David W. Eisele, MD, Section Editor
CONTEMPORARY MANAGEMENT OF SINONASAL CANCER K. Thomas Robbins, MD, FRCSC,1 Alﬁo Ferlito, MD, DLO, DPath, FRCSEd ad hominem, FRCS (Eng, Glasg, Ir) ad eundem, FDSRCS ad eundem, FHKCORL, FRCPath, FASCP, IFCAP,2 Carl E. Silver, MD,3 Robert P. Takes, MD, PhD,4 Primozˆ Strojan, MD,5 Carl H. Snyderman, MD,6 Remco de Bree, MD,7 Missak Haigentz Jr, MD,8 Johannes A. Langendijk, MD, PhD,9 Alessandra Rinaldo, MD, FRCSEd ad hominem, FRCS (Eng, Ir) ad eundem, FRCSGlasg,2 Ashok R. Shaha, MD,10 Ehab Y. Hanna, MD,11 Jochen A. Werner, MD,12 Carlos Sua´rez, MD, PhD13,14 1
Division of Otolaryngology–Head and Neck Surgery, Southern Illinois University School of Medicine, Springﬁeld, Illinois Department of Surgical Sciences, ENT Clinic, University of Udine, Udine, Italy. E-mail: [email protected]
3 Departments of Surgery and Otolaryngology–Head and Neck Surgery, Albert Einstein College of Medicine, Monteﬁore Medical Center, Bronx, New York 4 Department of Otolaryngology–Head and Neck Surgery, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands 5 Department of Radiation Oncology, Institute of Oncology, Ljubljana, Slovenia 6 Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania 7 Department of Otolaryngology–Head and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands 8 Department of Medicine, Division of Oncology, Albert Einstein College of Medicine, Monteﬁore Medical Center, Bronx, New York 9 Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 10 Head and Neck Service, Memorial Sloan-Kettering Cancer Center, New York, New York 11 Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 12 Department of Otorhinolaryngology–Head and Neck Surgery, Philipp-University Marburg, Marburg, Germany 13 Department of Otolaryngology, Hospital Universitario Central de Asturias, Oviedo, Spain 14 Instituto Universitario de Oncologı´a del Principado de Asturias, Oviedo, Spain 2
Accepted 3 May 2010 Published online 24 August 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/hed.21515
Keywords: sinonasal cancer; treatment; endoscopic surgical resection; radiation therapy; chemotherapy; quality of life Abstract: Background. Sinonasal cancer is a relatively uncommon entity encountered by head and neck oncologists, rhinologists, and skull base surgeons. Recent innovations in surgical and nonsurgical therapeutic modalities raise the question of whether there has been any measurable improvement for treatment outcomes. Methods. A retrospective review of data from recent studies that focus on surgery, radiation, and chemotherapy, or combinations thereof, was conducted. Results. Surgery continues to be the preferred treatment and provides the best results, albeit with an inherent bias based on patient selection. For advanced disease (T4 lesions), the survival rate remains only modest. Complications of treatment, including both surgical and radiation therapy, have been reduced. Conclusions. There is a need to improve the efﬁcacy of treatment for this disease. Recommendations for the future C 2010 direction of therapeutic investigations are outlined. V Wiley Periodicals, Inc. Head Neck 33: 1352–1365, 2011 Correspondence to: A. Ferlito This paper was written by members and invitees of the International Head and Neck Scientiﬁc Group. C 2010 Wiley Periodicals, Inc. V
Contemporary Management of Sinonasal Cancer
Sinonasal cancers represent a group of malignant neoplasms that arise in the nasal cavity or its adjacent paranasal sinuses. The histology of these cancers is rather varied, among which adenocarcinoma and squamous cell carcinoma are the most frequently seen.1 Many other malignant primary tumors with widely varying biology have been reported in this anatomic region, including variants of squamous cell carcinoma (verrucous, papillary, basaloid, spindle cell), lymphoepithelial carcinoma, esthesioneuroblastoma (olfactory neuroblastoma), sinonasal undifferentiated carcinoma, salivary gland-type carcinomas, sinonasal neuroendocrine carcinomas as well as sarcomas, and lymphomas. Even when these histologically and biologically diverse tumors are combined and reported as a collective entity, sinonasal cancer represents only 3% of the sitespeciﬁc malignancies of the head and neck in most parts of the world. Added to this rarity and diversity, a third confounding factor is the varied anatomic structures that surround these malignancies, including the HEAD & NECK—DOI 10.1002/hed
The majority of patients with sinonasal cancer have locally advanced (T3–T4) disease at the time of presentation. The current standard approach has traditionally used combined modality treatment, which is usually anchored by surgical extirpation followed by radiotherapy for patients with locally advanced disease. However, this approach is not without the morbidity resulting from the surgical and radiotherapy parts of combined treatment protocols, and offers only modest survival outcomes for patients with advanced disease. In 2007, Guntinas-Lichius et al2 reported the results of 229 patients with sinonasal cancer treated between 1967 and 2003. The 5-year overall survival for the group was 41%, the disease-speciﬁc survival was 51%, and the local control rate was 64%. They recommended radical surgery for stage I/II sinonasal cancers but multimodality therapy for stage III/IV disease. The majority of patients