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Management of oral cancer

Dr. Rafik Al Kowafi BDS, MSc, German board of Oral and Maxillofacial Surgery ( Berlin -Germany), Doctoral degree

by LBMS


• Malignancies of the oral cavity may arise froma variety of tissues, such as salivary gland,muscle, and blood vessels, or may evenpresent as metastases from distant sites.

• The most common malignancies areepidermoid carcinomas of the oral mucosa,which are the form of cancer that the dentistis in a position to discover first by doingthorough oral examinations.

16 December 2015 LIMU 2Dr. Rafik Al Kowafi

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• The seriousness of an oral malignancy canvary from the necessity for a simple excisionalbiopsy to composite jaw resection with neckdissection (i.e. removal of the lymph nodesand other visceral structures adjacent tolymph node channels in neck) to affect a cure.

• A thorough clinical examination and clinicalstaging should be undertaken before atreatment plan is formulated.


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Physical Exam – Oral Cancer

• Technique- Good lighting

- Proper instruments

- Systematic viewing

• Sequence

- Remove denture(s), if present

- Direct examination.

- Palpation – uni- & bimanual

- Indirect mirror examination.

- Flexible fiberoptic endoscopy, if required

16 December 2015 LIMU Dr. Rafik Al Kowafi 5

Physical Exam – Oral Cancer


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Squamous Cell Carcinomaof the Tongue

ExophyticUlcerative


Palpation


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Mouth

• With wooden tongue blade and a good light source.

• Inspect including the buccal folds and under thetougue

- Note any ulcers, white patches (leukoplakia), orother lesions

• Palpate using a gloved finger the anterior structuresand floor of the mouth

• Inspect the posterior oropharynx

- Note any tonsillar enlargement, redness, ordischarge



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Neck

• Inspect for asymmetry, scars, visible thyroid, or other lesions.

• For thyroid:

• Note the size, symmetry, position of the lobes, and presence of any thyroid nodules (The normal thyroid is often not palpable).

• Laryngeal movement.

• Palpate to detect areas of tenderness, deformity, or masses.


Cervical Lymph Nodes


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Lymph Node “Levels”


Indirect Laryngoscopy


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Flexible Laryngoscope


Radiologic Exam – Oral Cancer

• Mandible series / OPG/ CBCT – bone invasion?

• Chest X-ray – staging, second primary CA?

• CT – surface and deep extent of primary tumor and nodal disease, chest evaluation

• MRI

• PET (Positron Emission Tomography)

• CT/PET – increasingly utilized

Not all of these done at once!


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Radiologic Exam – Oral Cancer


Radiologic Exam – Oral CancerCT-scan with contrast material


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Radiologic Exam – Oral CancerPET


Biopsy – Oral Cancer

• Incisional

• Excisional

• Fine needle aspiration cytology (FNA)‏


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Tumor Staging

• T = Tumor size

• N = Lymph node involvement

• M = Distant metastases


Tumor StagingTX: Primary tumor cannot be assessed

T0: No evidence of primary tumor

Tis: Carcinoma in situ

T1: 2 cm or less in greatest dimension

T2: > 2 cm but not more than 4 cm

T3: > 4 cm in greatest dimension

T4a: > Tumor invades adjacent structures (eg, through cortical bone, into deep[extrinsic] muscle of the tongue, maxillary sinus, skin of face) (resectable)

T4b: > Tumor invades masticator space, pterygoid plates, or skull base or encases internal carotid artery (unresectable)


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Tumor Staging

• NX: Regional lymph nodes cannot be assessed

• N0: No regional lymph node metastasis

• N1: Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension

• N2: Metastasis in a single ipsilateral lymph node, > 3 cm but not > 6 cm; or in multiple ipsilaterallymph nodes, none > 6 cm; or in bilateral or contralateral lymph nodes, none > 6 cm in greatest dimension


