OROPHARYNGEAL CANCERS

Dr. Ayush Garg

Anatomy

Epidemiology

Risk factors

Clinical Features

Staging

Workup

Management

Conclusion

Outline

• According to American Joint Committee on Cancer (AJCC) staging definition:

• The oropharynx is theportion of the continuity of the pharynx extending from the plane of the superior surface of the soft palate to the superior surface of the hyoid bone (or vallecula).

Oropharynx

Base of the tongue,

Vallecula,

The inferior (anterior)

surface of the soft

palate

The uvula,

The anterior and

posterior tonsillar

pillars,

The glossotonsillar

sulci,

The pharyngeal tonsils,

and

The lateral and

posterior pharyngeal

walls.

Anatomy

Boundaries

Superior

Anterior

Lateral

Posterior

Inferior

(Netter 2003)

Superior

Anterior

Lateral

Posterior

Inferior

Anatomy

Boundaries Soft palate

(Netter 2003)

Superior

Anterior

Lateral

Posterior

Inferior

Anatomy

Boundaries

Oropharyngeal isthmus

Palatoglossal arch

(Netter 2003)

Superior

Anterior

Posterior

Inferior

AnatomyBoundaries

Palatopharyngeal arch

Palatine tonsil

Lateral

(Netter 2003)

Superior

Anterior

Lateral

Posterior

Inferior

Anatomy

Boundaries

Second and third cervical vertebrae

(Netter 2003)

Superior

Anterior

Lateral

Posterior

Inferior

Anatomy

Boundaries

Level of hyoid

Vallecula

(Netter 2003)

Lymphatic Drainage

Levels II, III, and IV most common

Retropharyngeal

Posterior pharyngeal wall

Palatine tonsil

Bilateral drainage

Tongue base

Soft palate

Posterior pharyngeal wall

The probability of lymphatic

metastasis is related to the size

and location of the primary tumor

within the oropharynx.

DISTRIBUTION OF CLINICAL METASTATIC NECK NODES FROM HEAD AND NECK SQUAMOUS CELL CARCINOMAS

Epidemiology

Account for approximately 10-12% of head and

neck malignancies worldwide.

Incidence is high in developing countries 4.8 in

100,000.

There is increase in HPV associated oropharyngeal

cancers.

Peak incidence in 6th or 7th decades of life.

More common in men(4:1).

Risk Factors

Patient related-

Age and gender: predisposition in males especially those who are smokers and older than 50 years.

Lifestyle: cigarette smoking, alcohol, tobacco; tobaccoand alcohol are synergistic risk factors.

HPV- associated orpharyngeal cancer

• HPV is a circular double stranded DNA virus

• Found to be associated with cervical cancer in 1983.

• Appr. 150 types of HPV have been identified

• HPV 16 is most common type asso. with more than 90% of all oropharyngeal cancers.

HPV structure

• HPV genome encodes 3 oncoproteins(E5,E6,E7),regulatory genes(E1,E2),capsidproteins(L1,L2).

• Oncogenesis is primarily mediated via the E6 and E7 proteins. HPV E6 complexes promote ubiquitin-mediated destruction of p53.

• Loss of cellular p53 function results in dysregulation of the G1/S and G2/M checkpoints.

• E7 is believed to be the major transforming oncogene during early carcinogenesis, with E6 functioning later.

Clinical characteristics-HPV associated

• more likely to occur among men than women (3:1)

• most of whom (80%) will not have a smoking history.

• diagnosed in individuals who are 5 to 10 years younger than HPV-unassociated oropharyngeal cancers

• p16 IHC testing is an accurate surrogate for HPV infection

Response of HPV associated cancers

• Patients with HPV-associated oropharyngeal cancers have significantly better outcomes compared to HPV-unassociated oropharyngeal tumors.

• In RTOG 0129, HPV status was independently associated with improved outcomes. Three-year overall survival was 82% in HPV-positive patients compared with 54% in HPV-negative patients

Pathology

• Squamous cell carcinoma (SCC) accounts for >90% of oropharyngeal cancer

• Minor salivary gland carcinomas

• Lymphoma

• Plasmacytoma

• Sarcoma

• Melanoma

Route of spread

Local

Oropharynx cancers may invade

vallecula/larynx,

parapharyngeal area into the pterygoid muscles/plates,

nasopharynx, and oral cavity (oral tongue and retromolartrigone)

Perineural invasion especially along branches of CN V and VII

Lymph node involvement is seen in 55% of oropharynxcancers.

