Combined-modality treatment improved outcome in sinonasal undifferentiated carcinoma: single-institutional experience of 21 patients and review of the literature

Sinonasal undifferentiated carcinoma (SNUC) is a rare type of malignancy which was first described by Frierson et al. [1]. SNUCs are usually presented at locally advanced stage involving the nasal cavity and paranasal sinuses with a propensity to extend into the (peri) orbital tissues and the central nervous system. In most series, 10–30 % of patients have a node-positive disease at diagnosis [2‐8]. The original reports on SNUC by Frierson et al. [1] painted a grim picture because of the aggressive nature of the disease and the limited knowledge about treatment. Early reports on radiation or surgical resection alone have generally yielded poor results [1, 9]. By multimodality therapy many patients achieve complete remission and prolonged survival, with a significant number potentially cured. Although different combination of surgery, chemotherapy and radiotherapy are nowadays used [2‐8], there is still no consensus about which modalities to use and the best sequence.

In the current study we report on a long-term single-institutional experience of the treatment of SNUC by combined modality. We also performed an exact logistic regression analysis to identify the parameters predictive of local failure and reviewed the literature.

Between September 1996 and September 2010, 21 consecutive patients with SNUC were treated with curative intent at our institution by any combination of surgery, radiotherapy, and chemotherapy (Table 1). Patients with recurrent or metastatic disease at presentation were excluded from this analysis.

Pre-treatment evaluation consisted of complete history and physical examination. All patients had chest X-ray, ultrasonography with fine-needle aspiration, and head and neck MRI or CT scan. All patients were presented in our weekly multidisciplinary head and neck conference. Based on the joint recommendations of that meeting, patients were selected for treatment with surgery followed by (chemo) radiotherapy, induction chemotherapy followed by surgery and radiotherapy, or definitive (chemo) radiotherapy. The goal of surgery is complete resection of the tumor with negative margins, with as low morbidity as possible. The type and extension of the surgery is dictated by the extent of the disease, and cosmetic and functional considerations. The surgical techniques ranged from (sub) total maxillectomy and/or ethmoidectomy to craniofacial resection. Endoscopes were used when reduction of morbidity or improved (angled) visualization could be achieved. Orbital exenteration is not an elective procedure but mandatory in patients with tumor invasion beyond the periorbital tissue. Criteria for unresectability were extensive intracranial or intradural spread, invasion of the optic pathway, invasion of cavernous sinus, and encasement of the carotid artery. These patients are offered either induction chemotherapy followed by surgery and postoperative radiotherapy (PORT) or definitive (chemo) radiation.

The patient’s characteristics are shown in Table 1. The tumor was occupying at least two paranasal sinuses. However, the tumor epicenter was in the ethmoid sinus in 76 %, and the maxillary sinus in 24 % of patients.

Since SNUC was first introduced in 1986, only seven studies reporting on the outcome of ≥10 patients have been published from different institutions in the USA and Australia. Gallo et al. [10] published in 1993 an immunohistochemical study on 13 patients with SNUC and reported briefly on the outcome of these patients treated at the University of Florence between 1970 and 1993, mainly with radiotherapy. Only one patient was treated surgically and four with non-platinum-based chemotherapy. The present study is one of the largest and is the first European study to date reporting on outcome and toxicity of patients treated at the Erasmus MC-Daniel den Hoed Cancer Center in the era of modern surgical and radiation techniques and platinum-based chemotherapy regimens.