Tumor Staging

• N2a: Metastasis in a single ipsilateral lymph node > 3 cm but not > 6 cm

• N2b: Metastasis in multiple ipsilateral lymph nodes, none > 6 cm

• N2c: Metastasis in bilateral or contralaterallymph nodes, none > 6 cm

• N3: Metastasis in a lymph node > 6 cm


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Neck dissection- Staging of the neck


Tumor Staging

• MX: Presence of distant metastasis cannot be assessed

• M0: No distant metastasis

• M1: Distant metastasis


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NO N1 N2a N2b N2c N3T1 Stage

IStage

IIIStage

IVaStage

IVaStage

IVaStage IVb

T2 Stage II

Stage III

Stage IVa

Stage IVa

Stage IVa

Stage IVb

T3 Stage III

Stage III

Stage IVa

Stage IVa

Stage IVa

Stage IVb

T4 Stage IVa

Stage IVa

Stage IVa

Stage IVa

Stage IVa

Stage IVb

General Summary of TNM System


Treatment modalities for oral malignancies

• Malignancies of the oral cavity are treated with:

1. Surgery.

2. Radiation.

3. Chemotherapy .

4. Combination of these modalities.

• Goals of therapy:1. Tumor control

2. Functional preservation

3. Cosmetic


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• The treatment for any given case depends on several factors:

1. Histopathologic diagnosis.

2. Location of the tumor.

3. Presence and degree of metastasis.

4. Radiosensitivity or chemosensitivity of the tumor.

5. Age and general physical condition of the patient.

6. Experience of the treating clinicians.

7. The wishes of the patient.



• If a lesion can be completely excised withoutmutilating the patient, this is the preferredmodality.

• If spread to regional lymph nodes is suspected,radiation may be used before or after surgery tohelp eliminate small foci of malignant cells in theadjacent areas.

• If widespread systemic metastasis is detected or ifa tumor, such as a lymphoma, is especiallychemosensitive, chemotherapy is used with orwithout surgery and radiation.


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• Currently malignancies are often treated in aninstitution where several specialists evaluateeach case and discuss treatment regimens.These "tumor boards" include at least asurgeon, a chemotherapist, and aradiotherapist. Most head and neck tumorboards also include a general dentist, amaxillofacial prosthodontist, a nutritionist, aspeech pathologist, and a sociologist orpsychiatrist.


1- Surgical Therapy of oral Cancer

Pathology:• Squamous Cell Carcinoma (SSC): >90% of oral cancers

• Verrucous Carcinoma: variant of SSC, broad based, warty growthmost common site is the buccal mucosa, lateral growth, raremetastasis and deep invasion

• Basal Cell Carcinoma: more common on the upper lip

• Other Types: Lymphoma, Kaposi’s Sarcoma, Salivary Gland,malignancies, Melanoma

• NOTE: Necrotizing Sialometaplasia and Granular Cell Tumors maybe mistaken for squamous cell carcinoma in the oral cavity due

to similar histology (pseudoepitheliomatous hyperplasia)


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• Long-term survival and functional results oftreatment depend on the stage of the tumor,histology, and treatment plan.

• The treatment plan is developed at pretreatmentconferences (tumor boards) by multidisciplinaryconsultants and subsequent patient/familyconcurrence.

• Additional important outcome factors includethe patient’s nutritional status, general health,tobacco use, alcohol intake, and anticipatedcompliance with the rigors of therapy.



• The surgical operation aims to remove thecarcinoma, with a 1-2 cm margin of normaltissue beyond the clinical edge of the tumourwhere possible.

• In addition to the treatment of the primarytumor, the cervical lymphatics commonly requiretreatment (Neck dissection). The clinicallynegative neck (no evidence of lymph nodeinvolvement) may be treated electively byradiation or modified neck dissection


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Early Oral Cancer (T1–T2)• Single-Modality Therapy: excision of primary tumor with

primary reconstruction, may consider primary radiation.• N0 Neck: elective ipsilateral or bilateral (midline or oral

tongue cancer) selective neck dissection (supraomohyoid)versus external beam therapy (early stage hard palate orlower lip do not require elective neck dissections becauseof lower rate of occult metastasis); if surgical specimen ispositive for tumor may consider observation, completion ofa comprehensive neck dissection, or radiation therapy toneck.