• most common location for lymph node metastases from oropharyngeal cancers is the ipsilateral level II.

• The typical order of metastatic progression is systematic, from the upper jugular chain nodes superiorly (level I/II; first echelon), to mid-cervical (level III), and to lower cervical nodes (level IV), inferiorly. Retropharyngeal nodes represent a nodal drainage for oropharynx cancers.

• Contralateral nodes are at risk for tumors near midline, advanced T- and N-stage diseases

Distant Metastasis in patients with advanced-stage disease

• The most common site of hematogenous metastasis is Lung.

• Seen in about 20% cases.

• However, a primary lung cancer should always be excluded.

Clinical Features

Asymptomatic neck

node/mass.

Pain

Dysphagia

Otalgia

Foreign body sensation

Hemoptysis

Weight loss

Voice changes

Otalgia

T, tumor

N, node

M, metastasis

Oropharyngeal Cancer

Staging Tx: primary site cannot be evaluated

T0: no evidence of carcinoma

Tis: carcinoma in-situ

T1: tumor < 2cm in greatest dimension

T2: tumor 2-4cm in greatest dimension

T3: tumor > 4cm in greatest dimension

T4

T4a: invades larynx, deep/extrinsic tongue

muscles, medial pterygoid, hard palate, or

mandible

T4b: invades lateral pterygoid, pterygoid plates,

lateral nasopharynx, skull base, or carotid

T, tumor

N, node

M, metastasis

Invasion of pre-epiglottic fat

(i.e. laryngeal involvement)Invasion of medial

pterygoid muscle

T4a: invades larynx, deep/extrinsic tongue muscles, medial

pterygoid, hard palate, or mandible

T4b: invades lateral pterygoid, pterygoid plates, lateral

nasopharynx, skull base, or carotid

T4

T4a: invades larynx, deep/extrinsic tongue muscles, medial

pterygoid, hard palate, or mandible

T4b: invades lateral pterygoid, pterygoid plates, lateral

nasopharynx, skull base, or carotid

Encasement of

carotid artery

Involvement of

foramen ovale

T, tumor

N, node

M, metastasis

Nx: Regional lymph nodes cannot be assessed

N0: No regional lymph node metastasis

N1: single ipsilateral node < 3cm

N2 N2a: single ipsilateral node involved, ˃3 but

˂6cm

N2b: multiple ipsilateral nodes, < 6cm

N2c: bilateral or contralateral nodal

involvement, none ˃6cm

N3: nodal involvement > 6cm

Staging

T, tumor

N, node

M, metastasis

Staging

Mx: distant metastasis cannot be evaluated

M0: no distant metastasis

M1: distant metastasis present

Diagnostic workup

• Complete physical examination-examination of oral cavity, oropharynx, neck.

• Endoscopic Examination

Fiberoptic laryngoscopy is done to assess local extent of dosease.

Evaluation of the upper aerodigestive tract is crucial to evaluate the primary site of disease and the presence of synchronous primaries.

Laboratory tests

Includes:

1) Complete blood count

2) Basic blood chemistry

3) Hepatic and metabolic panels

4) Testing for HPV in the biopsy specimen (p16 IHC testing)

Biopsy

Tissue from either primary tumor or neck lymphadenopathy is crucial for pathologic diagnosis.

Imaging-

CECT Face & Neck

Chest X-ray

Ultrasound whole abdomen

CECT Thorax (if indicated)

FDG-PET/CT scan

CT Scan

• Scan slice thickness <5 mm is desirable to optimize the detection of smaller pathologically involved lymph nodes.

• Pathologically involved lymph nodes are characterized on CT imaging as those that are enlarged, enhance with contrast, and have a necrotic centre.

• Primary tumors appear as contrast-enhancing masses, distorting normal anatomic relationships.

• Whereas ulceration and invasion into surrounding organs are readily assessed, submucosal spread is often difficult to characterize with CT.

• Thoracic CT should be performed routinely to assess for pulmonary spread of oropharyngeal cancer patients with N2 or greater nodal disease, as well as those with advanced primary tumors due to risk of pulmonary metastases.

