Key points
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In most cases of advanced sinonasal and ventral skull base cancer, a multimodal treatment approach provides the best chance for improved outcomes.
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Depending on the tumor type and extent of disease, systemic chemotherapy has been shown to play an important role in neoadjuvant, concomitant, and adjuvant settings.
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Prospective, high-quality studies are needed to understand ideal chemotherapeutic regimens and their role and sequential timing in sinonasal and ventral skull base cancer.
Introduction
Sinonasal cancer (SNC) represents less than 3% of all head and neck cancers with an overall incidence of less than 0.001%. Although more than half of tumors originate in the nasal cavity, tumors may also frequently originate in the maxillary or ethmoid sinuses. Due to the wide array of tumor histology and molecular profiles, as well as close proximity of vital structures, such as the brain and orbit, treatment planning can be complex. A multimodality therapeutic approach with complete surgical resection with postoperative radiotherapy remains standard of care. The advancement of endoscopic approaches as well as intensity-modulated radiation and proton therapy has improved survival and outcomes.
Despite these advances, the overall prognosis of patients with advanced SNC remains poor, with a reported 5-year survival rate of 30%. Following the treatment paradigm of other head and neck cancers, physicians have investigated the hypothesis that the inclusion of chemotherapy in the treatment of SNC may improve locoregional control rates and reduce the frequency of metastasis, ultimately resulting in improved survival. Classically, the role of chemotherapy in SNC has been limited to palliative treatment of locally advanced or metastatic SNC. This role has expanded, however, to neoadjuvant, concurrent, or adjuvant settings in appropriate patient cohorts. This article explores the role of systemic therapy in the management of SNC.
Introduction
Sinonasal cancer (SNC) represents less than 3% of all head and neck cancers with an overall incidence of less than 0.001%. Although more than half of tumors originate in the nasal cavity, tumors may also frequently originate in the maxillary or ethmoid sinuses. Due to the wide array of tumor histology and molecular profiles, as well as close proximity of vital structures, such as the brain and orbit, treatment planning can be complex. A multimodality therapeutic approach with complete surgical resection with postoperative radiotherapy remains standard of care. The advancement of endoscopic approaches as well as intensity-modulated radiation and proton therapy has improved survival and outcomes.
Despite these advances, the overall prognosis of patients with advanced SNC remains poor, with a reported 5-year survival rate of 30%. Following the treatment paradigm of other head and neck cancers, physicians have investigated the hypothesis that the inclusion of chemotherapy in the treatment of SNC may improve locoregional control rates and reduce the frequency of metastasis, ultimately resulting in improved survival. Classically, the role of chemotherapy in SNC has been limited to palliative treatment of locally advanced or metastatic SNC. This role has expanded, however, to neoadjuvant, concurrent, or adjuvant settings in appropriate patient cohorts. This article explores the role of systemic therapy in the management of SNC.
Neoadjuvant chemotherapy
Due primarily to the rare nature of SNC, no prospective, randomized trials have been performed examining the efficacy of neoadjuvant chemotherapy. Single-center studies have used chemotherapy protocols extrapolated from the head and neck literature, such as the larynx preservation studies. In addition, interpretation of such studies has been complicated by the inclusion of patient cohorts with varying histologic tumor types. As in all cases of neoadjuvant therapy, the potential benefit of optimal drug delivery through an intact tumor blood supply is weighed against the potential of delaying multimodal locoregional treatment due to systemic toxicity. Despite these limitations, single-center studies on neoadjuvant chemotherapy for advanced SNC have shown promising results ( Table 1 ).
| Tumor Type | Study | Stage of Tumors | Chemotherapy Regimen | N | Outcomes |
|---|---|---|---|---|---|
| PSSCC | Rosen et al, 1993 | Stage IV | NA 5-fluorouracil and cisplatin | 9 | 2-y DFS 92% |
| Björk-Eriksson et al, 1992 | Stages III and IV | NA 5-fluorouracil and cisplatin | 8 | 4-y DFS 83% | |
| Adenocarcinoma | Licitra et al, 2004 | AJCC I–IVb | NA cisplatin, 5-fluorouracil, and leucovorin | 30 | 55-mo DFS in pCR 100% |
| SNUC | Musy et al, 2002 | Kadish B and C | Variable NA regimens | 10 | 2-y OS 64% |
| Rischin et al, 2004 | Stage 4 | NA platinum and 5-Fluorouracil | 7 | 2-y OS 64% | |
| SNEC | Rosenthal et al, 2004 | Stages II–IV | NA | 8 | 5-y OS 64% DMR 14% |
| ONB | Loy et al, 2006 | Kadish C | NA vincristine and cyclophosphamide | 50 | 5-y DFS 87% 15-y DFS 83% |
| SNPMM | Lian et al, 2013 | Stage II–III | Adjuvant temozolomide and cisplatin | 63 | Significant improvement in DFS over surgery alone |
| Sarcoma | Callender et al, 1995 | Various stages | Various regimens | 24 | 5-y OS 60% |
A 2003 study from Licitra and colleagues investigated neoadjuvant 5-fluorouracil, cisplatin, and leucovorin in 49 patients with resectable paranasal sinus tumors. Although the 3-year overall survival rate was 69% and the achievement of a pathologic complete response predicted a favorable outcome, significant morbidity was reported. Namely, 2 deaths due to thromboembolic events as well as 8 cases of cardiac complications resulting in discontinued therapy were reported. In 2011, Hanna and colleagues published a retrospective series of 46 patients with sinonasal squamous cell carcinoma treated with a combination of neoadjuvant platinum and taxane or taxane and 5-fluorouracil followed by either chemoradiation or surgery and radiotherapy; 80% of patients had stage IV disease. Despite this advanced disease stage at presentation, response to neoadjuvant chemotherapy was reported in 67% of patients and predicted treatment outcome and prognosis. This effect was independent of subsequent choice of locoregional therapy.