in this latter group received radical surgery followed by postoperative radiation, whereas radiation therapy alone was used for only 25 patients. The authors’ conclusion that surgery is still the mainstay of treatment is based on the 5-year disease-free survival being signiﬁcantly better than that of patients who received nonsurgical therapy. A similar conclusion was made by Dulguerov et al,3 who reported the outcome results of 220 patients with sinonasal cancer treated at 2 institutions between 1975 and 1990. Also, this group demonstrated improved treatment outcomes throughout the decades of the 1960s through the 1990s in a larger series of patients analyzed from a systematic search of the literature.3 However, with regard to comparing the outcome results of treatment modalities, it must be assumed that the patients selected for nonsurgical therapy were more likely to have unresectable disease. This observation was convincingly demonstrated by Jansen et al,4 who analyzed the basis on which patients were selected for radiotherapy with surgery or radiotherapy alone. A logistic regression analysis was conducted that identiﬁed 6 parameters associated with selection for radiotherapy alone, of which all
were related to the feasibility of successful surgical removal of the tumor bulk: age >65 years; clinical T4 stage; and radiologic evidence of skin, nasopharynx, palate, and/or skull base invasion. Twenty-six serious complications in 21 patients were recorded in a group of 73 patients treated between 1977 and 1996, including 2 cases of panhypopituitarism, whereas all other 24 complications were of the optic tract. Tumor invasion of the optic tract was always the reason to accept irradiation doses above tolerance levels: in patients without local recurrence and intraorbital tumor extension serious visual complications developed in 13.6%, whereas in patients with clinical or radiologic tumor extension through the orbits, the incidence of visual complications was 33.3%.4 In 2009, Mendenhall et al5 reported the results of 109 patients with sinonasal cancer treated between 1964 and 2005. Within this group, 56 patients were treated with deﬁnitive radiation therapy, whereas 53 patients received surgery and postoperative radiation. Although the 5-year local control rate was 82% in patients with T1–T3 lesions, those patients with T4 disease had a lower local control rate of 50%. Local control at 5 years was 43% after deﬁnitive radiation therapy versus 84% with primary surgery and adjuvant radiation therapy (p63Gy, respectively, whereas after hyperfractionation, the corresponding incidence rates were 2% and 9%, respectively. For doses > 63 Gy the difference was statistically signiﬁcant (p ¼ .0019). Furthermore, the fraction dose in once-daily radiotherapy regimens also appeared to be of clinical importance: the 5-year rates of radiation-induced neuropathy for patients treated with 1.8 Gy/fraction was 7% but increased to 22% in those with the dose per fraction > 1.8 Gy (p ¼ .0005). Based on these data, the authors recommend IMRT only when the optic apparatus can be completely avoided. Dose inhomogeneity as an inherent feature of IMRT’s improved conformality could create hot spots over critical anatomic structures, having a detrimental effect on these structures. Hyperfractionation is therefore preferred over IMRT when the treatment ﬁeld must overlap optic structures, although further improvement of the therapeutic ratio could be expected when overcoming logistic barriers to hyperfractionated IMRT and combining both of them: the normal-tissue sparing advantages of conformal techniques (ie, IMRT) and radiobiologic superiority of hyperfractionation should be complementary. A more recent development that may enable effective delivery of radiation therapy with less toxicity by sparing normal tissues is proton beam radiotherapy. The results of a number of in silico planning comparative studies show that the dose to the normal structures can be reduced signiﬁcantly by protons instead of photons.34–37 In 2008, Resto et al38 reported a series of 102 patients with sinonasal cancer treated with proton beam radiation therapy with or without surgery. They concluded that high-dose radiotherapy with proton beam resulted in excellent local control rates in patients with locally advanced sinonasal cancer, irrespective of the extent of surgery. However, complete resection remained predictive of improved disease-free survival and decreased rate of distant metastasis. To summarize, radiation therapy is commonly used in the treatment of sinonasal cancer, usually fol-
Contemporary Management of Sinonasal Cancer
lowing surgical extirpation. Its use as a single modality has mainly been reserved for patients with unresectable disease or those not ﬁt for major surgery, in which case the treatment intent is more often palliative rather than curative. The complications of radiation therapy are well documented and predominantly dose dependent. New techniques and altered fractionation regimens, such as IMRT and hyperfractionation, have resulted in reduced morbidity, particularly as this relates to vision. However, there has been no survival improvement noted with these new techniques. Radiosurgery has a limited role in the treatment and palliation of recurrent disease and is unproven as a primary treatment modality.
