Abstract
Purpose
To evaluate the long-term effectiveness of radiotherapy (RT) in the treatment of sinonasal undifferentiated carcinoma (SNUC).
Materials and methods
The medical records of 23 patients treated with definitive or postoperative RT between 1992 and 2010 at the University of Florida were retrospectively reviewed. Fifteen patients (65%) received primary surgery and postoperative RT. Radiation doses ranged from 59.0 to 74.8 Gy (median, 70.2 Gy). The median follow-up time for all patients was 3.0 years (range, 0.9–19.9), and for living patients was 7.7 years (range, 2.5–19.9).
Results
The actuarial 5-year survival outcomes were as follows: progression-free survival, 42%; cause-specific survival, 43%; and overall survival, 32%. Actuarial 5-year disease control rates were as follows: local control (infield or marginal), 74%; local-regional control (excluding leptomeningeal spread), 58%, regional control 78%, freedom from leptomeningeal recurrence, 72%, and distant metastasis-free survival, 73%. Five of the 8 (62.5%) patients treated with definitive RT died with disease, and 6 of the 15 patients (40%) treated with primary surgery and postoperative RT died with disease. Three patients (13%) experienced severe complications including unilateral eye removal, osteoradionecrosis of the maxilla requiring hyperbaric oxygen and surgery, and brain necrosis. One patient died due to an infected bone graft and brain abscess.
Conclusions
A multimodal approach is best when treating SNUC patients. The prognosis for patients treated with definitive RT ± chemotherapy is less promising than for those who receive surgery and postoperative RT ± chemotherapy. Severe complications occur in about 17% of patients due to the high dose of RT alone or combined with surgery required for acceptable disease control.
1
Introduction
Carcinomas of the nasal cavity and paranasal sinuses are rare, making up less than 1% of all cancers . Sinonasal undifferentiated carcinoma (SNUC) was first described less than 30 years ago as an ectodermally derived tumor arising from Schneiderian epithelium in the nasal cavity or paranasal sinuses . It is clinically distinct from other neuroendocrine tumors in the nasal cavity and sinuses, such as esthesioneuroblastoma . SNUC is histologically heterogeneous, with its diagnosis requiring microscopic and immunohistological evaluation . It is also very uncommon, with less than 200 cases reported in the literature . The disease has a high propensity to recur, with reported local-regional recurrence rates ranging from 50% to 63% . In the largest metaanalysis review to date, Reiersen et al. reported on 167 cases identified and found the overall disease-free survival rate to be 26.3%.
Patients typically present with nondescript symptoms, including epitaxis, facial swelling or pain, periorbital swelling, diplopia, nasal obstruction, proptosis, cranial nerve deficits, headaches, or a combination of these symptoms . Symptoms tend to develop quickly, typically between weeks and months before the diagnosis of SNUC is entertained . At the time of diagnosis, the lesion is usually advanced , with extension beyond the nasal cavity and paranasal sinuses with involvement of the orbit(s) and/or brain . Some case reviews have observed that 84% to 92% of patients present with T4 disease as defined by the American Joint Committee on Cancer (AJCC) . SNUC is most commonly diagnosed in males, with a 2:1 to 3:1 male to female preponderance . The age range at diagnosis has been reported to be from 12 to 84 years , with the mean age in the fifth decade .
SNUC is histologically identified by the overexpression of cytokeratin markers . Various studies have attempted to define the etiology of SNUC. Cigarette smoking has been implicated by Frierson et al. and Jeng et al. . There is controversy over whether the Epstein-Barr Virus plays a role in the development of SNUC . Wadsworth et al. reported over-expression of p16 without the human papillomavirus (HPV) genome in some SNUC cases . SNUC may arise as a second malignancy following radiotherapy (RT) for nasopharyngeal carcinoma , or it may present after retinoblastoma . None of these correlations are clearly defined.
Because of the rarity of SNUC, its advanced presentation at diagnosis, and its aggressive nature, retrospective reviews continue to be of utmost importance in evaluating and improving treatment protocols. Current treatment typically includes a multimodal approach including RT alone or combined with surgery, with or without adjuvant chemotherapy . The role of chemotherapy is ill-defined largely due to the rarity of SNUC . Local control relies on high RT doses; thus, the use of proton therapy to produce a more conformal dose distribution may be beneficial in minimizing side effects when available.
2
Methods
Between 1992 and 2010, 23 patients were treated with RT for SNUC at the University of Florida Department of Radiation Oncology in Gainesville, Florida, and the University of Florida Proton Therapy Institute in Jacksonville, Florida. Radiation oncology medical records were retrospectively reviewed under an institutional review board-approved protocol. Patients included in this study were treated with curative intent, had no distant metastases at presentation, and had the potential for 2-year minimum follow-up. Patients who presented with disease beyond the primary tumor site and cervical lymph nodes or were treated palliatively were excluded. Patient and treatment characteristics are summarized in Table 1 . The median age was 56.5 years (range, 23–83 years). Median follow-up for all patients was 3.0 years (range, 0.9 to 19.9 years), and for survivors was 7.7 years (range, 5.5 to 19.9 years). No patient was lost to follow-up.
| Parameter | No. patients (%) |
|---|---|
| Male | 14 (61%) |
| White | 19 (83%) |
| Radiotherapy | |
| Alone | 8 (35%) |
| Preoperative | 2 (9%) |
| Postoperative | 13 (56%) |
| Radiotherapy modality | |
| Photons | 18 (78%) |
| Protons + photons | 5 (22%) |
| Treated twice daily | 20 (87%) |
| Chemotherapy ⁎ | |
| Induction | 4 (17%) |
| Concurrent | 14 (61%) |
| Maintenance | 6 (26%) |
| None | 7 (30%) |
| Overall American Joint Committee on Cancer Stage | |
| III | 1 (4%) |
| IVa | 7 (30%) |
| IVb | 15 (65%) |
⁎ Some patients received more than one chemotherapy regimen.
