Salivary gland cancers comprise 3-6% of all head and neck malignancies [1, 2]. Although they are commonly grouped together, these cancers are histologically diverse with varying natural histories. Surgery is the established initial treatment for salivary gland malignancies. Adjuvant radiotherapy in patients with high-grade tumors or high- risk features, improves locoregional control in select patients undergoing surgical resection compared to surgical resection alone [1, 3–9]. Chemotherapy is not routinely used outside of the palliative or recurrent disease setting for salivary gland tumors. The most commonly used regimen is cyclophosphamide, doxorubicin, and cisplatin (CAP) with response rates of 27-83%, and few of long duration [10–13]. In small, single-institution series, survival rates of 60-72% at 5 years have been reported in patients receiving chemoradiotherapy for salivary malignancies [14–18]. Previous studies from our institution have demonstrated the combination of 5-FU, hydroxyurea, and radiotherapy (FHX) an effective regimen for head and neck cancer (particularly those of squamous histology)[19]. Based on these favorable results we sought to improve locoregional control in patients with advanced and high- risk salivary gland malignancies, utilizing FHX based regimens. The present study was undertaken to report the outcomes of patients treated adjuvantly with concurrent FHX based chemoradiotherapy for salivary glands carcinomas.

Concurrent chemotherapy and radiotherapy has been shown to improve locoregional control and survival for many tumor types [21]. For head and neck cancers, primarily of squamous origin, concurrent chemoradiotherapy has been shown to result in an absolute 10% 5 year overall survival benefit [22]. Concurrent chemoradiotherapy has been established as the standard of care for many patients either definitively or adjuvantly with locally advanced head and neck cancer.

Despite the proven benefit of concomitant chemoradiotherapy for squamous and poorly differentiated head and neck cancers, the impact for locoregionally advanced and salivary gland malignancies is much less clear. While several case reports of sequential or concurrent chemoradiotherapy for locoregionally advanced salivary tumors exist, there is a paucity of data describing chemoradiotherapy in large series. Airoldi et al described 6 patients with inoperable salivary malignancy treated with radiotherapy to 66 Gy with concurrent cisplatin followed by 3 cycles of cisplatin and etoposide. Three patients had a complete response to therapy and median survival was 18 months [23]. In the largest previously reported series we are aware of, seventeen patients with Stage III or IV salivary malignancies were treated with definitive chemoradiotherapy consisting of daily radiotherapy to ~66 Gy and 2 monthly cycles of cyclophosphamide, cisplatin, and pirarubicin [17]. Nine patients had surgery for residual disease and 4 (24%) patients had pathologic complete response with chemoradiotherapy alone. The current analysis describes the largest series of patients treated with concurrent chemoradiotherapy for advanced, high- risk salivary gland malignancies. Our results compare favorably with the smaller previously described series of chemoradiotherapy, as the median survival for patients was 42 months with one local failure noted.

The locoregional control rate in this report (96%) compares favorably to large series of patients treated with definitive surgery and radiotherapy or radiotherapy alone. Published reports of surgery with or without adjuvant radiotherapy for salivary cancer demonstrate generally mediocre locoregional control rates, especially for Stage IV disease. The University of Florida reported locoregional control rates of 66% and 81%, for T4 tumors treated with surgery and surgery plus radiotherapy, respectively. Chen et al has reported on 45 patients with node-negative salivary malignancies treated with definitive radiotherapy to ~66 Gy. The ultimate local control rate was 57% and significantly worse for T3-4 tumors [24]. Laramore has summarized the published literature of definitive photon/electron radiotherapy for salivary gland malignancy and found a local control rate of only 30%. This is in contrast to the rate found for definitive fast neutron therapy, with a local control rate of 67% [25]. In a matched-pair analysis of surgery versus surgery plus radiotherapy, Armstrong et al reported that local control for stage III and IV disease was only 51.3% for combined treatment versus 16.8% for surgery alone [1]. In a series of over 500 salivary malignancies, postoperative radiotherapy improved local control over surgery alone for T3-4 tumors (84% vs. 18%), in close (95% vs. 55%) and incomplete resection (82% vs. 44%), and presence of perineural invasion (88% vs. 60%) [9]. Data from the Dutch Head and Neck Oncology Cooperative Group demonstrated that postoperative radiotherapy significantly improved regional control in the node positive neck, 86% vs. 62% for surgery alone. There were zero regional failures in the 18 node positive patients treated with chemoradiotherapy in this series. Current NCCN recommendations for adjuvant radiotherapy include intermediate and high grade, adenoid cystic histology, close or positive margins, perineural invasion, lymph node metastases and lymphovascular invasion.

Additionally, our results are promising when compared to patients treated with neutron therapy. In the University of Washington series of 279 patients, the 6-year locoregional control was 59% and late Grade 3-4 toxicity was 10% [26]. In subset analysis, stage III-IV (locoregional control 49%) and definitive radiotherapy (locoregional control 40%) were associated with worse outcomes. While the Medical Research Council (MRC) trial demonstrated improved locoregional control for patients with unresectable salivary gland malignancies treated with fast neutron therapy, severe and life-threatening complication rates were 69% and 15%, respectively after neutron radiotherapy versus 33% and 8% after photon radiotherapy [2]. The toxicity of neutron therapy and limited accessibility, only 3 operating neutron therapy centers in the United States, make photon therapy a more reasonable and widely available treatment. The acute and chronic toxicity of our regimen was encouraging with limited acute mucositis and hematologic toxicity. Chronic complications were also limited given the advanced stage of the treated patients. No fatalities in this series were thought to be treatment-related.

The dominant pattern of progression seen in our series was distant metastases, a relationship that has been noted in previous studies of FHX-based chemoradiotherapy [19]. This pattern of progression is consistent with the natural history of salivary gland malignancy. One hypothesis is that reducing distant progression requires improved systemic therapy. There are a number of Phase I and II trials that have investigated systemic therapy with mixed results [26]. Molecular targeted agents, including lapatinib and trastuzumab, have been used as monotherapy in the metastatic setting with generally cytostatic results [27–29]. Future trials of chemoradiotherapy plus molecular targeted therapy may be warranted for high-risk disease in the adjuvant setting and is warranted in the setting of locally advanced disease.

In patients with high- risk salivary gland malignancies treated with adjuvant chemoradiotherapy, locoregional control rates were favorable compared to other published reports in the literature. In particular, locoregional control was high even in node positive patients (93%) compared to 86% as reported in post-operative patients from The Dutch Head and Neck Oncology Cooperative Group [9]. Our data are limited by the retrospective nature of the study, but the same is true of almost all other published salivary gland malignancy reports. Unlike squamous cell carcinomas of the head and neck, where chemoradiotherapy has emerged as the dominant treatment paradigm, little evidence supports its use for salivary gland malignancy. However, our locoregional control rates suggest that chemotherapy acts as a radiosensitizing agent. The rare and heterogenous nature of salivary gland cancer limits the feasibility of prospective clinical trials with adequate power. Currently, the RTOG has initiated a study to investigate the role of adjuvant cisplatin based chemoradiotherapy for high-risk salivary gland malignancies.

In conclusion surgical resection followed by adjuvant chemoradiotherapy was associated with promising outcomes in this series. Ongoing investigations will be needed to verify the role of adjuvant chemoradiotherapy. Integration of active systemic agents are needed to reduce distant metastatic progression.

The authors declare that they have no competing interests.