Excellent long-term patient-reported quality of life and low levels of treatment regret after surgery and adjuvant radiation therapy for primary salivary gland malignancies

Introduction

Malignant primary salivary gland tumours are a rare, biologically heterogenous group of diseases which arise from major or minor salivary glands in the sinonasal cavities and upper aerodigestive tract and account for 6–8% of head and neck cancers (1,2). Five-year survival rates vary from 20% to greater than 90% depending on the histopathologic subtype and stage at presentation (1,2). Curative treatment involves upfront complete oncological resection, and neck dissection in the presence of clinically or radiologically positive cervical lymph node metastases, with the addition of radiation therapy (RT) for patients at high risk of locoregional recurrence.

Adjuvant RT is typically indicated in the presence of high risk clinicopathological features including large tumour size, nodal involvement, positive resection margins, and unfavourable histological type (3,4). The retrospective data that supports the local control (and in some cases survival) benefit of RT is limited to small institutional or large national database studies (3-14). This evidence is prone to the limitations of retrospective data, as well as in most cases lacking the granularity of histopathologic subtype, multidisciplinary decision making, and specifics of RT treatment. Thus, any potential oncological benefit of RT for patients with primary salivary gland malignancies must be weighed against the potential for causing additional toxicity on top of surgery, which is of particular importance in younger patients with potentially decades in which to manifest late RT-related side effects.

Although there is increasing efforts to report long-term, patient-reported quality of life (QOL) for patients undergoing treatment for head and neck cancers, there is limited information available for patients who have undergone surgery and adjuvant RT for primary salivary gland tumours specifically. Although RT fields are often smaller than for other mucosal head and neck cancers and thus acute side effects may be less, the majority of patients survive for many years after curative treatment and thus have potentially decades in which to manifest late effects. Thus, understanding the impact of treatment(s) on long term QOL is critical to improve current management paradigms and guide survivorship care.

This study aimed to review the long-term patient-reported QOL outcomes in selected high risk patients undergoing surgery and adjuvant RT for malignant primary salivary gland tumours, and to identify clinical, pathologic and dosimetric parameters associated with worse QOL, to guide survivorship care.

Methods

Patients with malignant primary salivary gland tumours who underwent surgical resection and post-operative RT with curative intent between November 2006 and December 2022 at Northern Sydney Cancer Centre, Royal North Shore Hospital comprised the study population. For this retrospective cohort study, patients were identified and data extracted from a prospectively maintained electronic institutional database. To minimise selection bias, all eligible patients treated within the study period were included, except for those where surgical, histopathologic information was unavailable. Dosimetric data was extracted from the treatment planning system (Eclipse). Where organs at risk (OARs) of interest were not contoured initially, these were retrospectively contoured by a Radiation Oncologist to obtain the relevant dosimetric information. The study is reported according to the STROBE reporting guidelines (available at https://www.theajo.com/article/view/10.21037/ajo-25-42/rc).

All patients were discussed at a dedicated head and neck multidisciplinary team (MDT) meeting prior to commencement of RT. Patients routinely underwent pre-operative cross-sectional imaging with computed tomography (CT) or magnetic resonance imaging (MRI) to assess for the extent of local tumour invasion, as well as positron emission tomography (PET)/CT to assess for distant metastases. Most tumours arose from the parotid gland, and surgery involved superficial or total parotidectomy as required for complete excision, with preservation of the facial nerve unless direct invasion was evident clinically or radiologically prior to surgery or identified intraoperatively. Tumours of the submandibular gland (SMG) were treated with oncological excision of the entire gland, and at other sites by wide excision as appropriate based on anatomical location. Margins were defined as involved, close (<5 mm), or clear.

