 (0) | 32 (25.8) | 85 (69.3) | 0 (0) | .403 |
| Fatigue | 30 (78.9) | 5 (13.2) | 1 (2.6) | 89 (70.1) | 27 (21.3) | 2 (1.6) | .351 |
As illustrated in Fig. 2, patients with acute xerostomia showed significantly greater parotid gland shrinkage compared with those without acute xerostomia, particularly at week 2 (15.4% vs 11.4%; P = .047) and at week 3 (21.0% vs 17.2%; P = .032). When comparing one-third of samples with greater parotid gland shrinkage at week 2 to the one-third with less shrinkage, the odds ratio was 2.0 (P = .041), indicating a clinically useful level of discrimination between the 2 groups. For the same comparison at week 3, the odds ratio was 1.8 (P = .061), indicating borderline statistical significance. Shrinkage of parotid glands at week 1 was not significantly associated with acute xerostomia (11.1% vs 8.9%; P = .190). Shrinkage of parotid glands observed at the last available CBCT scans acquired during RT correlated with acute xerostomia (29.9% vs 23.4%; P < .001). However, such a detection does not serve ART because it is too late to be an adaptive signal. Patients with acute xerostomia had greater submandibular gland shrinkage compared with those without acute xerostomia at week 2 (13.1% vs 7.7%; P = .007). Patients with acute xerostomia also showed significantly greater shrinkage in ipsilateral and contralateral submandibular glands: ipsilateral (13.1% vs 7.8% at week 2; P = .016) and contralateral (10.2% vs 5.1% at week 1; P = .048 and 13.1% vs 6.6% at week 2; P = .016).
Figure 2.
A typical example of a patient with acute xerostomia (above) and a patient without xerostomia (below) is illustrated on the left. Shrinkages of parotid glands observed in the second and third weeks are associated with acute xerostomia, as shown in the bar plot. Shrinkage in the first week does not correlate with xerostomia.
Abbreviations: CT = computed tomography.
Patients who developed acute xerostomia received significantly higher mean doses to the ipsilateral parotid (24.7 Gy vs 19.8 Gy; P = .003) and submandibular glands (60.7 Gy vs 57.4 Gy; P = .045). To investigate the impact of multistage planning techniques, we analyzed the dose contributions from each phase of the treatment plans (Table 3). The mean dose to the ipsilateral parotid gland at the initial phase, ie, treating both the elective nodes and gross disease, was 1.9 Gy higher in the xerostomia group compared with the nonxerostomia group (P = .004). In comparison, patients with acute xerostomia had a 2.9 Gy higher ipsilateral parotid mean dose from the CD phase (P = .005). The mean dose to the parotid gland was 1.8 Gy higher in the xerostomia group compared with the nonxerostomia group in the CD boost and subsequent adaptation (P = .015). We further divided the dose from the CD phase into 2 components: the original CD plan and the adaptive CD plan. The adaptive plan consistently reduced the parotid mean dose by 0.3 Gy, and the effect was especially significant for the contralateral parotid gland (P = .037).
Table 3.
Comparison of mean doses to the parotid glands between the xerostomia and nonxerostomia groups for each phase of a treatment course
| Ipsilateral (Gy) |
Contralateral (Gy) |
Average (Gy) |
|||||||
|---|---|---|---|---|---|---|---|---|---|
| Phase | No xerostomia | Xerostomia | P | No xerostomia | Xerostomia | P | No xerostomia | Xerostomia | P |
| Phase 1 | 11.9 | 13.8 | .004 | 9.4 | 8.7 | .295 | 10.6 | 11.2 | .265 |
| Phase 2: CDorig + ART | 8.1 | 11.0 | .005 | 4.4 | 5.1 | .353 | 6.2 | 8.1 | .015 |
| Phase 1 + 2 | 19.8 | 24.7 | .003 | 13.7 | 13.7 | .975 | 16.7 | 19.2 | .041 |
| CDorig – ART | 0.4 | 0.2 | .259 | 0.6 | 0.2 | .037 | 0.5 | 0.2 | .055 |
Abbreviations: ART = adaptive radiation therapy; CD = cone-down.
Bold indicates P < 0.05.