• N1–3 Neck: radical neck dissection for clinical nodes; parotidnodes require a superficial parotidectomy



A, Superficial squamous cell carcinoma of the right oral tongue. The tumor measured 3 cm and had minimal induration, and there were no palpable lymph nodes. B, Five weeks after excision, the patient was completely healed, with no pain or impediments in tongue function. The patient was followed for more than 5 years without any evidence of recurrence.


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Advanced Oral Cancer (T3–T4)• Single-Modality Therapy: excision of primary tumor with primary

reconstruction versus primary radiation for non-operable candidates.• N0 Neck: elective ipsilateral or bilateral (midline or oral tongue cancer)

selective neck dissection (supraomohyoid) versus radiotherapy; if surgicalspecimen is positive for tumor may consider observation, completion of acomprehensive neck dissection, or radiation therapy to neck

• N1–3 Neck: radical neck dissection for clinical nodes; parotid nodes requirea superficial parotidectomy.

• Adjuvant Therapy: postoperative radiation therapy may be considered forpositive margins; multiple positive neck nodes or extracapsular extension;perineural or intravascular invasion; or bone, cartilage, or soft tissueinvasion.

• chemotherapy indicated for palliation or may be considered for adjuvanttreatment for advanced disease.


1- Surgical Therapy of oral CancerLip Cancer• Single-Modality Therapy: excision of primary tumor with primary

reconstruction versus primary radiation therapy for small tumors ornon-operable candidates (must also consider functional and cosmeticoutcomes).

• Adjuvant Therapy: postoperative radiation therapy may be considered foradvanced stages (T3–4, N2–3), positive margins, multiple positive necknodes, perineural or intravascular invasion, or extracapsular extension.

• N0 Neck: elective ipsilateral or bilateral (for lower lip midline disease)selective neck dissection (supraomohyoid) versus radiotherapy foradvanced diseases (T3–T4); if surgical specimen is positive for tumor mayconsider observation, completion of a comprehensive neck dissection, orradiation therapy to neck.

• N1–3 Neck: radical neck dissection for clinical nodes; parotid nodes requirea superficial parotidectomy.

• chemotherapy may be considered for palliation or adjuvant treatment foradvanced disease.


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• Surgical approaches:

1. Transoral excision.

Premalignant lesions and small, superficial tumors ofthe anterior floor of mouth, alveolus, and tonguemay be resected through the open mouth.


Transoral excision of a tongue tumor

( A ) preexcision. ( B ) postexcision.


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2. Cheek flaps. Tumors of the posterior oral cavity are not easily accessibletransorally, and a cheek flap may give more adequate exposurein appropriate cases.I. Upper cheek flap (Weber Fergusson flap): is raised using

a median upper lip split and carrying the incision aroundthe nose with the corresponding mucosal incision in theupper gingivobuccal sulcus.

II. Lower cheek flap: requires a midline lip split thatcontinues over the chin into the neck. The flap is raisedsubplatysmally, but great care must be exercised not tostrip the periosteum off the mandible. Accuratereplacement of a cheek flap is facilitated by leaving asubstantial mucosal cuff on the alveolar side.



III. Midfacial degloving flap: through bilateralgingivobuccal incisions is preferable inappropriate cases as this avoids midfacial scars.

IV. A visor flap can give access to both sides of theneck and avoids splitting the lip, but adequatemobilization results in division of both mentalnerves with post-operative anesthesia of the lip.


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Surgical approaches

Intraoral deglovingWeber Fergusson (upper cheek flap)


Surgical approaches

a. Transoral.

b. Mandibulotomy.

c. Lower check flap.

d. Visor flap.

e. Upper check flap.


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3. Mandibulotomy.

– Larger tumors of the lateral border of the tongueor those involving or extending onto the floor ofthe mouth require a lip-splitting mandibulotomyapproach. Similarly, adequate surgical exposure oftumors located in the posterior oral cavity may beobtained using a mandibulotomy.