A 2.2-cm enhancing neoplasm of

the tongue base (open arrows)

indicating a T2 primary.

The lesion extends into the

vallecular (dashed white arrow)

but does not invade the adjacent

genioglossus muscle (dashed

black arrow). There are abnormal

heterogeneously enhancing

bilateral level IIa and right level IIb

lymph nodes (black arrows)

consistent with N2c nodal spread.

Magnetic Resonance Imaging

• Magnetic resonance imaging (MRI) can be a useful imaging tool for oropharyngeal tumors.

• Squamous cell carcinoma appears as low signal in T1 MRI and corresponding high signal in T2 sequences.

• The ability of MRI to differentiate tumor from soft tissues is particularly useful when determination of the extent of base of tongue or oral tongue invasion is needed.

• Additionally, MRI is useful in patients with compromised renal function who are not able to receive iodine-based CT contrast agents.

Positron Emission Tomography

• Positron emission tomography (PET) and/or PET/CT imaging incorporating tumor physiology in conjunction with anatomic information are now routinely recommended for the initial staging of oropharyngeal cancer patients.

• PET-based imaging can assess not only the locoregionalburden of disease but also detect and quantify distant metastases.

• It has high sensitivity approaching 100%, and about 60% specificity.

• As per NCCN guidelines FDG-PET/CT should generally considered in Stage III-IV disease.

Treatment modalities

• Surgery

• Radiotherapy

• Chemotherapy

• Targeted Therapy

• Stage I and stage II tumors are considered as early stage, whereas stage III and IV (nonmetastatic) are considered locoregionally advanced disease.

• Early-stage tumors are usually well controlled with a single local modality, either radiotherapy or surgery.

• For locoregionally advanced disease, two appropriate treatment strategies are used: (a) either surgery followed by radiation therapy with or without chemotherapy based on pathologic risk factors or (b) radiotherapy usually given with chemotherapy.

Surgery

• Base of Tongue

• Surgery plays a limited role in the management of base of tongue tumors given the inherent morbidity of a near-total or total glossectomy, which is required for large and/or midline tumors.

• For select, well-lateralized base of tongue tumors with minimal cervical lymphadenopathy, a partial glossectomycan be performed.

• Given the high propensity for occult microscopic nodal involvement, bilateral cervical lymph node dissection is often performed.

• Base of tongue tumors in close proximity to the laryngeal apparatus, such as those arising in the vallecula, often require a supraglottic or total laryngectomy to achieve adequate margins of resection.

• Traditional surgical approaches for base of tongue tumors include :

• The midline mandibulotomy (splitting the lip, mandible, and oral tongue midline),

• The lateral mandibulotomy (dividing the mandible near the angle and approaching the base of tongue from the side),

• The floor drop procedure (elevating the inner periosteum from the mandible from angle to angle, which releases the entire floor of mouth and oral tongue into the neck, exposing the base of tongue).

Tonsil Cancers

• For small (<1 cm) early-stage tonsil cancers confined to the anterior pillar, a wide local excision can achieve adequate tumor-free margins, whereas tumors involving the palatine tonsil often require a radical tonsillectomy.

• For both of these situations, the tonsil is approached transorally, with primary closure.

• Larger tumors with extension onto the tongue, onto the mandible or into surrounding tissue often require a composite resection, usually including resection of the tonsil, tonsillar fossa, pillars, a portion of the soft palate, tongue, and mandible.

• For tumors not adjacent or adherent to the mandible, a midline mandibulotomy approach is used.

• For tumors adherent to the mandible, a partial mandibulectomy is used.

• Defects are often closed with a myocutaneous flap.

• Complications from surgery depend on the extent of resection, with impairment in swallowing possible by removal of part of the tongue or soft palate.

Soft Palate Cancers• Surgical resection is rarely recommended as initial therapy

for soft palate tumors.

• Resection of the soft palate is often associated with significant reflux into the nasopharynx during swallowing, even with the use of custom prostheses.

• Additionally, because of the midline location, primary disease spreads bilaterally to the neck with frequency high enough to require elective treatment.

• However, when surgery is performed, the tumors are approached transorally and a full-thickness wide local resection is performed for tumors limited to the soft palate.