Five of the 23 patients (22%) received proton therapy as some portion of their treatment, and 18 (78%) patients received conventional photon therapy only. Due to the high likelihood of cervical lymph node metastases, 13 (72%) out of 18 patients with a clinically negative neck (cNo) received elective neck irradiation (ENI). No patients underwent neck dissection as part of their initial management. All patients with cervical lymph node involvement at presentation received chemotherapy.
Ten patients (43%) received trimodality treatment consisting of surgery, RT, and chemotherapy; 5 patients were treated with surgery and postoperative RT; 6 patients were treated with chemoradiation; and 2 patients were treated with definitive RT alone. The median RT dose to the primary tumor was 7020 cGy (range, 5940–7480). The median number of fractions was 54 (range, 39–68). The median fraction size was 120 cGy (range, 110–200 cGy). When the neck nodes were irradiated, the doses ranged from 5000 cGy to 7000 cGy based on clinical presentation. All patients had a continuous course of RT, with no unintended or prescribed breaks. All patients received their prescribed RT dose, except for 1 patient who terminated treatment at 6040 cGy due to severe depression. Twenty patients (87%) received twice-daily fractionation and 3 patients were irradiated once-daily.
Sixteen patients (70%) received adjuvant chemotherapy during their initial treatment, including all 5 patients with clinically positive neck nodes. Chemotherapy regimens varied greatly among treatment eras. Many patients received more than one chemotherapy regimen. Weekly concurrent cisplatin was the most commonly employed regimen, used in 10 patients (43%). Six patients received maintenance chemotherapy, 4 received induction chemotherapy, and 14 received concomitant chemotherapy with RT.
2.1
Statistical analysis
Statistical analyses were performed using SAS software (SAS Institute, Cary, NC) and the Kaplan-Meier product-limit method to evaluate rates of local control, regional control, local-regional control, distant metastasis-free survival, cause-specific survival, and overall survival.
2
Methods
Between 1992 and 2010, 23 patients were treated with RT for SNUC at the University of Florida Department of Radiation Oncology in Gainesville, Florida, and the University of Florida Proton Therapy Institute in Jacksonville, Florida. Radiation oncology medical records were retrospectively reviewed under an institutional review board-approved protocol. Patients included in this study were treated with curative intent, had no distant metastases at presentation, and had the potential for 2-year minimum follow-up. Patients who presented with disease beyond the primary tumor site and cervical lymph nodes or were treated palliatively were excluded. Patient and treatment characteristics are summarized in Table 1 . The median age was 56.5 years (range, 23–83 years). Median follow-up for all patients was 3.0 years (range, 0.9 to 19.9 years), and for survivors was 7.7 years (range, 5.5 to 19.9 years). No patient was lost to follow-up.
| Parameter | No. patients (%) |
|---|---|
| Male | 14 (61%) |
| White | 19 (83%) |
| Radiotherapy | |
| Alone | 8 (35%) |
| Preoperative | 2 (9%) |
| Postoperative | 13 (56%) |
| Radiotherapy modality | |
| Photons | 18 (78%) |
| Protons + photons | 5 (22%) |
| Treated twice daily | 20 (87%) |
| Chemotherapy ⁎ | |
| Induction | 4 (17%) |
| Concurrent | 14 (61%) |
| Maintenance | 6 (26%) |
| None | 7 (30%) |
| Overall American Joint Committee on Cancer Stage | |
| III | 1 (4%) |
| IVa | 7 (30%) |
| IVb | 15 (65%) |
⁎ Some patients received more than one chemotherapy regimen.
Five of the 23 patients (22%) received proton therapy as some portion of their treatment, and 18 (78%) patients received conventional photon therapy only. Due to the high likelihood of cervical lymph node metastases, 13 (72%) out of 18 patients with a clinically negative neck (cNo) received elective neck irradiation (ENI). No patients underwent neck dissection as part of their initial management. All patients with cervical lymph node involvement at presentation received chemotherapy.
Ten patients (43%) received trimodality treatment consisting of surgery, RT, and chemotherapy; 5 patients were treated with surgery and postoperative RT; 6 patients were treated with chemoradiation; and 2 patients were treated with definitive RT alone. The median RT dose to the primary tumor was 7020 cGy (range, 5940–7480). The median number of fractions was 54 (range, 39–68). The median fraction size was 120 cGy (range, 110–200 cGy). When the neck nodes were irradiated, the doses ranged from 5000 cGy to 7000 cGy based on clinical presentation. All patients had a continuous course of RT, with no unintended or prescribed breaks. All patients received their prescribed RT dose, except for 1 patient who terminated treatment at 6040 cGy due to severe depression. Twenty patients (87%) received twice-daily fractionation and 3 patients were irradiated once-daily.
Sixteen patients (70%) received adjuvant chemotherapy during their initial treatment, including all 5 patients with clinically positive neck nodes. Chemotherapy regimens varied greatly among treatment eras. Many patients received more than one chemotherapy regimen. Weekly concurrent cisplatin was the most commonly employed regimen, used in 10 patients (43%). Six patients received maintenance chemotherapy, 4 received induction chemotherapy, and 14 received concomitant chemotherapy with RT.
2.1
Statistical analysis
Statistical analyses were performed using SAS software (SAS Institute, Cary, NC) and the Kaplan-Meier product-limit method to evaluate rates of local control, regional control, local-regional control, distant metastasis-free survival, cause-specific survival, and overall survival.
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