Mandibulotomy


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Mandibulotomy



• Management of the Mandible:

– Mechanism of invasionof the mandible. Tumorsof the floor of themouth, the ventralsurface of the tongue,and the gingivobuccalsulcus spread along themucosa and submucosalto the adjacent gingiva.


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1. Marginal resection of the mandible (rim resection):

• The understanding of tumor invasioninto mandible enables the use ofmarginal resection of bone based onthe observation that the cortical partof the bone containing themandibular canal lies inferior to thedental roots, remains relativelyuninvolved in early stage disease, andcan be safely spared.

• Indications:a) Primary tumor abutting

against the mandibleb) Minimal involvement of the

alveolar processc) Minimal cortical erosion



2. Segmental mandibulectomy:

(Composite resection)

Indications:a) Invasion of the mandibular

canal and inferior alveolar nerve

b) Gross invasion of the mandible

c) Primary mandibular osseous tumor

d) Metastatic tumor to the mandible


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A, deeply infiltrating squamous cell carcinoma involving the entire anterior floor of the mouth and mandible. B, Treatment involved composite resection followed by radiation. Reconstruction was critical to function, appearance, and quality of life.


Neck Dissection

• ( A ) Incidence of occult lymph node involvement in the clinically node negative patient with alveolar ridge cancer.

• ( B ) Incidence of lymph node metastasis in the clinically node-positive patient

with alveolar ridge cancer.


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Lymph node levels/Nodal regions

• Level I: Submental and submandibular triangles.

• Levels II, III, IV: nodes associated with IJV withinfibroadipose tissue (posterior border of SCM andlateral border of sternohyoid).

• Level V: Posterior triangle of neck – Boundaries -posterior border of SCM, clavicle, and anteriorborder of trapezius.

• Level VI: Anterior compartment structures (hyoid,suprasternal notch, medial border of carotidsheath).


Lymph node levels/Nodal regions


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Classification of Neck Dissections

• Based on 4 concepts1) RND (Radical Neck Dissection) is the standard basic

procedure for cervical lymphadenectomy against which allother modifications are compared.

2) Modifications of the RND which include preservation ofany non-lymphatic structures are referred to as modifiedradical neck dissection (MRND).

3) Any neck dissection that preserves one or more groups orlevels of lymph nodes is referred to as a selective neckdissection (SND)

4) An extended neck dissection refers to the removal ofadditional lymph node groups or non-lymphatic structuresrelative to the RND.


Classification of Neck Dissections

1) Radical neck dissection (RND)

2) Modified radical neck dissection (MRND)

3) Selective neck dissection (SND)

– Supra-omohyoid type

– Lateral type

– Posterolateral type

– Anterior compartment type

4) Extended radical neck dissection


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Radical Neck Dissection

Definition:

Removal of all lymph nodes in Levels I-V

including spinal accessory nerve (SAN), SCM,

and IJV.

Indications:

– Extensive cervical involvement or lymph nodeswith gross extracapsular spread and invasion intothe SAN, IJV, or SCM


Modified Radical Neck Dissection

Definition:

Excision of same lymph node bearing regions as

RND with preservation of one or more

non-lymphatic structures (SAN, SCM, IJV)

Indications:

– Clinically obvious lymph node metastases

– SAN not involved by tumor

– Intraoperative decision


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Selective Neck Dissection

Definition:• Cervical lymphadenectomy with preservation of one or

more lymph node groups. Also known as an selective neck dissection.

• Rate of occult metastasis in clinically negative neck 20-30% Need for post-op XRT (Radiotherapy).

Four common subtypes:1. Supraomohyoid neck dissection (SOHND)2. Posterolateral neck dissection3. Lateral neck dissection4. Anterior neck dissection

Indications:– Primary lesion with 20% or greater risk of occult metastasis


SND: Supraomohyoid type

Most commonly performed SNDDefinition:En bloc removal of cervical lymph node groups I-III.