As per local and international guidelines, patients were recommended post-operative RT for T3–T4 tumours [according to the American Joint Committee on Cancer (AJCC) 8^th edition tumor-node-metastasis (TNM) classification], or presence of high-risk pathologic features; including histologically high grade tumours, adenoid cystic carcinoma, positive surgical margins, perineural or lymphovascular invasion, or lymph node involvement (15-17). RT was delivered via intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) technique using pre-operative fluorodeoxyglucose (FDG)-PET/CT fusion, a thermoplastic head and neck mask for immobilisation, and daily cone beam CT for image verification. RT was delivered to the surgical bed to a dose of 60 Gy in 30 fractions delivered 5 times per week over 6 weeks, with a concomitant boost to 63 Gy to any area with involved margins. Regional nodes were included if pathologically involved or deemed to be high risk. For adenoid cystic carcinoma the nerve pathways were typically chased proximally to the base of skull. Patients were typically followed up with clinical review every 3 months to 2 years, then every 4–6 months to 5 years, then discharged from routine surveillance.

As part of this retrospective cohort study, all patients who were still alive were contacted in late 2023 via phone and invited to participate in a cross-sectional assessment of QOL survey. Those who consented to participate were sent an electronic RedCap survey via email or text message, with up to two reminders. The QOL survey (see complete survey as sent to participants in Figure S1) included all 35 items from the European Organization for Research and Treatment of Cancer Head and Neck Module 35 (EORTC QLQ HN-35) (18), two items from the general European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) (19), and additional questions regarding perceived health and treatment regret.

The data were summarised as mean, standard deviation (normal data), median, range (skewed data or ordinal data), proportions, and hazard ratios with 95% confidence intervals (CIs). Kaplan-Meier survival analysis was used to summarise overall survival (OS) and disease-free survival (DFS). Log-rank test was used to assess factors associated with improved OS, DFS, defined from date of starting RT. Cox-proportional hazards regression was used to estimate the hazard ratio (risk of death or progression) for patient sub-groups. Quantitative and categorical variables were handled according to clinical relevance and data distribution. Patients with missing values for a variable were excluded from analyses involving that variable. Patient reported QOL was analysed as per the EORTC guidelines (19). A univariate binary logistic regression model was fitted and tested to identify factors associated with worse QOL (odds ratio for score >60 for EORTC HN-35 and QLQ-30 items, equivalent to moderate to severely impaired QOL). All the statistical analysis were performed at 0.05 level of significance. The statistical analysis was performed in R, version 4.4.2.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Northern Sydney Local Health District Human Research Ethics Committee (No. 2021/ETH12353) and informed consent was taken from all individual participants.

Results

Sixty-seven patients underwent surgery and adjuvant RT for malignant primary salivary gland tumours during the study period. Demographic information is summarised in Table 1. Median follow up time was 4.4 [interquartile range (IQR), 2.4–7.4] years, 1- and 5-year OS for all patients was 97% and 79% respectively, with median OS not reached (Figure 1). DFS at 1-year and 5-year was 97% and 79% respectively, with median DFS not reached (Figure 2). On univariate analysis, older age, worse Eastern Cooperative Oncology Group (ECOG) performance status, histology (carcinoma ex pleomorphic adenoma), larger primary tumours, more advanced TNM stage (AJCC 8^th edition), presence of perineural invasion, and high-grade tumours were all was associated with shorter OS and shorter DFS (Table 2).

Figure 1 Kaplan-Meier estimate of overall survival in patients with primary salivary gland malignancies treated with surgery and adjuvant radiotherapy. CI, confidence interval.

Figure 2 Kaplan-Meier curve of disease-free survival in patients with primary salivary gland malignancies treated with surgery and adjuvant radiotherapy. CI, confidence interval.

During the study period, 12 patients experienced disease recurrence: one local, 10 distant, and one concurrent local and distant (Figure S2). No patients had regional recurrence. Cumulative incidence function of local failure (LF) estimated 1- and 5-year LF rates of 1.5% and 3.1% respectively (Figure 3). The numbers of events of both LF and distant metastases were too low to undertake Cox regression analysis for prognostic factors.

Figure 3 Cumulative incidence functions of local failure in patients with primary salivary gland malignancies treated with surgery and adjuvant radiotherapy. CI, confidence interval.

