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Revista Română de Anatomie funcţională şi clinică, macro- şi microscopică şi de Antropologie

Vol. XV – Nr. 1 – 2016 UPDATES

PArAnASAl SinUSES CAnCErS – MoDErn AnD ACTUAl ConSiDErATionS

D.T. iancu1, roxana irina iancu2

University of Medicine and Pharmacy “Gr.T.Popa” Iasi1. Oncology & Radiotherapy Department

2. General and Oromaxilofacial Pathology Department

PaRanasal sInUses canceRs – MODeRn anD acTUal cOnsIDeRaTIOns (abstract): cancers of the nasal cavity and paranasal sinuses are relatively uncommon. Tumours arising in the sinonasal area usually present with symptoms of local invasion. The importance of local extent is reflected in the T stage. Whilst surgery is the treatment of choice for almost all sinonasal ma-lignancies, adjuvant radiotherapy is recommended in most cases as it is difficult to resect these tumours en bloc with clear margins. IMRT is rapidly becoming the standard of care technique for external beam therapy for sinonasal malignancies. Key words: RaDIOTHeRaPY, PaRanasal canceRs, IMRT

inTroDUCTionParanasal tumors develop after the age of 40

years, except for esthesioneuroblastoma, which has a unique bimodal age distribution and oc-curs twice as often in men than in women (1).

The etiologic factors vary by tumor type and location. cigarette smoking is reported to in-crease the risk of nasal cancer, with a doubling of risk among heavy or long-term smokers and a reduction in risk after long-term cessation.

The pattern of contiguous spread of carci-nomas varies with the location of the primary lesion. Tumors arising in the upper nasal cav-ity and ethmoid cells can extend to the orbit through the thin lamina papyracea and to the anterior cranial fossa via the cribriform plate, or they may grow through the nasal bone to the subcutaneous tissue and skin. lateral wall pri-maries invade the maxillary antrum, ethmoid cells, orbit, pterygopalatine fossa, and naso-pharynx. Primaries of the floor and lower sep-tum may invade the palate and maxillary an-trum. Perineural extension (typically involving branches of the trigeminal nerve) is seen most often with adenoid cystic carcinomas.

The pattern of spread of maxillary sinus cancers varies with the site of origin. supras-tructure tumors extend into the nasal cavity,

ethmoid cells, orbit, pterygopalatine fossa, in-fratemporal fossa, and base of skull. Invasion of these structures gives lesions of the supras-tructure a poorer prognosis.

lymphatic spread and distant metastases are unusual so surgery and radiotherapy to the pri-mary site are the main treatments. Fifty per cent of tumors appear to arise in the maxilla with 25 per cent each in the nasal cavity and ethmoids. Primary tumours of the frontal or sphenoid sinus are very rare.

Clinical presentation The presenting symp-toms and signs of ethmoid sinus tumors are central or facial headaches and referred pain to the nasal or retrobulbar region, a subcutaneous mass at the inner canthus, nasal obstruction and discharge, diplopia, and proptosis. In one study of 34 patients with ethmoid sinus cancers treat-ed at MD anderson cancer center between 1969 and 1993,nasal cavity symptoms (nasal obstruction, epistaxis, discharge) were reported in 25 patients (74%), orbital symptoms (diplo-pia, orbital pain, vision loss, proptosis, inner canthus mass, tearing) in 12 (35%), headache in 6 (18%), and hyposmia or anosmia in 5 (15%) (2).

Maxillary sinus cancers usually are diag-nosed at advanced stages. symptoms and signs

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are facial swelling, pain, or paresthesia of the cheek induced by disease extension to the pre-maxillary region, epistaxis, nasal discharge and obstruction related to tumor spread to the nasal cavity, ill-fitting dentures, alveolar or palatal mass, unhealed tooth socket after extraction from spread to the oral cavity, and proptosis, diplopia, impaired vision, or orbital pain due to orbital invasion (3).

nasal cavity tumors present with symptoms and signs of nasal polyps (e.g., chronic unilat-eral discharge, ulcer, obstruction, anterior head-ache, and intermittent epistaxis), hence delay-ing the diagnosis. additional symptoms and signs develop as the lesion enlarges: medial orbital mass, proptosis, expansion of the nasal bridge, diplopia resulting from invasion of the orbit, epiphora due to obstruction of the nasol-acrimal duct, anomaly of smell or anosmia from involvement of the olfactory region, or frontal headache due to extension through the cribriform plate (4).