• A more extensive composite resection is required if disease extends to surrounding structures.

• Flaps or prostheses are used to preserve velopharyngeal competence. Nasal speech is also often a consequence.

Transoral Laser Surgery

• Small series report favorable outcomes for selected patients with stage I through stage IV oropharyngeal tumors treated with transoral laser microsurgery with or without neck dissection, followed by adjuvant radiotherapy or chemoradiotherapy.

• Positive margin rates are variable (3% to 24%) and appear to vary based on primary site, being more common in base of tongue tumors.

• Complications include postoperative hemorrhage (5% to 10%). Temporary tracheostomy placement is relatively common (17% to 30%) and needed for exposure, airway control, or aspiration following extensive resection.

• High rates of locoregional control following this procedure have been reported, primarily for stage I/II patients (87% to 100%), although for stage III/IV patients, local recurrence is more common (20% to 30%).

Transoral Robotic Surgery

• The use of a computer-aided interaction between the surgeon andthe patient is commonly referred to as robotic surgery.

• The most common robotic surgical system, the da Vinci SurgicalSystem, is comprised of three surgical instruments and a binocularendoscope controlled by robotic arms and inserted under direct orendoscopic guidance by the surgeon from a patient-side apparatus.

• The surgeon controls the instruments from a console separated fromthe patient.

• The operative environment is visualized virtually, in a three-dimensional (3D) environment created via a computer that links theenvironment provided by the binocular endoscope to the position ofthe instruments.

• The surgeon’s movements are translated into the micromovementsof the instruments. The advantages of this system include motionscaling, which can increase precision as well as reduce hand tremorand fatigue.

• When the system is used for transoral surgeries, an assistant isoften positioned by the patient’s head.

• There are no prospective randomized studies supporting theuse of transoral robotic surgery (TORS) for oropharyngealtumor resection over conventional surgery.

• Until mature prospective multi-institutional series andrandomized data are available, the true utility of transorallaser microsurgery and TORS remains unknown.

• Although early results are favorable and associated withshorter hospital stays, long-term data are needed.

• Additionally, standard oncologic principles limiting thenumber of modalities used to minimize treatment relatedside effects should be carefully considered prior towidespread adoption of the surgical techniques.

Neck Management

• The type of neck dissection (comprehensive or selective) is defined according to preoperative clinical staging, is determined at the discretion of the surgeon, and is based on the initial preoperative staging as follows:

N0= Selective neck dissection, atleast Levels II-IV

N1-N2a-c= Selective or comprehensive neck dissection

N3= Comprehensive neck dissection

Radiotherapy

• Definitive chemoradiotherapy is the treatment of choice.

• For early-stage oropharyngeal cancers, the use of radiation therapy as a single modality is associated with good outcomes and functional preservation.

• Patients with locoregionally advanced oropharyngeal cancer, concurrent chemoradiotherapy is the standard treatment. Resection is generally not recommended given the associated surgical morbidity.

Chemotherapy

• Used in concurrent setting along with radiotherapy

• Recurrent and metastatic tumors

• As neoadjuvant chemotherapy, but there is no definitive role.

Radiotherapy techniques

• Two dimensional planning

• 3D planning

• IMRT

Conventional borders

Carcinoma Base of tongue lower Neck Field

Radiation Fields for Carcinoma Oropharynx

• Conventional RT films for oropharyngeal cancer

3D Planning

• Patients should undergo simulation, preferably CT based, to allow for optimal radiotherapy planning.

• A peripheral IV should be placed prior to simulation for the delivery of low osmolar iodinated contrast to optimize the distinction between vascular structures and lymph nodes.

• Patients are positioned supine, extended head position is preferable.

• The shoulders should be positioned as caudally as possible to allow adequate exposure of the neck. This can be achieved either with shoulder pulls or with commercially available devices. The head should be immobilized with a thermoplastic mask.

• Care should be taken to ensure that the mask is tight and should not allow movement of the nose, chin or, forehead.

Radiotherapy volumes-ICRU 50

• The GTV includes all known primary and cervical lymph node tumor extension based on clinical, endoscopic, and imaging findings. Care should be taken to look for fat stranding, which could be indicative of extranodal extension.