Dosimetric data was obtained for the 29 patients who completed the QOL surveys (Table 1). 20 patients (69%) underwent RT to the locoregional lymph nodes in addition to the primary site. Median clinical treatment volumes (CTVs) were 85 cc for the overall CTV (IQR, 20–265 cc) and 61 cc for the high dose CTV (IQR, 12–241 cc). Median doses to the contralateral parotid were 3 Gy (IQR, 1–15 Gy) and contralateral SMG 13 Gy (IQR, 0–62 Gy).

Thirty-five of 48 invited patients agreed to participate in the QOL survey (three declined and 10 were unable to be contacted), of which 29 subsequently completed the survey in full. Median follow-up for surveyed patients was 5.2 years (IQR, 3.9–9.2 years); 93% of patients were in remission. The remaining two patients were alive with distant metastases, diagnosed 2 and 8 years after completion of locoregional treatment. Survey results are summarised in Figures 4,5 and Table S1. Regarding perceived health compared to before RT, six patients reported better health (20%), 17 patients ‘about the same’ (59%) and five patients worse health (17.4%). For those five patients, two of these attributed their worse health to RT (Table S2). Twenty-six patients (90%) had no treatment regret regarding RT. General QOL (EORTC QLQ-30) was very good, with median 83 (out of total 100, IQR 79), 100 and mean 84 (range, 50–100), with higher scores indicating better QOL (Table 3).

Figure 4 EORTC HN-35 results by individual survey responses for patients with primary salivary gland malignancies treated with surgery and adjuvant radiotherapy. EORTC HN-35, European Organization for Research and Treatment of Cancer Head and Neck Module 35.

Figure 5 EORTC HN-35 results by domain for patients with primary salivary gland malignancies treated with surgery and adjuvant radiotherapy. EORTC HN-35, European Organization for Research and Treatment of Cancer Head and Neck Module 35.

With regard to head and neck specific toxicities, on the EORTC HN-35 items (where higher scores indicate worse QOL), most patients reported no ongoing toxicities (median score 0 out of 100) in most domains, including swallowing (IQR, 0–8.3), problems with senses (IQR, 0–17), social eating (IQR, 0–17), sexuality (IQR, 0–33), shoulder problems (IQR, 0–33), problems opening mouth (IQR, 0–67), coughing (IQR, 0–0), social contact (IQR, 0–0), neck swelling (IQR, 0–33), weight loss (IQR, 0–0), wound healing problems (IQR, 0–0), and neurological problems (IQR, 0–0). Significant problems (i.e., a response of ‘very much’) were reported by six patients for dry mouth (21%), five patients for wide mouth opening (17%), three patients worried about future health (10%), two patients feeling less physically attractive since RT (7%) and two patients worried about the results of future examinations and tests (7%). Taken as a whole, the most significant survivorship issues for participants were fear or progression (median 33, IQR, 17–50) and speech (median 33, IQR, 22–44) (Table 3). On univariate analysis, there were no patient, tumour or treatment-related factors nor any dosimetric factors that predicted for worse head and neck specific (EORTC HN-35) QOL (Table 4). Four of 29 patients reported global health status score less than 60, indicating most patients had minimal or no impairment in global QOL. The number of events was too small to conduct univariate analysis.

Discussion

This study demonstrates excellent local control and favourable DFS in a cohort of patients with high-risk malignant primary salivary gland tumours treated with surgery and adjuvant RT. Despite universally adverse clinicopathologic features (warranting receipt of RT in all patients), the 5-year LF rate was 3.1%, and 5-year DFS was 79%. Patient-reported QOL was high, and treatment regret regarding RT was low, underscoring the tolerability and patient-perceived benefit of this treatment strategy.

Although challenging to compare recurrence and survival outcomes directly between cohort studies with differing inclusion criteria, the reported 5-year OS of 79% compares similarly to previous studies. This 5-year OS estimate falls between the 5-year OS rates of 56% for patients undergoing surgery and RT in Safdieh et al.’s National Cancer Database (NCDB) study (which included only patients with pT1-4NX-1M0 high-grade disease or pT3-4NX-0M0 or pT1-4N1M0 disease), and 84.5% in those undergoing surgery and adjuvant therapy for AJCC stage I or II disease with adverse features (adenoid cystic histology, intermediate or high grade, positive surgical margins or pathologic nodal involvement) in Cheraghlou et al.’s NCDB study (9).

