Intensity-modulated radiotherapy for paranasal sinuses and base of skull tumors

Oral Oncology 86 (2018) 61–68

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Intensity-modulated radiotherapy for paranasal sinuses and base of skull tumors

T

Zhong-Guo Lianga,b,1, Grace Kusumawidjajaa,1, Farasat Kazmia, Joseph T.S. Weea,c, ⁎ Melvin L.K. Chuaa,c,d, a

Division of Radiation Oncology, National Cancer Centre Singapore, Singapore Graduate School of Guangxi Medical University, Nanning, Guangxi, China c Division of Medical Sciences, National Cancer Centre Singapore, Singapore d Oncology Academic Programme, Duke-NUS Medical School, Singapore b

A R T I C LE I N FO

A B S T R A C T

Keywords: Paranasal sinus tumor Base of skull tumor Intensity modulated radiotherapy Volumetric arc therapy Particle therapy Protons

Paranasal sinus and skull base tumors are rare aggressive head and neck cancers, and typically present in the locally advanced stages. As a result, achieving wide surgical resection with clear margins is a challenge for these tumors, and radiotherapy is thus usually indicated as an adjuvant modality following surgery to optimize local control. Given the integral role of radiotherapy in the management of this subgroup of head and neck tumors, the advent of intensity-modulated radiotherapy (IMRT) has led to substantial improvement of clinical outcomes for these patients. This is primarily driven by the improvement in radiation dosimetry with IMRT compared to conventional two dimensional (2D)- and 3D-techniques, in terms of ensuring dose intensity to the tumor target coupled with minimizing dose exposure to critical organs. Consequently, the evident clinical benefits of IMRT have been in reduction of normal tissue toxicities, ranging from critical neurological symptoms to less debilitating but bothersome symptoms of eye infections and radiation-induced skin changes. Another domain where IMRT has potential clinical utility is in the management of a subset of non-resectable T4 paranasal sinus and skull base tumors. For these inoperable lesions, the steep dose-gradient between tumor and normal tissue is even more advantageous, given the crucial need to maintain dose intensity to the tumor. Innovative strategies in this space also include the use of induction chemotherapy for patient selection. In this review, we summarized the data for the aforementioned topics, including specific discussions on the different histologic subtypes of paranasal sinus and skull base tumors.

Introduction Cancers of paranasal sinus and skull base are uncommon, and constitute only a small proportion of all head and neck malignancies [1,2]. The maxillary and ethmoid sinuses comprise the most frequent sites of origin. However, these tumors can be histologically diverse; squamous cell carcinomas comprise about half of all cases, with adenoid cystic-, mucoepidermoid-, sinonasal undifferentiated- and adenocarcinoma, esthesioneuroblastoma, melanoma and chordoma variants making up the remainder [3,4]. In terms of clinical presentation, tumors in the paranasal sinuses are relatively asymptomatic as they occur in large air cavities, and therefore patients often present with advanced disease when the tumors involve the adjacent critical normal structures like the orbits, optic pathways and skull base. It is for this reason that

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treatment of paranasal sinus tumors is often complex, requiring a multidisciplinary team approach. Consistent with the broad principle of management of head and neck cancers, surgical resection with wide margins is the preferred treatment modality for first-line therapy. Nonetheless, this can be a challenge given the close proximity to delicate normal organs and the restricted anatomical boundaries at the orbit, cranium, skull base, and parapharyngeal spaces. As a result, adjuvant radiotherapy is nearly always indicated to target macroscopic or occult microscopic disease following surgery. Likewise to surgery, there are several considerations when delivering radiotherapy, ranging from tissue in homogeneity (contributed by large air gaps post-surgery), significant anatomical variation post-surgery, ensuring adequate dose intensity to the surgical bed, and importantly, limiting normal tissue toxicities. These issues are now better circumvented by the technical

Corresponding author at: Division of Radiation Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore. E-mail address: [email protected] (M.L.K. Chua). 1 Co-first authors. https://doi.org/10.1016/j.oraloncology.2018.09.010 Received 31 August 2018; Accepted 11 September 2018 1368-8375/ © 2018 Published by Elsevier Ltd.

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Radiotherapy tumor target concepts

advancement of intensity-modulated radiotherapy (IMRT), given the wider degree of flexibility to conform radiotherapy doses and ensuring steep dose gradients at crucial tumor-normal tissue interphase. In this review, we will provide a background to the tumor targeting and technical concepts of radiotherapy for paranasal sinus and skull base tumors; focus on the clinical evidence supporting the advantages of IMRT and the utility of IMRT for each histological subtype; and lastly, we will highlight some of the upcoming potential advances in treatment for these tumors.