THE USE OF CHEMOTHERAPY IN SINONASAL CANCER Systemic Chemotherapy. Over the past decade, systemic (intravenous) chemotherapy has become a widely used modality in the combined treatment approach for advanced head and neck cancer. However, there has been a low level of interest for its use in the treatment of advanced sinonasal cancer. In 2008, Hoppe et al26 reported the outcome of 39 patients with unresectable stage IVB paranasal sinus carcinoma, of whom 35 patients were treated with chemotherapy and radiotherapy. All but 1 of the chemotherapy regimens were platin based and were given as induction, concurrent, or adjuvant therapy to irradiation, depending on the histology, but also to the protocol available at the time and the treating physician. After a median follow-up time for surviving patients of 90 months, the 5-year local progressionfree survival, disease-free survival, and overall survival were only 20%, 14%, and 15%, respectively. Despite aggressive treatment protocol implementing systemic chemotherapy, the risk of distant metastases was still signiﬁcant (distant metastases–free survival at 5 years of 51%), although the primary cause of death remained local recurrence. A more encouraging early report comes from the University of Chicago39 in which 12 patients were treated with neoadjuvant chemotherapy followed by radical surgery and radiotherapy. Eleven of the patients had T4 disease. With a mean follow-up of 55 months (range, 13–105 months), 11 of the 12 patients were alive and disease free. More recently, this group reported a subgroup analysis of 19 consecutive patients with stage III and stage IV locally advanced disease.40 Sixteen patients received induction chemotherapy with cisplatin and 5 ﬂuorouracil (5-FU) followed by surgical resection. In 15 of these patients postoperative concomitant chemoradiotherapy with 5-FU and hydroxyurea was given. Only 1 patient received postoperative radiation alone. At 10 years, the rate of disease-free survival was 67% and the rate of local control was 76%.
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Choi et al41 reported a 94% complete response rate and a 50% 5-year survival rate in 17 patients with stage III–IV nasopharyngeal (10 patients) and paranasal sinus tumors (11 patients) involving the facial bones and the base of the skull. The treatment regimen consisted of split course hyperfractionated radiation therapy at 1.2 Gy twice-daily fractions and concomitant cisplatin at 5 to 10 mg per square meter per day. The total radiation dose was 70.8 Gy. However, nasopharyngeal cancer in the eastern hemisphere is a completely different malignancy, which is characteristically radiosensitive and should not be compared with paranasal sinus cancer.