The low rate of local recurrence (<5%) is similar to, or better than, previously published data of patients undergoing surgery and RT for primary salivary gland malignancies. For example, the DAHANCA study by Terhaard et al. reported 5-year local control of 94% with surgery and RT (4), and a more recent large single institutional study from Memorial Sloan Kettering Cancer Center reported 5-year local recurrence free survival (LRFS) 82.5% for major and 89.1% for minor salivary gland tumours for patients who received adjuvant RT after surgical resection of salivary gland carcinoma (13).

Multiple established clinicopathologic risk factors for recurrence, including older age, carcinoma ex pleomorphic adenoma histology, advanced T-stage and TNM stage, perineural invasion, and high-grade tumours, were associated with poorer OS and DFS. These findings reinforce the prognostic relevance of these factors, even in the setting of comprehensive locoregional treatment. However, the extremely low rate of isolated LF raises the possibility that some patients, although classified as high-risk by conventional criteria, may be overtreated with RT. At present there is no strong evidence to support addition of systemic therapy to adjuvant RT (16,20), although androgen receptors, HER2 and NTRK gene fusions (neurotrophic tropomyosin receptor kinase) are potential therapeutic targets in the relapsed or metastatic setting (21). More refined risk stratification is needed to guide decisions regarding adjuvant therapy for primary salivary gland malignancies. Ideally, integrating molecular profiling, advanced imaging, or other biomarkers into current MDT decision-making paradigms may help identify patients who could safely forgo RT, reserving treatment for those most likely to benefit, or incorporating systemic therapy for those at higher risk of relapse. However, given the rarity and biological heterogeneity of these tumours, developing predictive biomarkers or validated decision tools remains challenging.

Many patients did report ongoing late side effects (albeit mild or moderate in severity), which underscores the need for structured and easily accessible survivorship care as recommended by the American Cancer Society and American Society of Clinical Oncology guidelines (22-24). Specifically, significant problems with xerostomia were reported in 21% of patients, in line with previous literature that surgery (with or without RT) can negatively impact xerostomia in the long term (25). RT in addition to surgery has been shown to worsen patient reported QOL in relation to dry mouth, although the additive contribution of RT in the current series could not be determined without a surgical alone comparator. Median scores for dry mouth and sticky saliva of 17 (IQR, 0–50) are much better than those reported for all-comers who undergo RT for head and neck cancer [e.g., median 33 in Wan Leung et al.’s study (26)], likely due to modern RT technique (IMRT/VMAT), ability to treat unilaterally with RT and thus spare the contralateral salivary glands, both of which have been associated with reduced xerostomia (clinician and patient-reported) after RT (26-28).

Treatment was well tolerated, as indicated by a 99% RT completion rate and a low (3%) hospital admission rate during RT. While acute toxicity data were not directly reported, these surrogate measures suggest a favourable toxicity profile. Long-term survivorship outcomes were also encouraging, with preserved overall and head and neck-specific QOL. Global QOL scores were much higher than a previous large cross-sectional series of over 500 patients using the EORTC QLQ-C30 which reported mean score 54.6 compared to 84 (range, 50–100) in the present study (26). This may be explained by the favourable survival outcomes of patients with salivary gland cancers in general and/or treatment received (more ipsilateral RT) but may also have been confounded by survivorship and selection biases associated with survey completion.

