Definitive radiotherapy for squamous cell carcinoma of the oral cavity: a single-institution experience

Oral cancer includes cancers of all subsites of the oral cavity (oral tongue, floor of mouth, buccal mucosa, upper lip, lower lip, upper gum, lower gum, palate, and retromolar area) and is the eighth most common cancer worldwide.1, 2 Worldwide incidence of oral cancer in 2018 was four cases per 100,000 people.3 Most related risk factors for oral cancer belong to tobacco and alcohol use.4

Treatment of oral cavity cancer (OCC) includes single modality surgery, radiotherapy (RT) or various combinations of these modalities with or without systemic agents. The selection of treatment is based on disease stage, considerations of disease control, anticipated functional and cosmetic outcomes and expertise. Standard treatment option for OCC is surgery.5 Prim ary RT with or without systemic therapy is not used routinely. There are less prospective trials available which directly compared primary surgery vs. primary RT in oral squamous cell carcinoma (OSCC) specifically.5, 6, 7, 8 In literature 5-year overall survival rate since first diagnosis in patients treated with RT alone was 15%.6,9 To improve local control and overall survival rates intensified treatment with concurrent chemotherapy to RT is necessary instead of RT alone.9, 10 Stenson et al. reported in a retrospective series overall survival rates with 66.9% in locally advanced oral cancer patients (stage III–IV) undergoing concurrent chemoradiotherapy (CCRT).10 In a meta-analysis from Pignon et al. of individual patient data from clinical trials comparing RT vs. CCRT (MACH-NC) in locally advanced head and neck cancers, OCC comprised 21% of cases. Results showed an improvement of survival in OCC with CCRT compared to RT alone.9, 10, 11

To examine the clinical significance and outcome in patients who do not underwent surgery we retrospectively reviewed our experience in treating OCC with primary RT with or without concurrent systemic therapies.

This study was performed following institutional guidelines and the Declaration of Helsinki of 1975 in its most recent version. Ethical approval for the study was given from the local ethics committee at University Hospital Heidelberg (S421-2015).

Clinical, operative, and hospital course records were reviewed. We analyzed data from Nationales Centrum für Tumorerkrankungen (NCT) Cancer Registry in Heidelberg and imported data into our HIRO Research Database.12 All patients underwent systemic workup including cross-sectional imaging with referring providers prior to commencing RT. Afterwards, the patients underwent CT simulation with a standard immobilization 5-point mask. Target volume definition was based on CT and MRI scans with contrast agents, included the primary tumor region as well as nodal involvement according to the International Commission on Radiation Units and Measurements (ICRU) definition.11, 12, 13, 14, 15, 16 Patients underwent regular follow-up, including CT examinations every three months in the first two years after definitive treatment, in year three and four every 6 months and year five and six once a year as well as regularly clinical examinations at the Department of Oral and Maxillofacial Surgery. All follow-up CT-scans were reviewed by an experienced radiologist by the institutions own diagnostics. We excluded all patients with a metastatic disease (M1) at initial diagnosis.

The primary purpose of the present study was to evaluate the outcome and prognostic factors for patients with unresectable OCC who underwent definitive RT. Several studies reported local control rates and 5-year OS for definitive RT in OCC ranging between 27% to 70%9,11,13 and 37–67%14, which goes in line with our results.

In our study 59.2% of patients had advanced-stage disease III–IV with significant OS in stage I–II. Over the last decades the role of concomitant systemic therapy has become clearer. Pignon et al. reported in MACH-NC about better outcome and locoregional control rates when using concurrent chemotherapy and RT with a better absolute benefit of 4.5% at 5 years.9,16 In our study there were 10.2% patients treated with RT alone due to either comorbidities, worse performance status or because of denied surgery. Patients who were treated with systemic treatment had a significantly better 5-year OS compared to those without (43.9% vs. 23.1%) (p = 0.05, HR 2.1, 1.1–4.2) but no significant difference for PFS and LDFS.

While other studies found T-stage, age, grading and gender to be prognostic factors for PFS and LC 14, 15, 16, 17, 18, 19, 20, the present study did not find these to have a significant effect in uni- or multivariate analysis. In our collective treatment with RT alone, cumulative total RT doses < 70 Gy and positive nodal stage were associated with a greater risk of death and worse local control. For LDFS and PFS only positive nodal stage was associated with a significant worse outcome.

Cumulative total doses of less than 70 Gy is standard in patients who underwent postoperative treatment and not suggested as definitive RT treatment concept which goes in line with literature.15

Early and late toxicity from definitive RT to the oral cavity of our collective is comparable to data from other published series.7,9,19,21,22,23 Most common acute RT-related complications (CTCAE grade > 3) in our study were oral mucositis (39.0%) and dysphagia (24.0%). Other significant acute toxicities grade 1/2 included dermatitis (56.2%) and xerostomia (39.7%). Late RT-related complications included xerostomia (64.4%), loss of taste (60.3%), trismus (26.0%), edema (47.3%). These late complications appear similar in other series.7,9,16,19,22 The rate of osteoradionecrosis in the present study was 9.6%, which falls in line with other studies – ranging from 1% to 56%23, 24, 25, 26, 27, 28 in which both conventional and IMRT were utilized. Reuther et al. reported that a total dose above 60 Gy was a significant parameter for osteoradionecrosis (ORN).29 This is similar with our study, all patients with ORN had a cumulative total dose of more than 66 Gy.

The limitations of this study include its retrospective nature, which led to a shortage of necessary data on some single cases. However, we were able to retrieve follow-up data covering a lengthy time period for all patients at a large department with a lot of experience in field of oral tumor diseases.

The power of this study is that we were able to show in a dedicated collective of patients with OCC undergoing definitive RT and an extended follow up of 73 months good control and overall survival rates with moderate toxicity.