Using a nonconventional trimodality therapy approach to minimize the cosmetic and dysfunctional effects of radical surgery for maxillary sinus cancer, Sato et al42 introduced the strategy of simultaneous surgery, radiotherapy, and regional chemotherapy in treating carcinomas of the maxillary sinus. Their combined therapy consisted of the following protocol: (1) surgical reduction of the tumor mass, succeeded by daily cleaning of the residual tumor; (2) 6 external irradiation treatments (with mean dose of 1200 rads administered over a period of 9 days); and (3) 5 intraarterial infusions of 5-FU (250 mg daily) and broxuridine (BUdR, 500 mg daily). Seventy-six percent of 45 treated patients were still living after 5 years, with functional preservation of the orbit and palate. Several centers in Japan have experience using regional chemotherapy for sinonasal cancer.43–45 Among the varied regimens, all have incorporated a trimodality approach combining chemotherapy with surgery and radiation therapy. The 5-year survival results, ranging from 45% to 76%, appear to be at least equal to, if not superior to, the more conventional approaches. In the United States, a novel trimodality approach was introduced at the University of Tennessee, using the intra-arterial route for the delivery of high-dose cisplatin chemotherapy.24 This group used a modiﬁcation of their RADPLAT (radiation þ platinum) technique46 to deliver intra-arterial cisplatin with radiation simultaneously followed by organ-sparing surgery. The intent of treatment was to limit the total dose of radiation therapy to 50 Gy (to minimize side effects), and following the chemoradiation, to perform transfrontal and/or transnasal conservation surgery based on piecemeal removal of residual disease without facial incisions. Among the 19 patients treated with this protocol, 14 patients had squamous cell carcinomas (74%), 2 patients had adenocarcinomas (10%), 2 patients had adenoid cystic carcinomas (10%), and 1 patient had an undifferentiated carcinoma (5%). Sixteen patients (84%) had T4 disease. Treatment consisted of preoperative radiation therapy (2.0 Gy per fraction per day; total dose, 50 Gy in 5 weeks) given concomitantly with 3 to 4 weekly infu-
sions of intra-arterial cisplatin (150 mg per square meter per week) immediately followed by systemic sodium thiosulfate neutralization. The regimen included planned surgery performed approximately 8 weeks after completion of radiation therapy. With a median follow-up of 53 months, the overall survivals at 2 and 5 years were 68% and 53%, respectively. One patient died of a myocardial infarction during treatment. No other treatment-limiting toxic effect was noted. Although 3 patients had persistent disease, delayed local failure occurred in only 2 patients and distant metastasis in 3 patients. Except for cataract formation in 2 patients, no visual loss was observed. In 2009, Homma et al47 reported on the use of RADPLAT for the deﬁnitive treatment for sinonasal cancer without any dose reduction of radiation therapy, with surgery reserved for salvage of persistent disease. Forty-seven patients with advanced cancer of the nasal cavity and paranasal sinuses were treated between 1999 and 2006. Patients received superselective intra-arterial infusions of cisplatin (100–120 mg per square meter per week) and simultaneous intravenous sodium thiosulfate and conventional external beam radiotherapy (65–70 Gy). Seven patients had T3 disease, whereas 22 patients had T4a disease and 18 patients had T4b disease. With a median follow-up of 4.6 years, the estimated 5-year local progression-free and overall survival were 78.4% and 69.3%, respectively. There were no treatment-related deaths. Osteonecrosis occurred in 7 patients and brain necrosis in 2 patients. Sixteen patients had ocular and visual problems as late adverse effects. Knegt et al48 in the Netherlands used a topical chemotherapy approach to treat adenocarcinomas arising in the ethmoid sinuses. Sixty-two patients underwent surgical debulking via an extended anterior maxillary antrostomy followed by a combination of repeated topical chemotherapy (5-FU) and necrotomy. Eight patients subsequently received radiotherapy for local recurrence. Complications included temporary periorbital swelling (25 patients), temporary cerebrospinal ﬂuid leakage (5 patients), and meningitis (1 patient). The adjusted disease-free survival at 5 years was 87%. They concluded that the combination of surgical debulking and repeated topical chemotherapy for patients with adenocarcinoma of the ethmoidal sinuses represents the current treatment of choice for these patients. Additional experience with topical chemotherapy comes from the United Kingdom, where there are endemic regions for woodworkers’ adenocarcinoma of the ethmoid sinuses. Fourteen patients were treated with primary radiotherapy, and 11 patients with surgery and topical 5-FU. The 5-year disease-free survival improved from 50% with primary radiotherapy to 86% with surgery and topical 5-FU. This analysis did not compare treatment outcomes with the more conventional approach of radical surgery followed by postoperative radiation.49
Contemporary Management of Sinonasal Cancer
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Intra-arterial and Topical Chemotherapy.
