High-grade salivary gland cancer: is surgery followed by radiotherapy an adequate treatment to reach tumor control? Results from a tertiary referral centre focussing on incidence and management of distant metastases

The basis for data collection was provided by the clinical reports from 69 patients with previously untreated high-grade salivary gland cancer who had previously undergone surgery followed by photon radio(chemo)therapy from December 1999 to May 2020 at the Department of Radiation Oncology in Erlangen.

We excluded patients with low- or intermediate-grade SGC, squamous cell carcinomas and distant metastases at the time of first diagnosis.

All tumors were classified according to the TNM classification system of 2017.

Detailed information about patient characteristics is shown in Table 1.

All patients were treated with surgery followed by photon radiotherapy or photon radio-chemotherapy in curative intention.

Local resection of the primary tumor was performed in all patients, mostly combined with neck dissection in 65 patients (94.2%). 56 patients (81.2%) underwent unilateral neck dissection and 9 patients (13.0%) underwent bilateral neck dissection. Bilateral neck dissection was performed if there was evidence for contralateral neck lymph node metastasis on ultrasound or if the primary tumor was located at or crossing the midline (e.g. in cases of primary tumors arising from submandibular or minor salivary glands). Only four patients (5.8%) had surgery without neck dissection.

We defined the date of biopsy or (first) surgery (in case there was no preoperative biopsy) to the primary tumor as the date of first diagnosis.

The indications for postoperative radiation in SGC are based on retrospective trials [3, 4, 14]. In detail, these indications include locally advanced tumor stage (classified as pT3/pT4), bone invasion, peri-nodal or peri-neural spread, close or positive resection margins, high-grade histology and all adenoid cystic carcinomas except for tumors classified as pT1. As all of our patients had high-grade carcinomas, every patient underwent adjuvant radiotherapy.

The median radiotherapy dose was 64 Gy (range 45.0–74.0 Gy). Radiotherapy usually was applied up to 64 Gy in high-risk region (primary tumor region, peri-nodal spread) and in case of suspected macroscopic tumor after resection a dose of a minimum of 70 Gy was delivered. Single fraction dose was 2 Gy. In one patient, a hypo-fractionated accelerated radiotherapy up to 45 Gy with a single dose of 3 Gy (EQD 2 value (α/ß = 10): 48.75 Gy) was performed because of advanced age and reduced ECOG performance status of the patient.

3D-conformal radiotherapy was performed in 37 patients (53.6%), whereas 34 patients (46.4%) underwent volumetric-modulated arc therapy or intensity-modulated radiotherapy. The clinical target volume always included the region of the primary tumor and the nerve tracts up to the base of the skull. If there were positive ipsilateral neck nodes, this region was also included in the clinical target volume (39 patients, 56.5%). In case of multiple positive ipsilateral neck, nodes with extracapsular spread or primary tumor at/crossing the midline, bilateral neck nodes were additionally included (19 patients, 27.5%). Patient positioning was checked daily with portal imaging or cone-beam-ct.

Concomitant platinum-based chemotherapy was usually recommended in locally advanced situations (pT3/pT4), peri-nodal spread, ≥ three lymph node metastases or positive/close resection margins. Patients with any of these tumor characteristics would have been treated with chemotherapy unless they either refused or had comorbidities that did not allow chemotherapy. 52 of our patients (75.4%) received combined postoperative radio-chemotherapy.

After radio(chemo)therapy, we planned follow-up visits for every patient at regular intervals at the Department of Otorhinolaryngology, Head and Neck Surgery as well as at our own Department of Radiation Oncology in Erlangen. Usually, follow-up visits are scheduled every 3 months for the first 2 years after treatment, then every 6 months from year 3 to 5 after treatment and as yearly follow-up visits afterwards. During follow-up visits, patients underwent an examination of the ear, nose and throat and an ultrasound scan of the parotid region and the neck (Levels I–V). During the first 5 years after treatment, patients had a CT of their chest (usually including the upper abdomen) every 6 months. If patients developed symptoms pointing towards distant metastases, they underwent additional investigations according to their symptoms (mostly additional diagnostic imaging and, if appropriate, tissue sampling).

In case of occurrence of distant metastases, local therapeutic options were evaluated in every patient.

The statistical analysis was carried out using IBM SPSS version 26 (IBM Corporation, Armonk, NY, USA).

Overall survival (OS), disease-free survival (DFS), local-recurrence-free survival (LRFS) and distant-metastases-free survival (DMFS) were calculated using the Kaplan–Meier method from the date of first diagnosis till the date of a patient’s death/disease recurrence/loco-regional recurrence/occurrence of distant metastases or the last available follow-up visit. To correlate patient-related, tumor-related and treatment-related factors with OS, DFS, LRFS and DMFS in a univariate analysis, the log-rank test was used. Considering the limited number of included patients, the following dichotome risk-classification was used: gender, age (< 70 vs. ≥ 70 years), tobacco consumption (never vs. yes/earlier), hypertension (no vs. yes), primary tumor site (parotid vs. non-parotid), histologic subtype (adenoid cystic vs. non-adenoid cystic), T classification (T1/2 vs. T3/4), primary tumor size (≤ 3 cm vs. > 3 cm), N classification (N0 vs. N1/2), number of metastatic lymph nodes (≤ 1 vs. > 1), perinodal spread, lympho-vascular and vascular invasion, perineural spread, neck dissection (no vs. yes), number of dissected lymph nodes (< 10 vs. ≥ 10 and ≤ 27 vs. > 27), lymph node density (≤ 4% vs. > 4%), resection margins (R0 vs. R1/X), second primary tumor resection, planning target volume (primary tumor region vs. primary tumor region and regional lymph node drainage), radiation dose (< 64 Gy vs. ≥ 64 Gy), radiation technique (3D vs. IMRT/VMAT) and postoperative treatment (radiation vs. radio-chemotherapy).