This study collected detailed dosimetric data for the subset of patients who completed QOL surveys, reporting low mean doses to OARs, specifically median doses to the contralateral parotid gland and SMGs of 3 and 13 Gy respectively. This reflects the highly conformal treatment techniques used (IMRT/VMAT) and likely contributed to the favourable patient-reported QOL outcomes and minimal treatment regret observed. OAR doses were much lower than published dose constraints for general head and neck RT (e.g., Cancer Institute NSW EviQ guidelines) (29), although not unexpected as these guidelines are typically used for mucosal head and neck cancers requiring bilateral neck irradiation. Doses to (untreated) salivary glands were also much lower than those reported for unilateral IMRT for oropharyngeal cancer in a substudy of TROG 12.01 (mean contralateral parotid gland 23 Gy and SMG 17.2 Gy) (30). Again, this is not surprising given the smaller treatment volumes and 30% of patients not receiving treatment to the neck. Future studies incorporating longitudinal QOL assessment and dose-toxicity modelling could help refine dose constraints for critical OARs for patients undergoing adjuvant RT for resected primary salivary gland malignancies where the treatment volumes are smaller than typical head and neck RT and tighter planning protocol are both achievable and necessary.

This study is limited by its retrospective, single-centre design and small (35 patients), heterogeneous cohort. These factors limit generalisability and preclude robust subgroup analyses. Additionally, the small number of patients who completed the QOL survey introduces a variety of potential biases, including selection bias (only those alive, contactable and willing to respond may participate), survivorship bias (prevalence and/or severity of late toxicities may be underestimated due to loss to long term follow-up), recall bias (potential misclassification of toxicity or QOL over time), response bias (potential distortion if individuals with particularly positive or negative post-treatment experiences more inclined to participate), and social desirability bias (wanting to appear stoic or grateful to treating medical team). More specifically with regard to survivorship bias, the underrepresentation of carcinoma ex pleomorphic adenoma (3% vs. 9%) and overrepresentation of adenoid cystic carcinoma (41% vs. 27%) among survey respondents compared to the initially treated cohort likely reflects the association between the more aggressive biology of carcinoma ex pleomorphic adenoma with both shorter OS and DFS. This may have skewed the outcomes in favour of those patients with more indolent disease.

The absence of a surgery-only comparator group restricts the ability to determine the independent effect of adjuvant RT [although not the focus of this study, as this has already been addressed by other much larger studies (5,6)]. While the cohort is reflective of real-world clinical practice at a high-volume tertiary referral centre, the findings may not be directly generalisable to other settings, particularly those with different patient demographics or treatment protocols. Despite lengthy follow-up periods for the entire cohort (over 5 years), further assessment of QOL and late toxicities beyond 10 years, particularly in younger patients, would provide valuable information in this cohort with long life expectancy. Prospective, multicentre studies will be required to identify and validate biomarkers for RT de-escalation and/or intensification in this group of patients.

Conclusions

This study demonstrates that surgery followed by adjuvant RT achieves durable local control, excellent patient reported QOL and low levels of treatment regret in patients with high-risk primary salivary gland malignancies. It also identifies areas in which to focus survivorship care, improve current RT planning protocols, and the need for additional biomarkers to refine patient selection for adjuvant treatments.

Acknowledgments

An earlier version of this work was presented at the Royal Australian and New Zealand College of Radiologists ASM in 2021 (poster presentation).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://www.theajo.com/article/view/10.21037/ajo-25-42/rc

Data Sharing Statement: Available at https://www.theajo.com/article/view/10.21037/ajo-25-42/dss

Peer Review File: Available at https://www.theajo.com/article/view/10.21037/ajo-25-42/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://www.theajo.com/article/view/10.21037/ajo-25-42/coif). A.L. reports that she has received three research grants awarded by the Royal Australian and New Zealand College of Radiologists (RANZCR)—all paid to her institution and unrelated to the present manuscript—comprising AUD 25,000 for the 2024 Withers & Peters Grant and AUD 20,000 each for the 2024 and 2025 Radiation Oncology Research Grants. She also holds unpaid committee memberships with the Northern Sydney Local Health District Ethics Committee, the Trans-Tasman Radiation Oncology Group Head and Neck/Skin Working Party, and the Head and Neck Cancer International Group Young Investigators Committee. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Northern Sydney Local Health District Human Research Ethics Committee (No. 2021/ETH12353) and informed consent was taken from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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