Although these studies analyzed SNCs with differing histologies, the results highlight the potential benefit of neoadjuvant chemotherapy in the multimodal treatment of advanced SNC. In the future, efforts should focus on elucidating the effect of induction chemotherapy on varying tumor types to allow for development of disease-specific protocols.
Concurrent chemotherapy
Advanced head and neck cancer has been successfully treated with concurrent chemoradiotherapy, but data regarding its use in SNC remain less robust. Recent evidence suggests that concomitant chemotherapy and radiotherapy can achieve promising survival and locoregional control rates in certain cases of SNC. Protocols typically describe weekly carboplatin regimens. Individualized concurrent chemotherapy with cetuximab has been described in patients whose tumors overexpress epidermal growth factor receptor.
Comparative studies demonstrating a statistically significant survival benefit for concurrent chemoradiotherapy compared with neoadjuvant chemotherapy, however, have not yet been performed. A 2008 retrospective study by Hoppe and colleagues analyzed survival in 39 patients with unresectable stage IVB SNC, 35 of whom received concurrent chemoradiotherapy (82% with cisplatin). With a median follow-up of 90 months, overall survival rate was only 15%. Furthermore, the importance of surgical resection was highlighted in a 2012 retrospective review of resectable maxillary sinus tumors treated with either surgery with adjuvant chemoradiation or concurrent primary chemoradiotherapy alone. Patients in the surgical arm had statistically significant better progression-free survival as well as overall survival. Ultimately, prospective, comparative studies are needed to further inform physicians on the role of concurrent chemoradiotherapy in advanced cases of SNC.
Intra-arterial chemotherapy
The intra-arterial approach to directly delivering chemotherapy to advanced SNC remains largely an experimental option. In 2004, Samant and colleagues examined the long-term efficacy of intra-arterial cisplatin and concomitant radiotherapy followed by organ-preserving surgery in 19 patients. Of those patients, there were 14 with squamous cell carcinoma, 2 with adenocarcinoma, 2 with adenoid cystic carcinoma, and 1 with undifferentiated carcinoma. They reported that overall survival rates at 2 and 5 years were 68% and 53%, respectively, and concluded that despite the advanced level of the SNC, intra-arterial chemotherapy holds promise as a treatment option. Despite exciting organ-preservation rates, intra-arterial chemotherapy carries substantial risk of toxicity, including brain necrosis, osteonecrosis, and ocular complications, including loss of vision, which have limited its application in the treatment of advanced SNC.
The role of chemotherapy in specific tumor types
Depending on the tumor type and extent of disease, systemic chemotherapy has been shown to play an important role in various phases of care including neoadjuvant, concomitant, and adjuvant settings (see Table 1 ).
Squamous Cell Carcinoma
Although paranasal sinus squamous cell carcinoma (PSSCC) accounts for 3% of all head and neck malignancies, no randomized trials have been conducted to guide management decisions. Reported prognostic factors for PSSCC include disease stage, site of origin, histopathology, and patient characteristics. The combination of radiation therapy and surgery has demonstrated superiority compared with radiotherapy alone, which was the original treatment of choice. For PSSCC involving the orbit, dura, or brain, induction chemotherapy followed by concurrent chemoradiation or surgery followed by radiation therapy remain the considered options. Degree of response to chemotherapy can also be used to direct chemotherapy/radiation therapy before surgery. The decision to undergo adjuvant therapy is based on extent of tumor, stage, subsite, and various prognostic indicators, including orbital involvement, perineural invasion, and dural involvement. If nonsurgical treatment is chosen, post-treatment biopsy and PET scanning can be used to assess persistent disease, recurrent disease, and distant metastasis. Despite these guidelines, disease-free survival for advanced (stage III or IV) PSSCC is reported as low as 25% to 30%, underscoring the importance of early detection and aggressive treatment.
Adenocarcinoma
Adenocarcinoma is reported as 1 of the 3 most common tumor types within the sinonasal passages. Normally classified as a primary SNC of minor salivary origin, this tumor is classically treated with surgery followed by radiation therapy in the setting of high-grade disease or positive margins Chemotherapy has not been shown to provide a survival advantage for sinonasal adenocarcinoma. Studies out of Italy have shown, however, that the use of cisplatin, 5-fluorouracil, and leucovorin induction chemotherapy can be justified in a specific subset of patients with advanced sinonasal intestinal-type adenocarcinoma with functional p53 status.
Sinonasal Undifferentiated Carcinoma
Sinonasal undifferentiated carcinomas (SNUCs) are characterized by very aggressive local destruction, high rates of regional and distant metastasis, and poor overall survival. Although optimum treatment varies from patient to patient, multimodality therapy has been reported as the preferred approach. Several studies have focused on establishing the chemosensitivity of SNUC. A 2012 meta-analysis of data from 167 SNUC patients reported improved patient survival with the addition of systemic therapy to surgery.
Induction and concomitant chemoradiotherapy for SNUCs have yielded reasonable locoregional control rates. In 2002, Musy and colleagues demonstrated a 2-year overall survival rate of 64% with the addition of induction chemotherapy and radiation therapy prior to anterior craniofacial resection. A 2004 study by Rischin and colleagues reported a 2-year overall survival rate of 64% in 10 patients treated with induction chemotherapy followed by chemoradiotherapy. Although these and other single-institution reviews need confirmation by prospective studies, they suggest that SNUC may be a chemosensitive disease with potential to improve local control and decrease the rate of distant metastasis through the addition of systemic therapy.
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