MOLECULAR TARGETED THERAPIES
Clinical research in head and neck cancer has recently focused on improving the efﬁcacy of current multimodal approaches by targeting cellular pathways associated with carcinogenesis. Because the epidermal growth factor receptor (EGFR) signaling pathway and angiogenesis play a fundamental role in the growth of squamous cell carcinomas, EGFR with its downstream effectors and molecular factors implicated in the angiogenesis process, such as the vascular endothelial growth factor receptor (VEGFR) and its receptors, represent the main targets of the new therapeutic agents now in development. Blocking EGFR and VEGFR constitutes an emerging primary strategy that accounts for the success of current targeted therapies in cancer. Recent studies with cetuximab, a monoclonal antibody inhibitor of the EGFR, in association with radiotherapy, have demonstrated survival beneﬁts across the range of treatment settings in advanced head and neck cancer, and it is the only targeted therapy approved for use in this malignancy. In a recently published trial, patients with locoregionally advanced squamous cell carcinoma of the oropharynx, hypopharynx, or larynx were randomly assigned to receive radiotherapy with (n ¼ 211) or without (n ¼ 213) cetuximab. Five-year overall survival was 45.6% in the cetuximab-plus-radiotherapy group and 36.4% in the radiotherapy-alone group.50 Future progress is expected with the integration of cetuximab into induction chemotherapeutic regimens or in association with concurrent chemoradiotherapy for locally advanced tumors because a new phase II trial with induction chemotherapy, consisting of 6 weekly cycles of paclitaxel and carboplatin with cetuximab, has shown that 19% of patients achieved a complete response and 77% a partial response.51 Another potentially promising approach is the inhibition of vascular endothelial growth factor, alone or in combination with EGFR inhibition, with the development of other molecular targeted therapies such as antiangiogenic drugs. We can expect that all these strategies will prove to be of similar value in squamous cell sinonasal carcinomas, and new trials will be soon ongoing at this particular location. On the other hand, the CD117 (KIT) protein is overexpressed by immunohistochemistry in many human neoplasms, including almost all adenoid cystic carcinoma and gastrointestinal stromal tumors (GISTs). Point mutations in domains similar to those described in GIST have been detected in roughly 60% of adenoid cystic carcinomas overexpressing KIT.52 Identiﬁcation of such potential gain-of-function mutations in exon 11 suggests that KIT may be involved in the pathogenesis of adenoid cystic carcinoma of salivary glands. Imatinib mesylate (Gleevec) inhibits autophosphorylation of several protein-tyrosine kinases, including c-kit, and offers excellent results in the treatment of GIST. In consequence, imatinib may be
Contemporary Management of Sinonasal Cancer
an effective drug in patients with locally advanced or metastatic adenoid cystic carcinoma. Nevertheless, despite 2 initial reports on isolated cases with advanced or recurrent tumors overexpressing KIT successfully treated with imatinib,53,54 2 different trials with a total of 26 patients with c-kit positive tumors failed to demonstrate any objective response, with 11 patients having stable disease as best response.55,56 In conclusion, overexpression of c-kit is not sufﬁcient for clinical beneﬁt from Imatinib in adenoid cystic carcinoma, and raises the question as to whether the study of c-kit mutation could be a better marker of the candidates for a potential treatment of these tumors with tyrosine kinase inhibitors.52 To conclude, trials are ongoing in all stages of disease and with a variety of modalities and agents, and those trials should provide critical insight into the best way to use these agents to improve patient outcomes. TREATMENT OF THE NECK
Treatment of the neck in node-negative patients is a matter of debate. The neck failure rate in patients with sinonasal cancer is reported to be approximately 3%.57 However, subgroups of higher-stage tumors, particularly those arising in the maxillary sinus, may have higher rates of relapse in the untreated neck and elective neck treatment may be considered in these patients.6,58,59 Highly indicative is a report from Houston, Texas, describing the inﬂuence of 3 changes in radiotherapy technique on the outcome of 146 patients irradiated postoperatively for maxillary sinus cancer, 1 of them being elective radiotherapy to the ipsilateral upper neck nodes in patients with T2 to T4 squamous cell or undifferentiated carcinoma.60 Of the 36 patients with these histologic subtypes in whom the ipsilateral neck was left untreated, 13 patients (36% developed nodal recurrence vs only 3 patients [7%]) of the 45 patients in whom elective neck irradiation was administered (p