Target volume delineation and prescribed radiotherapy doses In the post-operative setting, residual gross tumor volume (GTV) and the pre-operative GTV using co-registered pre-operative computed tomography (CT) and/or magnetic resonance imaging (MRI) datasets should be outlined. This process should be performed taking into account the details of the operative procedure and surgical histopathology report, so that the pre-surgery tumor extent and subclinical tumor spread are comprehensively included into the clinical target volume (CTV). Additionally, the post-operative CTV includes the resection cavity, and the immediate adjacent paranasal/anatomical compartments, regardless of involvement. For example in a maxillary sinus tumor, this would include the adjacent ipsilateral nasal cavity, nasopharynx, ethmoid and sphenoid sinuses (Table 1). In special instances where the tumor extends intracranially, and a craniofacial resection is performed, the dural bed with a 0.5–1 cm margin ought to be included in the CTV. Separately, in adenoid cystic carcinoma of the paranasal sinuses, the CTV should also include the involved nerve(s), tracked from the tumor region to the base of skull. For non-resectable tumors, CTV delineation largely follows the principles outlined for the postoperative cases, but also includes a circumferential 5- and 10-mm expansion margin around the intact primary GTV, taking into account anatomical boundaries. Radiotherapy dose prescription patterns are largely consistent across institutions, and vary by clinical scenarios. 60 Gy and 66 Gy are typically employed for microscopic disease in the adjuvant setting, with the latter higher dose being reserved for cases with high-risk features

Search strategies and outcome We searched the PubMed, MEDLINE and EMBASE databases for articles published in English before June 1, 2018, with the keywords: “paranasal sinus”, “sinonasal”, “sinus”, “skull base”, “radiotherapy”, “adjuvant”, “postoperative radiotherapy”, “radical”, and “intensitymodulated radiotherapy”. Priority was accorded to original research articles focusing on radiotherapy role in the treatment of paranasal and skull base cancers. Selected references were judged on relevance, and included widely referenced and highly regarded older seminal work. We identified 20 clinical studies that matched the above criteria, which comprised of nine retrospective studies reporting on outcomes of radical and adjuvant radiotherapy [5–13], and eleven studies comparing outcomes using conventional radiotherapy and IMRT [14–24] (Fig. 1).

Fig. 1. Selection process for studies reporting on outcomes of radical and adjuvant radiotherapy for patients with paranasal sinus tumors. 62

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Table 1 Target definitions for paranasal sinuses of different sites. Sites

Nasal Cavity

Maxillary sinus

Ethmoidal sinus

Sphenoid sinus Frontal sinus

Definitions of clinical target volume Primary

Empirical nodal coverage

(Anterior 2/3) Lateral wall of nasal cavity, ethmoidal sinus, the medial wall of maxillary sinus or whole maxillary sinus. (Posterior 1/3) Nasopharynx, pterygoid lamina; if medial or lateral pterygoid is invaded, pharyngonasal cavity should be included. GTVp + 5–10 mm, ipsilateral nasal cavity, nasopharynx, ethmoid, sphenoid sinuses, and contralateral nasal cavity if the tumor breaks through the septum, interior wall of sinus plus dural bed and flap GTVp + 5–10 mm, nasal cavity, nasopharynx, sphenoid sinus, and the medial wall of maxillary sinus or whole maxillary sinus, frontal sinus, dural bed if craniofacial resection is performed GTVp + 5–10 mm, nasal cavity, nasopharynx, ethmoid sinus, ± frontal sinus GTVp + 5–10 mm, sphenoid sinus, ethmoid sinus, and dural bed

(1) For patients with T3-4 disease, or aggressive histologic variants,a recommend irradiation regions: levels 1b and 2. (2) If posterior 1/3 posterior nasal cavity is invaded, the recommend irradiation regions: bilateral levels 2, 3, and the retropharyngeal lymph nodes. (3) If nasopharynx is invaded, the recommend irradiation regions: bilateral levels 2–5, and the retropharyngeal lymph nodes

*GTVp: Gross tumor prior to resection and/or residual disease. a Includes sinonasal undifferentiated, poorly differentiated, melanoma, adenocarcinoma, hyman grade 2–3 esthesioneuroblastoma.

to improved accuracy of tumor targeting due to reduced intra-fraction motion. This contrasts to the delivery modes in the two dimensional (2D)and 3D-era, whereby beam arrangements were limited to orthogonal placements, and conformity was achieved by crude shielding techniques using lead or MLC. The commonest beam arrangement utilized was a three-field technique (one anterior and bilateral wedged lateral beams), with dose weighting of 2:1 or 3:1 ratio to the anterior field, so as to reduce irradiation of the contralateral orbit and the ipsilateral optic nerve. In the 2D era, the volume of irradiated tissue was simply determined by field borders that are based on 2D radiological bony anatomy landmarks, and therefore it is likely that excess normal tissue was irradiated [19,21,23,30]. Fig. 2 provides an illustrative comparison of beam placement, radiation dosimetry, and dose-volume exposure to tumor and normal tissues between 3D radiotherapy and IMRT (5-field technique) in the adjuvant treatment of a T4 ethmoid sinus tumor.