Diagnostic workup Imaging has a crucial role in the staging of sinonasal tumors. Mag-netic resonance imaging (MRI) and computed tomography (cT) scans are complementary (5). MRI is superior at detecting direct intracranial/perineural/leptomeningeal spread (6). T2-weight-ed MRI can be helpful in distinguishing tumor (low signal) from obstructed secretions (bright). cT is superior for detecting early cortical bone erosion or extension through the cribriform plate or orbital walls (7).

Transnasal biopsy is preferred for tumors arising from or extending into the nasal cavity or nasopharynx. some paranasal sinus tumors may be more easily sampled using transoral procedures or an open caldwell-luc approach.

complete blood counts and serum chemis-

tries can be used to screen for the presence of distant metastases. abnormalities of these tests can be further investigated as necessary.

The seventh edition of the american Joint committee on cancer’s (aJcc) AJCC Cancer Staging Manual tumor-nodemetastasis (TnM) classification includes staging for cancers of the maxillary sinus, ethmoid sinus, and the nasal cavity (8).

Pathologic Classification Most nasal vesti-bule cancers are squamous cell carcinomas; the remaining tumors are basal cell or adnexal carcinomas. Most cancers of the nasal cavity and paranasal sinuses are also squamous cell carcinomas, although minor salivary gland neo-plasms (adenocarcinoma, adenoid cystic carci-noma, and mucoepidermoid carcinoma) account for 10% to 15% of lesions in these locations. Melanoma accounts for 5% to 10% of nasal cavity malignancies but is rare in the paranasal sinuses. neuroendocrine carcinomas of the sinonasal region (including small cell carci-noma, esthesioneuroblastoma, and sinonasal undifferentiated carcinomas), lymphomas, sar-comas, and plasmacytomas are even less com-mon (9).

General management There is non-rando-mised trial evidence that radiotherapy improves local recurrence rates for all tumour types. It may also be appropriate not to irradiate after surgery for sinonasal melanoma, reserving ra-diotherapy for the almost inevitable recurrence.

combined surgery and postoperative radio-therapy lead to optimal 5-year survival rates of 50 per cent in maxillary sinus squamous cell cancers, 60 per cent in ethmoid adenocarci-noma, 75 per cent in olfactory neuroblastoma and 30 per cent in sinonasal melanoma (10).

If complete resection is considered impos-

Fig. 1. a – cT scan of a left sinonazal cancer; b – MRI scan of a rinosinusal cancer

a b

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sible because of invasion of local structures (e.g. cranial fossae, masticator space) or if the patient declines surgery, primary radiotherapy is used to obtain local control and, occasion-ally, cure.

Mucosal melanomas and other locally ad-vanced sinonasal tumours in patients with poor performance status are treated with palliative radiotherapy as cure is unlikely. This approach should be discussed with individual patients.

neoadjuvant chemotherapy (i.e., chemo-therapy given before surgery) can reduce tumor volumes, which may allow a less extensive sur-gical resection than would be possible other-wise. similarly, chemotherapy given before primary radiation therapy can also reduce tu-mor volumes and facilitate radiotherapy plan-ning by increasing the distance between tumor borders and critical organ structures such as brain, chiasm, optic nerve, or spinal cord.

concurrent chemoradiation therapy can also be used for patients with medical conditions that preclude surgery if those patients have good performance status. Depending on the patient’s performance status and renal function, single-agent cisplatin or carboplatin can be used con-currently with external beam radiation for lo-cally advanced, unresectable squamous cell carcinoma. neoadjuvant chemotherapy or con-current chemoradiation with etoposide and cis-platin or carboplatin can be used to treat sinon-asal undifferentiated carcinoma, neuroendocrine carcinoma, or small cell carcinoma (11).

adjuvant radiotherapy should begin after adequate surgical healing – usually within six weeks of operation. concomitant chemotherapy with cisplatin may be given in stage III and IV squamous cell carcinomas, particularly if dis-ease is unresectable or if excision margins are positive. If primary radiotherapy is given, dis-

ease should be reassessed 4–6 weeks later by a surgeon to see if resection is then possible.