• CTV indicating the margin needed to cover microscopic extension not visible on clinical and imaging modalities is not known. Current RTOG guidelines specify an extension of 0.5 to 1 cm from the GTV to form the high-dose CTV.

• CTVs are expanded to account for organ motion and setup uncertainty ideally based on institution-specific data to form PTV.

(T4aN2bM0). The patient was treated with concurrent chemotherapy with the primary and nodal gross disease receiving 70 Gy using IMRT. Contours: red colorwash(GTV, 70 Gy), blue colorwash (CTV1, 60 Gy), yellow colorwash (CTV2, 56 Gy), blue (left parotid gland). Parts A to D are sequential axial isodose images with the following isodose lines: green (70 Gy), teal (60 Gy), orange (56 Gy), and dark green (50 Gy). E is reconstructed AP radiographicstudy shows the contoured structures projected craniocaudally.

Dose & fractionation

Standard is 66-70 Gy delivered @ 1.8-2 Gy/# for 6-7 wks along with concurrent cisplatin 35mg/m2 weekly.

Hyperfractionation -81.6Gy @ 1.2Gy/# twice daily in 7 weeks,

EORTC 22791,hyperfractionated radiotherapy was associated with statistically significant improvements in locoregionalcontrol (5-year, 59% vs. 40%).

Additionally, there was a trend toward improved overall survival (p = 0.08) particularly in stage III patients.

Other Fractionation Regime

1. Accelerated regimen of 66 to 70 Gy delivered in 2-Gy daily fractions 6 days a week

2. Accelerated fractionation with concomitant boost regimen -72 Gy in 1.8-Gy fractions for 14 fractions followed by a 1.8-Gy morning and a 1.5-Gy afternoon boost to gross disease

3. Simultaneous integrated boost(SIB)-RTOG completed a study (00-22) in early-stage (T1-2, N0-2) oropharyngeal cancer patients treated with bilateral neck radiotherapy, gross tumor-2.2Gy, intermediate-risk,-2Gy and low-risk-1.8Gy planning target volume

Brachytherapy

Indications

• <= 5 cm lesions in BOT, Soft palate, tonsil or valeculla may be implanted

• Primary implant in lesions < 1cm or exophytic leisions

• Used in conjunction with EBRT after 40-50 Gy to primary and the nodes

• Recurrent leisions or new lesions in previously irradiated regions

• Brachytherapy, the application of radioactive materials in close proximity to tumors, was developed in the pre-IMRT, preconcurrentchemoradiotherapy era as a means to deliver a tumoricidal dose to gross tumors while minimizing dose to the mandible.

• The advent of improved radiotherapy planning and delivery techniques, in addition to a recognition that osteoradionecrosis secondary to brachytherapy is significantly underreported, has corresponded to a major decrease in the utilization of brachytherapy for oropharyngeal tumors.

• Typically, catheters are implanted under general anesthesiain the operating room, with two capable physicians present to handle unexpected events.

• Although low dose rate brachytherapy has previously been the most common type of brachytherapy used, high dose rate (HDR) and pulsed dose rate (PDR) techniques are becoming much more common and sometimes preferred given the ability to control dwell times and develop more customized dose distributions.

• High rates of locoregional control have been achieved using an integrated treatment approach of external-beam radiotherapy directed at the primary and bilateral neck, followed by a brachytherapy boost.

• Complications of brachytherapy for base of tongue tumors include osteoradionecrosis of the mandible. The risk of complication appears to be related to the technique of implantation but may approach 30%.

• There is limited information regarding the use of brachytherapy and chemotherapy concurrently, which should be avoided.

• When brachytherapy is planned following external-beam radiotherapy, care should be taken to delineate the pretreatment tumor extent because regression is not always uniform.

• Tattoos and gold seeds have been used to accomplish this.

• The CTV used is recommended by the European Society for Radiotherapy and Oncology (ESTRO) to be 5 mm at minimum and more commonly 1 to 1.5 cm for base of tongue tumors.

• The PTV is usually equal to the CTV as the implanted catheters move with the tumor.

• Catheters are typically positioned parallel and equidistant at 1 to 1.5 cm apart.

• The methods of calculating dose are the Paris, Manchester, or New York systems, computer-derived brachytherapy plans.