like positive margin and extranodal extension. In the case of radical radiotherapy, two dose-levels of 66–70 Gy to the GTV and 54–63 Gy to the CTV are often prescribed. At times, the CTV may be divided into intermediate- and low-risk targets, with corresponding differential dose prescriptions of 63 Gy and 54 Gy, respectively. However, apart from tumor features, another consideration of dose prescription also relates to the proximity of critical normal tissues to the GTV and CTV, and at times, the prescription is limited by the dose-limiting toxicities of these organs at risk (Table 1). Management of the neck Unlike other head and neck cancers, nodal involvement at the neck is typically uncommon for this anatomical subgroup of head and neck cancers. While ethmoid, sphenoid and frontal sinus tumors generally do not metastasize to the neck [25], cumulative incidence of nodal spread for tumors originating from the maxillary sinus can be up to 30%, especially in the more advanced T-status tumors and squamous cell and undifferentiated carcinoma subtypes [26,27]. In these tumors, elective nodal irradiation (ENI) has been shown to reduce regional and distant relapses in several retrospective series [20,26,28,29]. Nodal stations to be treated therefore depend on the site of tumor origin; levels 1b (submandibular) and 2 nodes are the commonest sites of metastases for ethmoid and maxillary sinus tumors. Additionally, in advanced maxillary sinus tumors, the retropharyngeal (7–16%) and lower jugular (level 4) nodes may be involved and ought to be included in the CTV [20].

Toxicities and tumor control outcomes Based on the dose-volume histogram illustrated in Fig. 2, we can observe that the main differences in radiation dosimetry between IMRT and 3D radiotherapy relate to the CTV coverage and exposure to the optic apparatus. Specific to the latter, the low and high dose spectrums to the lens, eyes and optic nerves are reduced with IMRT. This corresponds to the clinical observations from retrospective studies indicating a reduction in both acute and late ocular complications with the more contemporary technique (Table 2); reported rates of late optic retinopathy and blindness were significantly reduced from 9 to 29% with 2D-, 3D-techniques to negligible (< 5%) with IMRT, along with rates of other late ocular toxicities including keratoconjunctivitis, xerophthalmia (dry eyes) that were also observed in less than 10% of the majority of cohorts. With regard to tumor coverage, dose intensity is improved with IMRT than 3D radiotherapy, and this is likely attributed to the increased degrees of freedom with dose conformity. Retrospective data also suggests that local tumor control may be improved with IMRT; reported 5-year rates with IMRT have been observed to be 47–71% [9,16,21]. However, these series comprise a mixture of radically treated and post-surgical cases, and therefore it is uncertain if IMRT is more advantageous over conventional techniques for both clinical scenarios. Nonetheless, the therapeutic ratio of radiotherapy is dependent on both tumor control probability and dose-limiting normal tissue complications; it is intuitive that in the presence of dose sparing to the critical normal tissues, we could then afford higher dose intensity to the tumor targets, which may thus explain these clinical findings. Randomized controlled clinical trials or prospective observational registries are

IMRT vs conventional radiotherapy Radiation dosimetry and techniques In the early stages of IMRT implementation, this technique is delivered via a 5- to 7-fields beam arrangement using either 6 MV or 10 MV energy photons, and each beam is further modulated by 5–10 mm multi-leaf collimators (MLCs), which enables the variation of the physical dose fluence. This contributes to significantly increased degrees of freedom for “dose-shaping”, and circumvented the perennial limitation of dose conformity to concave tumor targets [19,21,23,30]. More recently, this advantage is enhanced by the transition from 5- to 7-fields beam arrangement to volumetric arc therapy (VMAT); for VMAT, this entails continuous arcs that are coupled with dose modulation using micro-MLCs. This technique offers greater degrees of freedom to conforming radiotherapy doses and affords a steeper dose-gradient than the fixed-beam techniques. Moreover, the mode of delivery (using arcs) results in substantially shorter treatment time, and possibly translates 63

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Fig. 2. Comparison of IMRT vs 3D-RT in beam placement, radiation dosimetry, and dose-volume exposure to tumor and normal tissues in the adjuvant treatment of a T4 ethmoid sinus tumor. Upper: The axial, coronal, and sagittal radiation dosimetry of 3D-RT; Middle: 3D Beam eye view (BEV), and Dose volume histogram of IMRT vs 3D-RT; Lower: The axial, coronal, and sagittal radiation dosimetry of IMRT.