Data acquisition Patients should be immo-bilised supine in a Perspex or thermoplastic shell. If the neck is not irradiated, the shoulders do not need to be immobilised. If the low neck nodes are to be treated (level III–V) the neck should be extended to allow treatment of most of the neck nodes with an anterior beam, avoid-ing the oral cavity and pharynx where possible.

a mouth bite is used to depress the tongue and oral cavity away from the treated volume and reduce acute morbidity. Patients should be asked to look straight ahead to avoid rotating the lens or retina, particularly if the orbital cavity is included in the treated volume. Wax plugs in the nostrils are used if the tumour extended inferiorly in the nasal cavity to enable a more uniform dose distribution.

CT scanning a cT scan is performed with 3 mm slices from 2 cm superior to the supe-rior orbital ridge to the hyoid bone (but ex-tended to include the low neck if neck nodes are to be treated). Fused cT-MRI images can be useful in the definition of the optic pathways and skull base. MRI also allows retained secre-tions to be differentiated from tumor where resection has been incomplete.

Because maxillary cancers are usually diag-nosed at a locally advanced stage and surgery is the primary therapy, most patients receive postoperative radiation therapy. Delineation of target volumes is based on physical examina-tion, pretreatment imaging, intraoperative find-ings (tumor extension relative to critical struc-tures such as orbital wall, cribriform plate, cranial nerve foramina, and ease of resection), and pathologic findings (such as positive mar-gin or perineural invasion).

Where resection is not possible or has been incomplete, the GTV is outlined but defining

Fig 2. Perspex immobilization shell fixed to the couch top in fifth places.

Fig 3. cT- scan for a pT4a carcinoma of the left maxilla

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the cTV is the most important step for most patients. The proximity of these tumours to critical structures such as the optic nerves and chiasm, brainstem, and lacrimal glands man-dates meticulous cTV definition so that radio-therapy can be targeted to sites at highest risk of relapse in individual tumours and reduce the risk of long-term radiation damage. The impor-tance of discussion between the surgeon, pa-thologist and radiation oncologist in defining sites at greatest risk of recurrence after surgery cannot be overemphasised. Preoperative imag-ing should be viewed beside the cT planning dataset to ensure that initial sites of disease are covered.

The cTV should encompass all initial sites of disease (presurgery GTV), the mucosa of adjacent compartments of the sinonasal com-plex and a 10 mm margin at least from initial sites of GTV where no good bony barrier to invasion exists (e.g. masticator space, cribri-form plate and infraorbital fissure). For most tumours, the cTV will include the ipsilateral maxillary sinus and nasal cavity and the ethmoid sinuses bilaterally. The superior extent can be modified for a very inferior tumour. Where the primary involved the maxilla, consideration should be given to including the pterygopalatine and masticator space. When a maxillary tumour has invaded inferiorly, the hard palate should be included in the cTV so as to allow a 10 mm margin around original disease.

The cTV for tumours involving the ethmoid sinuses should include the sphenoid sinus. Where initial disease came close to the orbit or invaded the lamina papyracea, the cTV should include that portion of the medial and inferior orbital wall. The orbital cavity should be in-

cluded in the cTV if the orbital wall has been breached by tumour or if tumour has grown superiorly through the inferior orbital fissure. Where a craniofacial excision has been carried out, the cTV should extend 10 mm superior to the cribriform plate or 10 mm superior to initial sites of disease, whichever is greater. Olfactory neuroblastomas arise from the cribriform plate and particular attention should be paid to the cTV at this site.

The cTV is expanded isotropically (usually by 3–5 mm but determined by local audit) to form the PTV. Organs at risk to be outlined include the lenses, lacrimal glands (in the su-perolateral orbit and upper eyelid), optic nerves and chiasm, spinal cord, brainstem and pitui-tary gland. some centres also expand these structures (in particular the optic nerves) by 2–3 mm to create a PRV to account for system-atic and random errors. PTV so adding a 3 mm margin to both the cTV and the OaR may be unnecessary (12).