– Posterior limit is the cervical plexus and posterior border of the SCM.

– Inferior limit is the omohyoid muscle overlying IJV.

Indications:– Oral cavity carcinoma with N0 neck, – Subsites - Lips, buccal mucosa, upper and lower alveolar ridges,

retromolar trigone, hard palate, and anterior 2/3s of the tongue.

– SOHND + parotidectomy• Melanoma and cutaneous SCCA of the cheek


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SND: Supraomohyoid type



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2- Radiotherapy

• Radiotherapy (RT) is an extremely effective treatment forhead and neck cancer, as a primary modality and as anadjuvant treatment following surgery.

• In early-stage disease, single modality radical RT can cure>90% of cancers in some tumor subsites (e.g., larynx). Inmore advanced-stage diseases, RT is usually used incombination with chemotherapy (e.g. cisplatin), either asradical chemoradiotherapy or in an adjunctive fashion aftersurgery.

• Most cancers of the head and neck are squamous cellcarcinomas (HNSCC) and are generally considered to beradiosensitive lesions. There is a well-establishedrelationship between the radiation dose delivered to thetumor and the probability of tumor control.


2- Radiotherapy

• RT can be delivered via external beam and/orbrachytherapy.

• For stage III and IV HNSCC, surgery and postoperativechemoradiation are effective. Lesions with highprobabilities of cure (>70%) should ideally be treatedwith a single therapeutic modality (either surgical ornonsurgical). The increased morbidity of combinedsurgical and nonsurgical treatment is unjustified,especially when not associated with a significantlyimproved control rate. However, there arecircumstances in which RT and surgery are used as partof a planned treatment program.


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2- Radiotherapy• How RT works?• Ionizing radiation may be delivered in the form of external beams of x-rays or

gamma rays, external beams of electrons or particles (neutrons or protons), orinternally implanted sources of beta or gamma rays. Radiation kills cells by primaryand secondary interactions with the cells making up the tissues.

• In general, the photons of x-rays or gamma rays dislodge electrons from the atomsof the tissue. These charged particles cause ionization along their tracks, whichresults in chemical changes in the water in the cell and in the criticalmacromolecules of the cell, primarily the deoxyribonucleic acid (DNA). The majorsite of action of ionizing radiation on mammalian cells is in the nucleus, where itcauses breakage of chromosomes and disruptions or misrepair of the DNAmolecule.

• In some types of cells, such as mature lymphocytes and tumor cells, radiation hasa direct effect on the function of the nucleus and causes programmed cell death(apoptosis). In most cases, the damage is to the DNA and chromosomes, and celldeath results after several divisions. It should be noted that cells need not actuallydie to be mitotically “dead.” For instance, they may divide once or twice but thenremain in a postmitotic state and form giant cells that are no longer capable ofcausing tissue or tumor regeneration.

• Rad (Radiation Absorbed Dose): amount of energy deposited by ionizing radiationper gram of tissue (1 Gy = 100 rads)


2- Radiotherapy

• Types of RT:1. Preoperative Radiation Therapy:

• Preoperative RT is infrequently used and should not beconsidered to be a standard of care.

• It can be indicated in:(1) fixed, inoperable neck nodes.(2) in situations where the initiation of postoperative RT is likely to

be delayed by more than 6–8 weeks due to the need forextensive surgical reconstruction.

2. Postoperative Radiation Therapy:• Postoperative RT is usually considered when the risk of

recurrence above the clavicles exceeds 20%. The operativeprocedure should be one stage and should ideally allowirradiation to start no later than 6 weeks after surgery.


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2- Radiotherapy

• Indications for Postoperative Radiation Therapy1. Positive margins at the primary tumor resection site.2. Less than 5 mm safe margins.3. Extracapsular spread of involved lymph nodes.4. Two or more involved cervical lymph nodes.5. Invasion of the soft tissues of the neck.6. Lymphovascular and perineural invasion.