radiotherapy approach ranged between 50 and 85% [22,31,32]. In this setting, there is limited evidence suggesting that IMRT offers superior control to 2D and 3D radiotherapy, which is perhaps expected since radiotherapy is primarily targeted at controlling microscopic disease. For this purpose, radiotherapy doses of 54–60 Gy are often prescribed, and as such there is less difficulty in fulfilling normal tissue dose constraints during planning. However, in a subset of patients with nonresectable tumors, IMRT may be advantageous over conventional radiotherapy, since higher radiotherapy doses of 66–70 Gy are needed for local control. Given the characteristics of steep dose gradients that are achievable by IMRT, using a more conformal modality would therefore allow for improved dose intensity to the tumor targets, without overexposing critical structures. To further optimize tumor control, IMRT is often delivered with concurrent cisplatin for both radiosensitization and to also target occult metastases [32]. Interestingly, comparable rates of local and distant tumor control between combinatorial chemo-radiotherapy and surgery with post-operative radiotherapy have been observed [31]. Likewise, acute and late toxicity rates do not seem to differ with both approaches [31,32]. Given that functional preservation is appealing for head and neck cancers, it may be worthwhile to consider a comparative study between conventional surgical approaches against the organ preservation approach of chemoIMRT. Throwing caution however, in a subset analysis of a randomized phase 3 comparison between either therapeutic strategies, Lyer and colleagues observed that surgery was significantly superior to chemoradiotherapy (5-year disease-specific survival of 71% vs 0%) for locally advanced maxillary sinus squamous cell carcinoma, albeit the cohort of these tumors was very small (N = 10), and radiotherapy was delivered using 2D and 3D techniques [33,34].

needed to formally assess the advantages of IMRT for this clinical purpose. Other normal tissue toxicities that were reduced with IMRT include dermatitis and acute mucositis (Table 2). Dermatitis is a common radiotherapy-induced complication for these tumors given the proximity of the CTV to the skin, and the anterior weighting of the anteriorposterior beam with 2D and 3D radiotherapy. While there may be a higher integral skin dose (due to the low dose splash), IMRT is able to reduce the exposure of the high dose spectrum (Figure 2); in a single institution series, it was observed that incidence of late G3-4 dermatitis was significantly lower among IMRT-treated patients than those treated with conventional techniques (13% vs 18–27%) [16]. Similarly, reported rates of acute mucositis with IMRT significantly decreased by 31–41% than 2D and 3D radiotherapy [19,23]. Given that cranial irradiation is often unavoidable given the proximity of the sinuses to the temporal and frontal lobes, low rates of temporal lobe injury of 1–3% have been observed with IMRT [9,15].

Radiotherapy in specific histological subtypes Squamous cell carcinoma Among the different anatomical subsites of paranasal sinus and skull base tumors, tumors of squamous epithelial origin occur primarily in the maxillary sinus and nasal cavity, and represent the commonest histologic subtype. In these anatomical regions, surgical resection is usually possible, unless the tumor invades the optic apparatus, the cavernous sinus and/or the major carotid vessels. Thus radiotherapy is often employed in the adjuvant setting, and retrospective series have indicated that control rates with this combined surgery and 64

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Table 2 Summary of studies reporting on clinical outcomes of patients with paranasal sinus tumors treated by definitive and adjuvant intensity modulated radiotherapy (IMRT). Study

N

Follow- up duration (mo)

Retrospective series of IMRT Claus, 2002 32 15 mo

Indication

Histology

RT technique

Overall survival

Locoregional control rate

Toxicities grade III and above (%)

Radical 3% PORT 97%

SCC 25%, AdenoCa 53%, Others 22% SCC 21%, AdenoCa 31%, Others 48% ACC 43%, AdenoCa 17%, Others 40% SCC 33%, ENB 19%, Others 48% ACC 64%, SCC 20%, Others 16% SCC 54%, ENB 13%, Others 33%

IMRT

NR

NR

Acute: Mucositis 13%, conjunctivitis 0%, xerophthalmia 0%

IMRT

59% (4-y)

68% (4-y)

Late: Ocular 13%

IMRT

90% (3-y)

49% (3-y)

Acute: Mucositis 22%, conjunctivitis 28%

IMRT

45% (5-y)

58% (5-y)

Only 1 case of eye symptoms reported.