Only variables with a ρ value of ≤ 0.05 were included in multivariate analysis using Cox regression. Two-sided ρ values of < 0.05 were considered statistically significant.

The estimated cumulative OS was 91.3% after one year, 76.8% after two and 65.2% after five years.

The estimated cumulative DFS was as follows: 76.8% after one year, 56.5% after two years and 47.8% after five years (see Fig. 1a). On univariate analysis, a significant association was shown between DFS and the histologic subtype (ρ = 0.005; see Fig. 2a) as well as the T classification (ρ = 0.009; see Fig. 2b). Both of these tumor-related factors were also significant on multivariate analysis using Cox regression (see Table S2 and S3 in the supplementary information). A higher T classification and an adenoid cystic histologic subtype were associated with a significantly lower DFS.

The estimated cumulative LRFS was 94.2% after one year and 92.8% after two and five years (see Fig. 1b).

The estimated cumulative DMFS was 79.7%, 65.2% and 56.5% after one, two and five years (see Fig. 1c).

On univariate analysis, a significantly lower DMFS was associated with a higher T classification (ρ = 0.009) and an adenoid cystic histology (ρ = 0.004). See also Fig. 3a, b for reference. In multivariate analysis, both factors remained significant (see Table S2 and S3 in the supplementary information).

30 (43.5%) of our 69 included patients developed distant metastases during their follow-up. The median time from the date of first diagnosis to the time of DM diagnosis was 13.5 months (range 2–43). The median time of follow-up after the diagnosis of distant metastases was 12 months (range 0–80). For detailed information, see Fig. 4.

The most common anatomical site for the appearance of distant metastases was the lung (73.3%), followed by bone (20%) and the brain and non-regional lymph nodes each accounting for 10% of the total. Other localizations included the liver, the abdominal wall and the pleura. Seven patients (23.3%) developed distant metastases at multiple anatomical sites (defined as two or more involved organ systems), whereas 23 patients (76.7%) developed their distant metastases at one single anatomical site.

In seven out of 30 patients (23.3%), local ablative therapy to distant metastasis was possible. These patients underwent local ablative therapy for oligo-metastatic disease only without systemic therapy. In patients with local ablative therapeutic options, six patients underwent surgery (five resection of lung metastases, one resection of a peritoneal metastases) and one patient underwent heavy ion radiotherapy of a sella metastases. Six of these seven patients (85.7%) showed disease progression after a median time of 10 months (range 2–23) following local therapy to distant metastases. Disease progression after local therapy was disseminated in multiple organs in 3 patients, in the same organ with further local treatment options in 2 patients and in-Radiation-Field in one patient.

Among patients with no local ablative therapeutic options of distant metastases patients underwent the following treatments: 15 patients palliative chemotherapy, two patients palliative chemotherapy and radiotherapy of brain metastases (used agents were Cisplatin/Carboplatin combined with Docetaxel and Trastuzumab), two palliative radiotherapy of bone metastases, two best supportive care and two were lost to follow-up after diagnosis of DM. Chemotherapy was mostly platinum-based (eleven out of 15 patients, 73.3%) using combinations with taxanes (five patients, 33.3%) and/or monoclonal antibodies (two patients, 13.3%). The exactly used combinations were as followed: Cisplatin and Docetaxel (two patients, 13.3%), Cisplatin and Paclitaxel (one patient, 6.7%), Cisplatin and Cetuximab (6.7%), Cisplatin and Vinorelbine (6.7%), Carboplatin mono (13.3%), Carboplatin and Etoposid (6.7%), Carboplatin and Paclitaxel (6.7%), Carboplatin and Pemetrexed (6.7%), Carboplatin combined with Docetaxel and Trastuzumab (6.7%) and Vinorelbine mono (13.3%). In two cases (13.3%), the administered chemotherapy was unknown.

Another sixteen patients (53.3%) showed disease progression after diagnosis and treatment of distant metastasis. The median time from first diagnosis of distant metastases to diagnosis of renewed disease progression was 9 months (range 2–23). The median time of follow-up after progressive disease was 7 months (range 2–51). Out of these sixteen patients, the treatment of 10 patients with furthermore progressive disease was reproducible. 50% received a palliative chemotherapy. The administered combinations were as follows: Cisplatin and Vinorelbine, Trastuzumab and Lapatinib, Trastuzumab and Paclitaxel and Carboplatin mono. In one case, the used drugs were unknown. The other patients received chemotherapy (Carboplatin and Paclitaxel) combined with whole-brain radiotherapy (WBRT), palliative radiotherapy of bone metastases and palliative WBRT (one patient each, 10%). In case of oligo-progressive disease, one patient underwent surgery and one patient surgery and radiotherapy.

Comparing patients who underwent local ablative therapy after first diagnosis of distant metastases to those who were not eligible for local ablative therapy, there is no significant survival benefit (p-value: 0.206). See Fig. 5.