Table 3 illustrates patients’ demographics and outcomes of eight studies where patients with SNUC were treated with combined-modality treatment. Our review included only studies where at least ten patients were treated because smaller series cannot provide the means to draw solid conclusions. Comparison between these studies is complicated by major differences with respect to patients’ demographics, the used staging system, end points and therapeutic strategies. Patients’ characteristics and outcomes of the current study have more similarities with the reported data from the University of Florida [6] and the M.D. Anderson Cancer Center [5]. Small differences were observed, for instance in the length of the follow-up time, type of chemotherapy used, and the percentages of patients having T4 tumor, who received chemotherapy and were irradiated by means of IMRT. As shown in Table 3, the outcomes in the current study compares favorably with those reported in the other five studies. Possible explanations are [1] that higher radiation dose and highly conformal radiation techniques were mostly applied in our study. Dose–response relationship might exist in case of SNUC [11]. In the present study, patients who received >60 Gy showed better LC rates, compared to a dose of ≤60 Gy (75 vs. 44 %), albeit statistically not significant. The same is true for patients treated with IMRT, compared to 2D or 3DCRT (77 vs. 38 %). In patients treated with 2D or 3DCRT, underdosage of the target volume should often be tolerated to prevent late toxicity. Dirix et al. [12] showed that IMRT, compared to 3DCRT, improved DFS (p = 0.02) and LC (p = 0.06) and decreased acute and late toxicity [2]. Relatively more T4 tumors and (when reported) more tumors with orbital and/or intracranial invasion were treated in other studies [3]. In our study, more patients received induction chemotherapy with down-staging and subsequently resection and PORT. In most of the reviewed studies, the benefit of implementation of aggressive surgery as part of the treatment modality was clearly demonstrated [2‐8]. In our study, the patients who underwent surgical resection had significantly better LC than those in whom it was omitted (85 vs. 25 %, p = 0.005). Adding induction chemotherapy to achieve down-staging before surgery should be considered, when resectability upfront is questionable. Carful selection of patients who are more likely to benefit from an attempt at such an organ preservation approach is of paramount importance. The benefit of induction chemotherapy to reduce the incidence of DM was suggested by Rischin et al. [8], since none of the seven patients with SNUC treated with induction followed by concurrent chemotherapy developed DM (follow-up 8-62 months), whereas both patients treated with surgery and PORT developed DM at 8 and 20 months, respectively.

In the reviewed literature, the incidence of node-positive disease at presentation varied from 10 to 30 % (mean 13 %). In our study, 42 % of high-risk node-negative patients received ENI. None of them developed RF. Two RFs were reported in patients who did not receive ENI, resulting in regional control rates of 100 and 82 % for patients who did or did not receive ENI, respectively. Our results are comparable with those reported by the University of Florida (100 and 66 %) [6] and the University of California (94 and 75 %) [2]. However, Rischin et al. [8] reported a 50 % nodal recurrence rate. In that study, ENI was, to our knowledge, not applied. The question whether ENI should be given to all patients with SNUC is difficult to answer because in most of these studies ENI is recommended on a case-by-case basis. However, the results of the small studies (where ENI was applied) are encouraging with respect to regional control. Therefore, we would advocate ENI in patients with locally advanced SNUC. According to our local treatment protocol, ENI was advocated in T4 high-risk node-negative patients with involvement of the skin of the cheek, infratemporal fossa, or pterygoid or cribriform plates.

The good LC seen in our study was associated with a high rate of grade ≥2 late toxicity (30 %). However, the incidence of serious late toxicity was reduced over time with the implementation of IMRT compared to 2D and 3DCRT, albeit statistically not significant (14 vs. 57 %; respectively p = 0.2). Furthermore, the incidence of permanent visual impairment was significantly reduced in patients treated by IMRT compared to 2D and 3DCRT with an ultimate organ preservation rate of 86 and 14 %, respectively (p = 0.006). The improved therapeutic ratio achieved by the use of IMRT would allow us to escalate the dose of radiotherapy locally to further improve LC rates, since local recurrence is the most significant problem in SNUC.

In the current study, combined-modality treatment with three, or at least two, modalities for patients with SNUC resulted in good LC, but with high overall rate of late toxicity. However, the incidence of late toxicity and visual impairment were decreased over time by the introduction of IMRT. The reduction in late toxicity was also associated with slight improvement in LC rates, albeit statistically nonsignificant. The improved therapeutic ratio achieved by IMRT would allow dose escalation of radiotherapy and subsequently improve LC as the most significant problem in patients with SNUC. Therefore, highly conformal radiotherapy techniques as IMRT should be the standard of care in patients with SNUC.

Although all of the reported series in our review are small, some important conclusions can be drawn from the review of the literature. First, gross tumor resection should be considered in all patients, as better outcome has been noted with the implementation of aggressive surgery as part of the treatment modality. In case of doubt about the feasibility of primary surgical resection, induction chemotherapy would be offered to patients with good performance and where an attempt of organ preservation is reasonable. Second, a treatment schedule comprising three, or at least two, treatment modalities should be offered to all patients. The sequence of these modalities would be dictated by disease extent, performance state, and the available treatment resources. Furthermore, ENI would be advocated in all patients with locally advanced disease, as the results of the small studies where ENI was applied are encouraging with respect to regional disease control.