IMRT

59% (5-y)

71% (5-y)

IMRT

66% (2-y)

64% (2-y)

IMRT

56% (5-y)

59% (5-y)

IMRT

NR

NR

Acute: Ocular (blurred vision, 2.6%; diplopia, 1.3%) Late: Ocular 8%, TLN 3.4% Acute: Mucositis 33%, dermatitis 15%, keratitis 4%, epiphora 12% Late: ORN 2%, optic neuropathy 2%, blindness 0% Acute: Ocular 18% (conjunctivitis 2%, blurred vision 5%, xerophthalmia 1%) Late: Ocular 13% (Tearing 12%, blindness 0%, optic neuropathy 1%), ORN 1%, TLN 1% Late: Ocular 19%

IMRT

54% (5-y)

47% (5-y)

Late: Ocular 34%

SCC 38%, AdenoCa 13%, Others 49% SCC 82%, AdenoCa 18% SCC 58%, ACC 32%, Others 10%

IMRT, 3DRT

46% (5-y)

63% (5-y)

Late: Ocular 26% (ischemic optic atrophy, keratoconjunctivitis, optic neuropathy, blindness 1%)

IMRT, 3DRT

27% (5-y)

58% (5-y)

IMRT, 2D-/3D-RT

52% (5-y)

62% (5-y) IMRT 65% vs 3DRT 62% (5-y)

SCC 49%, ACC 13%, Others 38% SCC 38%, SNUC 21%, Others 59% AdenoCa 78%, SCC 5%, Others 17%

IMRT, 3DRT

67% (5-y)

62% (5-y)

IMRT, 3DRT

15% (5-y)

21% (5-y)

Late: Ocular (blindness 2%, optic retinopathy 1%, keratitis 1%, conjunctivitis 1%), TLN 1%, trismus 1% Late (IMRTvs 3DRT vs 2DRT):Ocular (Visual 0% vs 9% vs20%), auditory 4% vs 9% vs 15%, skin 13% vs 18% vs 27%, ORN 9% vs 16% vs 15% Acute: Ocular 0%, acute mucositis 21%, dermatitis 6%, Late: Blindness 1% Late: Blindness 1%, TLN 5%

IMRT, 3DRT

IMRT 89% vs 3DRT 73% (2-y)

IMRT 89% vs 3DRT 76% (2-y)

Duthoy, 2005

39

31 mo

PORT 100%

Combs, 2006

46

16 mo

NR

Daly, 2007

36

51 mo

Radical 11% PORT 89%

Madani, 2009

84

40 mo

Radical 11% PORT 89%

Wiegner, 2012

52

31 mo

Radical 10% PORT 90%

Duprez, 2012

130

52 mo

Radical 22% PORT 78%

Batth, 2013

40

29 mo

Radical 65% PORT 35%

Askoxylakis, 2016

82

36 mo

Radical 30% PORT 70%

Comparative series of IMRT vs conventional modalities Jansen, 2000 73 66 mo Radical 32% PORT 68%

AdenoCa 63%, SCC 18%, Others 19% SCC 50%, AdenoCa 10%, Others 40% ACC 38%, SCC 21%, Others 41%

Blanco, 2004

106

60 mo

Radical 35% PORT 65%

Chen, 2007

127

49 mo

Radical 16% PORT 84%

Hoppe, 2007

85

60 mo

PORT 100%

Hoppe, 2008

39

90 mo

Radical 100%

Dirix, 2010

81

30 mo

PORT 100%

Guan, 2013

59

28 mo

Radical 58% PORT 32%

SCC 100%

IMRT, 3DRT

68% (3-y)

63% (3-y)

Al-Mamgani, 2013

21

54 mo

Radical 33% PORT 67%

SNUC 100%

IMRT, 3DRT

74% (5-y)

80% (5-y)

Duru Birgi, 2015

43

32 mo

SCC 100%

76% (5-y)

54

60 mo

IMRT, 3DRT IMRT, 3DRT

71% (5-y)

Suh, 2016

Radical 42% PORT 58% PORT 100%

IMRT 78% vs 3DRT 75% (3-y)

IMRT 89% vs 3DRT 60% (3-y)

SCC 50%, ACC 26%, Others 24%

IMRT vs 3DRT Acute: Xerostomia 13% vs 34%, mucositis 67% vs 98% Late: Xeropthalmia 8% vs 32%, optic neuropathy 0% vs 16%; mucositis 30% vs 74% Acute: Dermatitis 0.8%, mucositis 4.1%, xerostomia 1.6% Late: Ocular 34% IMRT vs 3DRT Acute: Ocular 14% vs 57% Late: Blindness 0% vs 29% NR IMRT vs 3DRT Acute: Mucositis 16% vs 57%

(continued on next page)

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Table 2 (continued) Study

N

Follow- up duration (mo)

Indication

Histology

RT technique

Overall survival

Locoregional control rate

Toxicities grade III and above (%)

Chopra, 2017

23

60 mo

Radical 100%

SCC 43%, ACC 26%, Others 31%

IMRT, 3DRT

IMRT 73% vs 3DRT 59% (3-y)

41% (5-y)

Late: Blindness 5%, conjunctivitis 10%, xeropthalmia 5%

Abbreviations: RT = Radiotherapy, IMRT = Intensity-modulated radiation therapy, 3DRT = Three-dimensional radiotherapy, 2DRT = Two-dimensional radiotherapy, PORT = Post operative radiotherapy, MO = Months, SCC = Squamous cell carcinoma, AdenoCa = Adenocarcinoma, ACC = Adenoid cystic carcinoma, SNUC = Sinonasal Undifferentiated Carcinoma, ENB = Esthesioneuroblastoma, NR = Not reported, ORN = Osteoradionecrosis, TLN = Temporal lobe necrosis.