• Radiation therapy techniques:1. Brachytherapy.2. Conventional Radiation Therapy.3. Three-Dimensional Conformal Treatment Planning.4. Intensity Modulated Radiotherapy


2- Radiotherapy

1- Brachytherapy:Brachytherapy describes the situation in which Radioactivesources are brought close to the tumor mass (or evenimplanted within it) to deliver a highly localized radiation dose.


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2- Radiotherapy2- Conventional Radiation Therapy:

– Conventional RT involved treatment planning byfluoroscopic X-ray screening and treatment delivery by oneto four regular square or rectangular fields.

– Blocks of lead (or of a dense alloy called Cerrobend) werepositioned by hand such that they shielded parts of theradiation field encompassing normal structures.


2- Radiotherapy

3- Three-Dimensional Conformal Treatment Planning (3-DCRT):

• CT-scan is taken with the patientimmobilized in the RT treatment position.Data from these scans provide theradiation oncologist with preciseanatomical and electron density data ontumor and normal tissues.

• This technique is more time-consumingthan conventional RT and requiresspecialist technical support, but it offersthe opportunity of achieving clinicallyimportant improvements in tumor controland reductions in normal tissuecomplication.


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3- Chemotherapy

3- Intensity Modulated Radiotherapy.– This treatment technique

permits the generation ofconcavities in the isodoseswithin tissues such that normalstructures can be spared fromexcessive radiation doses.

– IMRT uses sophisticatedcomputer software andhardware to vary the shapeand intensity of radiationdelivered to different parts ofthe treatment volume.


Radiation doses and treatment delivery

• A conventional course of RT for HNSCC isdelivered over a 6–7-weeks course with smallfractions of radiotherapy delivered 5 days a week.

• A standard schedule (e.g. in the U.K) is 70 Gray(Gy) delivered in 35 fractions over 7 weeks.

• RT is delivered in multiple small fractions to allowrecovery of normal tissues between doses andthus facilitate the delivery of a larger totalradiation dose to the tumor.


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Palliative Radiotherapy

• RT can also be used with palliative intent in patients for whom acurative treatment option does not exist.

• Indications:1. As initial treatment for locally advanced tumors in patients with very

poor health status who will not be able to tolerate radicaltreatment.

2. For short-course treatment of local disease in patients withmetastatic (M1) disease at the initial presentation.

3. For symptom relief (pain, bleeding, airway compromise) in patientswith locally recurrent.

4. For symptom relief of distant metastatic disease (e.g., bone pain,spinal cord compression).

• Palliative RT is usually delivered as a short course of treatment thatcan vary from a single fraction to 10 doses of RT over a 2-weekperiod.


Case Presentations /Radiation Planning

• Case Study:

– 39 yr old male with 25 yr history of cigaretteuse (2 packs per day) and intermittent historyof marijuana use.

– He complains of 2 month history of “biting theinside of his right cheek”

– Physical exam shows bilateral leukoplakia onbuccal mucosal and no palpablelymphadenopathy


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– OMF surgeon notes small area of erythroplakiaon left buccal mucosa

– Bilateral biopsies reveal moderate dysplasia onthe right buccal mucosa and moderatelydifferentiated squamous cell carcinoma on theleft.

– Multidisciplinary tumor board recommendsdefinitive radiation therapy for a 1 cm tumor(T1N0) on the left buccal mucosa.



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–Patient received definitive, radiationtherapy to the primary tumor andipsilateral levels I, II, and III LN stations.

–Primary tumor had a complete responseby the end of 72 Gy of radiation.

–Patient only had mild xerostomia sincecontralateral salivary glands were spared.


Radiation- Induced side effects

1- Acute Effects1. Mucositis.

2. Oral candidiasis.

3. Tongue sensitivity.

4. Decreased taste.

5. Fatigue.

6. Xerostomia.

7. Dysphagia.

8. Weight loss.

9. Hair loss.


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• Dental Recommendations for Acute Effects:1. No dental prostheses should be worn during radiation

once irritation, mucositis, or ulceration develops.