Discussion
Unsurprisingly, decreases in the volume of the salivary gland affect their functionality, and large shrinkage is associated with a significant risk of acute xerostomia occurring during or right after RT. AWARE achieved the goal of systematically assessing the longitudinal geometric changes of parotid and submandibular glands. Although using CBCT to measure anatomic changes has many challenges due to CBCT artifacts and uncertainty in contour propagation via deformable image registration (DIR), the accuracy regarding the parotid and submandibular glands is clinically acceptable.20 Many reports suggested that DIR has a submillimeter accuracy of the mean distance to agreement in the ART setting.21,22 Among the AWARE patient cohort, the volumetric shrinkage of the parotid and submandibular glands in the second week averaged 12.6% and 12.0%, respectively. The longest diameter of the parotid and submandibular glands was shortened by about 5 to 10 mm and 2 to 5 mm, respectively. Modern DIR algorithms can reliably detect such a noticeable change. In addition, deep learning–based image segmentation has become increasingly accessible and popular in the clinic. It can serve as a quality check of the DIR-propagated contours and flag suspicious cases for human review. Finally, the new-generation imager improves the CBCT image quality. We have been further developing AWARE and multimodal imaging to enhance monitoring capabilities and provide essential support for both online and offline ART.
In this retrospective study, we demonstrated that radiation dose is a determining factor causing acute xerostomia. The larger contribution of the dose difference from the CD phase compared with the initial phase (Table 3) to acute xerostomia suggests that high-dose target geometry is a primary driver, and that adapting during this phase is particularly important. There is greater variability in CD geometry among patients, depending on the location of gross disease. In the initial phase, the treatment volume is fairly uniform, covering the whole neck, whereas the CD is more fine-tuned to where the gross disease is. The proximity of the ipsilateral parotid gland to the primary gross tumor makes it difficult to spare the gland. When the patient had an unfavorable geometry in the CD phase, or when the shrinkage of GTV and parotid gland resulted in an unfavorable geometry for plan adaptation, patients received significantly higher parotid doses with CD replanning, which eventually differentiated the xerostomia and nonxerostomia patients. Our previous analysis found that patients with larger parotid gland shrinkage also exhibited a larger reduction in mean parotid doses due to ART.18 These findings underscore the importance of personalized treatment, as CD and adaptation are more closely related to the specific patient’s anatomy and their response to RT. Furthermore, modifying the treatment volume based on biological factors (such as including or excluding elective nodes, which distinguishes the initial phase from the CD phase) appears to have a greater impact on treatment-related toxicities than adapting the plan to changing anatomies.
We found multiple significant geometric and dosimetric factors associated with the risk of acute xerostomia. More frequent assessment of these factors during RT, eg, increasing the image surveillance frequency during the second and third week of RT, can provide valuable information, enabling clinical teams to better tailor treatment for patient benefit. Plan adaptation could start in the initial phase to reduce the parotid dose according to the early geometric shrinkage. Combined with tumor response assessment, the intended treatment volume may also be modified to reduce the parotid dose aggressively without compromising the tumor control rate. Furthermore, although we used a subjective grading system to assess acute xerostomia, we recognize the need for objective assessment methods such as stimulated whole mouth saliva flow measurements, which represent a limitation of the current analysis. We propose a prospective study that addresses the limitations of the current retrospective study, integrates predictive biomedical markers of RT-induced salivary gland injury, and designs treatment plans with biologically and anatomically informed adaptations to clinically realize the full potential of ART.
Conclusions
Increased mean doses to the ipsilateral parotid and submandibular glands were associated with larger salivary gland shrinkage during RT and a significantly higher risk of acute xerostomia. This early indicator could trigger adaptive replanning promptly. A significant dose reduction in the salivary glands through CD and adaptive planning can help mitigate the risk of acute xerostomia.
Disclosures
Nancy Y. Lee serves on the advisory boards (consultant) of Merck, Merck Serono, Nanobiotix, Galera, LEO SAB, and GSK; holds stock options in LEO SAB; and has served as an invited speaker for Shanghai JoAnn Medical Technology Co, Ltd, Yingming Consulting, the RANZCR ASM Australia 2022 Targeting Cancer Meeting (funded by Varian), and the SYS Cancer Center (funded by Suzhou Liangyihui Network Technology Co, Ltd.).The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
Jung Hun Oh was responsible for statistical analysis.
Footnotes
Sources of support: This research was partially supported by the Memorial Sloan Kettering Cancer Center Support Grant/Core Grant (P30 CA008748).
Due to confidentiality agreements, supporting data can only be made available to bona fide researchers subject to a nondisclosure agreement. Details of the data and how to request access are available from Pengpeng Zhang (zhangp@mskcc.org) at Memorial Sloan Kettering Cancer Center.
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