Sinonasal adenoid cystic carcinoma

Adenocarcinoma and melanoma

Histomorphologically, adenoid cystic carcinoma tends to originate in salivary glands, and in the paranasal sinuses, these tumors originate from the minor salivary glands. Like squamous cell carcinoma, they commonly arise from the maxillary sinuses and nasal cavity. Though indolent, these tumors have the proclivity to metastasize to the regional nodes and lungs, and do not typically respond to platinum- or taxolbased chemotherapy [35,36]. The most unique feature about these tumors however relates to their propensity to infiltrate the nerves, and therefore, post-operative radiotherapy is routinely indicated. In this regard, prescribed radiotherapy doses do not differ compared to other histological subtypes, but the main difference relates to target contouring where it is necessary to include the involved major and minor nerves up till the afferent and efferent nerve roots [37]. In this tumor type, a single report by Chopra et al. suggests that IMRT may improve disease control compared to 3D radiotherapy [24].

Intestinal-type adenocarcinoma is a locally aggressive tumor that exists almost exclusively in the ethmoid sinus, with an etiological linkage to saw dust exposure and leather tanning industry. Surgery followed by radiotherapy is standard treatment, but operative techniques are often extensive, involving craniofacial resection and/or lateral rhinotomy with medial maxillectomy, and thus, perioperative morbidity and mortality rates are non-negligible. For this reason, endoscopic resection is preferred over open surgery due to the lower complication rates, and it is therefore crucial that high quality adjuvant radiotherapy is delivered with minimally invasive surgery. With this approach, optimistic outcome of approximately 60% local control was reported [48–50]. Additionally, combination cisplatin, fluorouracil and leucovorin has been shown to be efficacious in intestinal-type adenocarcinoma with wild-type or functional TP53 protein [51]. Therefore, it is essential to evaluate novel combinatorial chemo-radiotherapy regimes and biomarkers for patient selection and treatment intensification for this tumor type. Separately mucosal melanoma of the paranasal sinuses is a rare form of melanoma (0.2–4%), and is notoriously resistant to conventional chemo-radiotherapy [52]. Nonetheless, improved loco-regional control has been reported with IMRT, albeit this did not translate to superior overall survival [53,54]. With the advent of novel therapies like immunotherapy, combinatorial immuno-IMRT may potentially enhance the therapeutic ratio of local treatment through synergy between the DNA damage signaling pathway and modulation of the tumor microenvironment immune response [55].

Sinonasal neuroendocrine carcinoma Sinonasal neuroendocrine carcinoma accounts for only 5% of all sinonasal malignancies, and can be histomorphologically diverse ranging from the well-differentiated neuroendocrine subtype to the undifferentiated variant that may resemble undifferentiated nasopharyngeal carcinoma. The histomorphological differentiation is also correlated with prognosis, as inferred by a large meta-analysis that is based on the Surveillance, Epidemiology, and End Results database; the undifferentiated variant has a tendency to recur locally and possesses the worst prognosis [38–40]. For the more aggressive sinonasal undifferentiated carcinoma, there is a potential role for adjuvant radiotherapy or chemo-radiotherapy in terms of improving tumor control, but the efficacy of adjuvant treatment for the neuroendocrine and small cell subtypes is less certain. Likewise to other paranasal sinus subtypes, IMRT offers the similar advantage of reducing ocular complications in the adjuvant treatment of sinonasal tumors. Interestingly however, it appears that there may be a dose-response of > 60 Gy for tumor control specific to this histologic subtype, and thus offers an additional compelling rationale for the preference of IMRT over conventional techniques [41].

Recurrent paranasal sinus carcinoma Despite surgery and adjuvant IMRT, local recurrence rates of paranasal sinus tumors can still range from 29% to 79% [9,18]. While reexcision is the preferred therapeutic modality for these radioresistant tumors, often re-irradiation is the only option in the instance where local tumor recurrence extends to the major carotid vessels and critical intracranial structures like the cavernous sinus and brainstem. In these unfavorable subset of patients, IMRT may result in long-term survival in a minority of them (5-year overall survival of 36%) [13].

Esthesioneuroblastoma

Chordoma

Esthesioneuroblastoma originates from the neural crest in the upper nasal cavity. Various studies have shown that surgery and adjuvant radiotherapy is the most frequently used approach, as this combination offers superior survival compared to surgery alone [42–45]. However, esthesioneuroblastoma is typically radioresistant, and therefore, radiotherapy has limited efficacy as a single modality. In terms of radiotherapy techniques, it is evident 3D radiotherapy significantly improves local control compared to 2D technique (74% vs 59%) [46,47]. If so, IMRT may be even more superior to 3D radiotherapy, but comparative studies are needed.