Dose solutionsconventional treatment - The commonest

beam arrangement for sinonasal tumours uses an anterior beam to provide most of the dose with an ipsilateral or bilateral wedged lateral beams added to provide extra dose to the pos-terior part of the PTV. For 3D-conformal ra-diation, a three-field technique consisting of an anterior and right and left lateral field is used for tumors involving the suprastructure or ex-tending to the roof of the nasal cavity and ethmoid cells. This arrangement cannot provide a uniform dose distribution. Hot-spots of >110 per cent are usually found anteriorly and inad-equate posterior coverage occurs in spite of the lateral beams. Mlcs are used to shape each beam to the PTV. The lateral fields have their anterior border behind the lens and can be angled 5° posteriorly to avoid exiting through the contralateral lens. as a result, not all the PTV will be within the lateral beams. The course of the optic nerves becomes more me-dial at the posterior part of the orbital cavity as they exit through the optic canal. at this point, the nerves commonly overlap the PTV. The authors recommend a dose limit of 50 Gy (in 2 Gy fractions) for the optic nerve and chi-asm, but where there is particularly high risk of local recurrence (which could itself cause blindness) 55 Gy can be accepted to one optic nerve. In practice, this necessitates a two-phase

Fig. 4. conformal radiotherapy for a maxillary sinus with invasion of ethmoidal cells.

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technique (13). The whole PTV is treated to 50 Gy. Then the Mlcs are moved to ensure the optic nerve doses remain acceptable, al-though inevitably the posterolateral part of the PTV will not be in the treated volume. Where the orbital contents are included in the cTV (or after an orbital exenteration) equally weighted anterior and lateral wedged beams are used. The shape of the PTV means that simple con-ventional planning will not be able to produce adequate dose to the PTV and spare critical normal structures (14).

complex treatment - IMRT provides a more conformal dose distribution to the unusual PTVs in sinonasal cancer. Five-or seven-field coplanar beams have been used but these ar-rangements will increase dose to the orbital contents. a non-coplanar arrangement of three to five sagittal midline beams with right and left lateral beams avoids entry or exit of beams through the eyes and provides a uniform dose distribution. Where the PTV overlaps the optic nerve, there must still be either an acceptance of increased risk of blindness or a reduction in PTV coverage (15). IMRT is the preferred treatment method as it generally yields better dose distribution in terms of both tumor cover-age and sparing of normal tissues than can be achieved with 3D-conformal radiation therapy.

IMRT is rapidly becoming the standard of care technique for external beam therapy for sinonasal malignancies (16). Proton therapy may offer additional advantages over IMRT in terms of further reducing the dose to normal tissues while achieving equivalent doses to the target volume.

For primary radiation therapy using IMRT, the prescription doses are 66 to 70 Gy to the

gross tumor volume (the prechemotherapy vol-ume for those receiving systemic treatment), plus a 1- to 1.5-cm margin of normal-appearing tissue 59 to 63 Gy to other secondary clinical target volumes such as the rest of the involved sinus and wider region around the primary tar-get, and 54 to 57 Gy to the tracts of nerves (if perineural invasion is present) and to elective nodal regions.

More recently, there has been some inter-est in arc-based or rotational therapies in an attempt to overcome some of the limitations associated with fixed field IMRT. The basic concept of arc therapy is the delivery of radia-tion from a continuous rotation of the radiation source and allows the patient to be treated from a full 360° beam angle. arc therapies have the ability to achieve highly conformal dose distri-butions and are an alternative form of IMRT. However, a major advantage over fixed gantry IMRT is the improvement in treatment delivery efficiency as a result of the reduction in treat-ment delivery time and the reduction in MU us age with subsequent reduction of integral ra-diation dose to the rest of the body. In addition to the subsequent advantages from the shorter treatment delivery time, a further potential ben-efit is the availability of extra time within a set treatment appointment time slot to employ image-guided radiotherapy (IGRT). IGRT in-volves the incorporation of imaging before and/or during treatment to enable more precise verification of treatment delivery and allow for adaptive strategies to improve the accu-racy of treatment. The main drawback of IGRT is the requirement for more time on the treat-ment couch and an increase in the total amount of radiation to the patient, especially with dai-

Fig.5. IMRT dose solution: a – right maxillary sinus; b – left sinonasal tumour.

a

b

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ly IGRT imaging schedules. These disadvan-tages are less of an issue with arc therapies, which have shorter treatment delivery times and fewer MU.

arc therapies have gained widespread clini-cal interest in radiation oncology over the past decade. arc therapies have several potential advantages over standard techniques such as intensity-modulated radiation therapy, with im-plications for patients, administrators, and on-cologists. This review focuses on the rationale for arc therapy, descriptions of the modern arc techniques that are currently clinically availa-ble, and highlights some distinguishing features of arc therapies, such as dose distributions, treatment times, and imaging capabilities. arc therapies are exciting examples of progress in radiotherapy through technological innovation, aimed at ultimately improving the therapeutic ratio for patients receiving radiation.