Brachytherapy Guidelines

• The American Brachytherapy Society (ABS) has published guidelines for the use of HDR brachytherapy for head and neck tumors and oropharyngeal tumors in particular.

• Prophylactic tracheostomy is recommended because posterior and large tumors are at risk to cause airway obstruction.

• External-beam radiotherapy doses of 45 to 60 Gy followed by an HDR brachytherapy boost of 3 to 4 Gy per fraction for 6 to 10 doses with locoregional control of implanted tumors reaching 82% to 94%.

• The European Brachytherapy Group (GEC) and ESTRO have also published joint guidelines for the use of brachytherapy for head and neck malignancies.

• For oropharyngeal tumors, these guidelines recommend 45 to 50 Gy external-beam radiotherapy followed by 25 to 30 Gy boost for tonsillar tumors, and 30 to 35 Gy boost to base of tongue tumors. The total brachytherapy boost dose is fraction-size dependent: 21 to 30 Gy in 3-Gy fractions and 16 to 24 Gy in 4-Gy fractions.

• Quality of life analyses comparing a combined regimen of brachytherapy and external-beam radiotherapy to surgery and PORT favored a primary radiotherapy-only approach.

• Interstitial brachytherapy

• Mass General Hospital, 2005 → 40 cases. Primary or recurrent base of tongue. 54% T3/T4 tumor.

• Median implant dose 17.4 and 61 Gy external RT (equivalent total dose 80 Gy).

• Five-year OS: 62%. Local control: 78%. Ten-year local control: 70%.

• Organ preservation rate: 78%. Grade III osteoradionecrosis in two patients (2%).

• Foote RL et al (1990) Is interstitial implantation essential for successful radiotherapeutic treatment of base of tongue carcinoma? Int J Radiat Oncol Biol Phys. 18(6): 1293–8

Toxicity-chemoradiotherapyAcute

• Fatigue,

• Nausea, emesis,

• Thickened secretions,

• Xerostomia,

• Mucositis,

• Dysphagia, odynophagia,

• Alopecia, dermatitis,

• Anemia, neutropenia,

• Hoarseness,

• Dysphagia is perhaps the most difficult acute complication of chemoradiotherapy for oropharyngeal cancer.

• Patients should be instructed to swallow as large a volume as possible during and after treatment and to perform exercises shown to improve swallowing ability.

Late toxicity

• Fibrosis,

• Osteoradionecrosis,

• Trismus,

• Xerostomia,

• Dental caries,

• Feeding tube dependence, and neuritis.

Chemotherapy

Role of Targeted therapy

• Weekly Cetuximab loading dose of 400 mg/m2 followed by 250 mg/m2 for locoregionally advanced head and neck cancer patients. The combination therapy was found to improve locoregional control, disease-free survival, and overall survival.

• Consideration should be given to the use of altered radiation fractionation with cetuximab because improved overall survival was seen in patients who were treated with accelerated concomitant boost and hyperfractionated radiotherapy.

Follow up

• Every 1 to 3 months for the first year post RT

• Every 2 to 4 months in the second year post RT, and every 4 to 6 months in the next 3 to 5 years.

• The intensity of the examinations within the first 2 years coincides with the likelihood of recurrence in the interval. Given that radiation to the neck commonly causes hypothyroidism, thyroid-stimulating hormone levels should be evaluated every 6 months.

• Follow-up imaging should be performed within the first 3 months of treatment

Reirradiation for Locoregionally Confined Recurrent or Second Primary Disease

• Surgical resection is recommended, although this is possible only in a small proportion of patients.

• Following surgery in those with high-risk pathologic features or in those who are not surgical candidates,a second course of full-dose radiotherapy with chemotherapy has been shown to result in long-term survival in approximately 20% of patients.

Conclusion

• Oropharyngeal cancers include 10-12% of head & neck cancers

• Squamous cell carcinoma is most common histopathology

• HPV is most common risk factor associated

• Concurrent chemoradiotherapy is mainstay of treatment.

T H A N K Y O U

• LN Incidence and Percentage

• Role of ImagingDiagnostic RoleCT IndicationsMRI IndicationsPET Indications

• Role of HPV in Oropharynx

• Radical Surgery role in Oropharynx- Stage, Site and Name of Surgery

• Brachy in Oropharynx