Chordomas are locally aggressive tumors, accounting for 1–4% of all bone malignancies. It arises from the cellular remnants of the embryonic notochord, and about 35% of chordomas occur at the skull base [2]. It has been demonstrated that adjuvant radiotherapy improves survival of chordoma patients [56,57]. However, due to the intrinsic radioresistance of these tumors coupled with the increased sensitivity of the adjacent delicate critical neural structures, long-term control with radical IMRT alone is suboptimal, but in cases where surgery is feasible, 5-year overall survival rate of 93% has been reported with IMRT [58].

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Future directions for radiotherapy and management of paranasal sinus and base of skull tumors

Supervised research: MC, JW Wrote the first draft of manuscript: all authors Approved the manuscript: all authors.

While IMRT is an appealing solution for dose conformity in paranasal sinus and skull base tumors, radiation dosimetry may be enhanced by particle beam therapy given that this modality could ensure even sharper dose gradients in the tumor-normal tissue interphase. This is because of the physical characteristics of the Bragg’s peak that is unique to particle therapy, which includes both proton beam and carbon ion therapy. Between them, carbon ions harbor a higher relative biological effect than protons given the higher linear energy transfer [59], and this is consistent with clinical observations by Sulaiman et al.; they observed very promising 5-year survival rates of 74% for adenoid cystic carcinoma of the head and neck, although late toxicity rates were also substantial (grade ≥ 3 of 15%) [60]. It has been demonstrated that proton beam therapy delivers substantially lower mean doses to the oral cavity, esophagus, larynx and parotid glands than IMRT, but these normal structures are not the main organs at risk for this anatomical subsite of tumors [61]. Conversely, in a meta-analysis of 41 studies by Patel et al., it was observed that the primary clinical advantage of proton beam therapy relates to the better tumor control compared to even IMRT (HR 1.44 in favor of protons), thereby suggesting that perhaps additional advantages in terms of radiation dosimetry not limited to steep dose-gradients and biological effects that are exclusive to protons may be responsible for the improved efficacy [62]. Ongoing randomized and prospective studies will provide prospective level 1 data to inform us if charged particle therapy should be the standard radiotherapy modality for these tumors (ClinicalTrials.gov; NCT03274414, NCT00797498, NCT01586767). Next, despite the advent of chemo-IMRT in non-resectable T4 paranasal sinus tumors, outcomes of these patients remain poor, with high rates (30–50%) of 5-year distant metastasis [16,18,22]. In this subset of aggressive tumors, an alternative approach of using induction chemotherapy to select “sensitive” patients for concurrent chemo-IMRT has revealed optimistic results [63,64]. Using a variety of induction chemotherapy regimes that included platinum-taxane combination for squamous cell types and platinum-etoposide combination for esthesioneuroblastoma, Hanna and colleagues observed that patients with at least a partial response or stable disease to neoadjuvant treatment experienced a significantly higher tumor control rate of up to two-fold (77% vs 36%) compared to those who progressed on treatment [63]. This could represent an attractive option to spare patients who are unlikely to respond to radical treatment from debilitating radiotherapyinduced late toxicities. In such cases, CTV delineation and prescribed doses may be modified to consider post-chemotherapy tumor shrinkage, which would facilitate fulfillment of normal tissue constraints without compromising tumor control. More prospective evidence is needed in this regard to confirm the efficacy of this innovative approach.