Follow-Up and recurrences salvage is pos-sible for some persistent or recurrent lesions. In particular, recurrent cancers of the nasal vestibule remain curable with salvage surgery after primary radiation or occasionally with salvage radiation after primary surgery. Re-gional recurrences can be treated successfully with neck dissection with or without postop-erative radiation depending on the pathologic features. Treatment options are limited for tu-mors that recur after combined-modality ther-apy, although a few highly selected patients may qualify for reirradiation with curative intent. cumulative doses of radiation to neural tissues (spinal cord, brainstem, brain, optic structures) are the main limitation to reirradiation.

Most oncologists recommend a second base-line physical examination together with cT, MRI, or positron emission tomography with cT for patients with nasal cavity or paranasal

sinus tumors at 3 months after treatment. com-mon practice is to repeat clinical examination and imaging when indicated every 4 months for the first 3 years after treatment, every 6 months for the fourth and fifth years after treatment, and annually thereafter. In addition to monitor-ing possible tumor recurrence, these follow-up visits are critical .

The aim of this study was to evaluate the dosimetric parameters (cI – conformity index, HI – homogeneity index) in main radiotherapy techniques (3D-cRT, IMRT and VMaT-Rapi-darc) and to compare the differences between techniques.

MATEriAl AnD METHoDThe study included 11 patients diagnosed

with rino-sinusal cancer treated in IRO Iasi with curative intenttion (60-66Gy) during January 2013 - October 2015. all patients were evalu-ated preoperative (cT or MRI) and then they perform a cT-scan with 3 mm slices, from 2 cm superior to the superior orbital ridge to the hyoid bone (but extended to include the low neck if neck nodes are to be treated), and ther-moplastic immobilization mask.

Fused cT-MRI images were performing in the definition of the optic pathways, skull base and for target volume delineation (diagnostic imaging and image simulation). The plans were validated by using the dosimetric evaluation protocols for OaR Quantec and emami.

For a right maxillary sinus cancer patient with locally advanced, alternative plans were proposed to compare IMRT and VMaT tech-niques dosimetric by-Rapidarc® (a semiarc of 180o, 360o arc and full double arc. as equip-ment we used a Varian clinac iX, arccHecK® and a software planning: eclipse Treatment Planning system ™.

Fig. 6. VMaT – Maxillary carcinoma: a – arcTherpy solutions; b – IMRT solutions

a b

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Fig. 7. Different radiotherapy tehcniques, same case

Fig. 8. Dosimetric comparision between different radiotherapy tehcniques

rESUlTScI (ratio between volume framed by 95%

isodose and the volume of PTV’s) closest to the optimum value “1” is in IMRT and VMaT-Rapidarc® techniques.

HI (ratio between volume framed by 98% isodose and volume framed by 50% isodose) is closest to the optimum value “0” through IMRT technique.

concerning OaR (organs at risk) there are significantly decreases in VMaT-Rapidarc® for the dose received by controlateral eye. VMaT-Rapidarc® incomplete 180° arc offers a better

solution of treatment for maxillary sinus ma-lignancies.

ConClUSionS

IMRT offers a high dose gradient around PTV for tumors located close to OaR, but in creases the risk of under-dosage by errors of conturing and dosimetry concerning the 3D-cRT.

Reduced tumoral volumes receiving high dose decreases acute toxicity and enable dose escalation, with the compromise of irradiation of large volumes at low level of dose.

Implementing of dosimetry for IMRT plans

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together with DVH biological effects, fully cor-related with functional imagistic (PeT-cT, MRI diffusion) will offer clear new benefits of IMRT and VMaT-Rapidarc®.

In busiest centers by saving over 40% of the time-machine, VMaT-Rapidarc® technique (especially with semiarc 180º) solution is a feasible variant.

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