Funding support MC is supported by the National Medical Research Council Singapore Clinician-Scientist Award – #NMRC/CSA/0027/2018, and the Duke-NUS Oncology Academic Program Proton Research Program. Zhong-Guo Liang is supported by International Communication of Guangxi Medical University Graduate Education in 2018. Conflict of interest The authors do not declare any conflict of interest. Acknowledgements We thank Jun Hao Phua and Lloyd K.R. Tan for assisting with the preparation of Figure 2. References [1] Llorente JL, Lopez F, Suarez C, Hermsen MA. Sinonasal carcinoma: clinical, pathological, genetic and therapeutic advances. Nat Rev Clin Oncol 2014;11:460–72. [2] Chugh R, Tawbi H, Lucas DR, Biermann JS, Schuetze SM, Baker LH. Chordoma: the nonsarcoma primary bone tumor. Oncologist 2007;12:1344–50. [3] Turner JH, Reh DD. Incidence and survival in patients with sinonasal cancer: a historical analysis of population-based data. Head Neck 2012;34:877–85. [4] Youlden DR, Cramb SM, Peters S, Porceddu SV, Moller H, Fritschi L, et al. International comparisons of the incidence and mortality of sinonasal cancer. Cancer Epidemiol 2013;37:770–9. [5] Claus F, Boterberg T, Ost P, De Neve W. Short term toxicity profile for 32 sinonasal cancer patients treated with IMRT. Can we avoid dry eye syndrome? Radiother Oncol 2002;64:205–8. [6] Duthoy W, Boterberg T, Claus F, Ost P, Vakaet L, Bral S, et al. Postoperative intensity-modulated radiotherapy in sinonasal carcinoma: clinical results in 39 patients. Cancer 2005;104:71–82. [7] Combs SE, Konkel S, Schulz-Ertner D, Munter MW, Debus J, Huber PE, et al. Intensity modulated radiotherapy (IMRT) in patients with carcinomas of the paranasal sinuses: clinical benefit for complex shaped target volumes. Radiat Oncol 2006;1:23. [8] Daly ME, Chen AM, Bucci MK, El-Sayed I, Xia P, Kaplan MJ, et al. Intensitymodulated radiation therapy for malignancies of the nasal cavity and paranasal sinuses. Int J Radiat Oncol Biol Phys 2007;67:151–7. [9] Madani I, Bonte K, Vakaet L, Boterberg T, De Neve W. Intensity-modulated radiotherapy for sinonasal tumors: Ghent University Hospital update. Int J Radiat Oncol Biol Phys 2009;73:424–32. [10] Wiegner EA, Daly ME, Murphy JD, Abelson J, Chapman CH, Chung M, et al. Intensity-modulated radiotherapy for tumors of the nasal cavity and paranasal sinuses: clinical outcomes and patterns of failure. Int J Radiat Oncol Biol Phys 2012;83:243–51. [11] Duprez F, Madani I, Morbee L, Bonte K, Deron P, Domjan V, et al. IMRT for sinonasal tumors minimizes severe late ocular toxicity and preserves disease control and survival. Int J Radiat Oncol Biol Phys 2012;83:252–9. [12] Batth SS, Sreeraman R, Dienes E, Beckett LA, Daly ME, Cui J, et al. Clinical-dosimetric relationship between lacrimal gland dose and ocular toxicity after intensitymodulated radiotherapy for sinonasal tumours. Br J Radiol 2013;86:20130459. [13] Askoxylakis V, Hegenbarth P, Timke C, Saleh-Ebrahimi L, Debus J, Roder F, et al. Intensity modulated radiation therapy (IMRT) for sinonasal tumors: a single center long-term clinical analysis. Radiat Oncol 2016;11:17. [14] Jansen EP, Keus RB, Hilgers FJ, Haas RL, Tan IB, Bartelink H. Does the combination of radiotherapy and debulking surgery favor survival in paranasal sinus carcinoma? Int J Radiat Oncol Biol Phys 2000;48:27–35. [15] Blanco AI, Chao KS, Ozyigit G, Adli M, Thorstad WL, Simpson JR, et al. Carcinoma of paranasal sinuses: long-term outcomes with radiotherapy. Int J Radiat Oncol Biol Phys 2004;59:51–8. [16] Chen AM, Daly ME, Bucci MK, Xia P, Akazawa C, Quivey JM, et al. Carcinomas of the paranasal sinuses and nasal cavity treated with radiotherapy at a single institution over five decades: are we making improvement? Int J Radiat Oncol Biol Phys 2007;69:141–7. [17] Hoppe BS, Stegman LD, Zelefsky MJ, Rosenzweig KE, Wolden SL, Patel SG, et al. Treatment of nasal cavity and paranasal sinus cancer with modern radiotherapy techniques in the postoperative setting–the MSKCC experience. Int J Radiat Oncol Biol Phys 2007;67:691–702. [18] Hoppe BS, Nelson CJ, Gomez DR, Stegman LD, Wu AJ, Wolden SL, et al. Unresectable carcinoma of the paranasal sinuses: outcomes and toxicities. Int J Radiat Oncol Biol Phys 2008;72:763–9. [19] Dirix P, Vanstraelen B, Jorissen M, Vander Poorten V, Nuyts S. Intensity-modulated

Conclusions Given the advanced presentation of paranasal sinus and skull base tumors at diagnosis, radiotherapy either as an adjuvant or definitive treatment is an integral therapeutic modality in the management of these tumors. IMRT has therefore contributed to the substantial improvement in clinical outcomes of these patients, both in terms of primary tumor control and importantly, avoidance of debilitating neurological toxicities. Going forward, innovative strategies such as charged particle therapy and neoadjuvant chemotherapy may further enhance the therapeutic ratio of radiotherapy, adding to the gains achieved by IMRT. Author contributions Data collection, analysis and interpretation: ZL, GK, FK, MC Initiated the project: MC, JW 67

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