2. Meticulous oral hygiene:• Frequent brushing (after meals, night)

• Daily flossing

• Daily fluoride gel applications with custom carriers

• Chlorhexidine mouthwash.– Disadvantages (more discomfort, taste alteration, teeth staining).

• Baking soda and salt rinses are most beneficial.

• BMX ((Benadryl-Maalox- Xylocaine) mouth rinse and liquidpain medicines are helpful



2- Potential late effects:

1. Permanent xerostomia.

2. Change in taste

3. Dental caries (Why?)

4. Soft tissue necrosis (Ulcers)

5. Bone necrosis (osteoradionecrosis)

6. Radiation-induced tumors


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• Dental recommendations for Late effects:– Frequent, professional dental care may prevent

demineralization of teeth– If enamel breakdown, calcium phosphate remineralizing gel

is used.– Ideally a healing time of at least 3 weeks between dental

procedures such as extractions and the initiation ofradiotherapy significantly decreases the chance of bonenecrosis.

– Teeth extractions should be avoided if possible especially inregions of bone receiving over 50 Gy.

– If teeth extractions are necessary, conservative surgery,antibiotic coverage, and possibly hyperbaric O2 should beconsidered.

– Removable prosthesis are constructed after mucosa ishealed.



• Soft tissue necrosis– Relatively common

– Typically small, and self-limited

– Must rule out recurrent cancer

– Management:• Observation

• Antibiotics (tetracycline)

• Comfort agents: viscous lidocaine or BMX

• Hyperbaric O2 is used for larger lesions or bone necrosis


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• Osteoradionecrosis

– Dentures discontinued, or modified to decreasetrauma

– Usually no cases of bone necrosis are reported if dose

bone<65 Gy

– Risk increases greatly for dose bone >75 Gy

– Management is conservative (analgesics, antibiotics,good hygiene)

– Hyperbaric O2 is sometimes helpful.

– Surgery is used as a last resort for treatment of softtissue or bone necrosis.



• Xerostomia– Dependent on dose (tolerance ~ 32 Gy)– Dependent on volume of salivary gland tissue irradiated

(mild if can spare 1 parotid).– Treatment options: Pilocarpine post-radiation,

amifostine concurrent with radiation for prevention ofxerostomia.

– Artificial saliva

• Muscles of Mastication– If included in radiation field, fibrosis may occur.– Patient should exercise muscles to prevent trismus

(open/close, open against pressure).


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3- Chemotherapy

Chemotherapy:

• The treatment of cancer using specific chemicalagents or drugs that are destructive to malignantcells and tissues.

• Traditional chemotherapeutic agents act by killingcells that divide rapidly, one of the mainproperties of most cancer cells. This means thatchemotherapy also harms cells that divide rapidlyunder normal circumstances: cells in the bonemarrow, digestive tract, and hair follicles.


3- Chemotherapy• This results in the most common side-effects of

chemotherapy: myelosuppression (decreased production ofblood cells, hence also immunosuppression), mucositis(inflammation of the lining of the digestive tract), andalopecia (hair loss).

• Some newer anticancer drugs target proteins that areabnormally expressed in cancer cells and that are essentialfor their growth. Such treatments are often referred to astargeted therapy, and are often used alongside traditionalchemotherapeutic agents in antineoplastic treatmentregimens.


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3- Chemotherapy

• Two Broad Classes of Chemotherapy Drugs:1. Cytotoxic agents:

• Cisplatin – causes DNA damage• 5-Fluourouracil – blocks

enzymes necessary for RNA and DNA synthesis

• Docetaxel – inhibits microtubule formation

2. Targeted therapies:• Erlotinib – small molecule

inhibitor the EGFR (epidermal growth factor receptor) tyrosine kinase

• Cetuximab – antibody that binds to EGFR


Common Chemotherapy Agents andCombinations in Head and Neck Cancer

Cisplatin• Mechanism of Action: heavy metal that acts as an alkylating agent that

covalently binds DNA and RNA• Common Side Effects: nausea, nephrotoxicity, peripheral neuropathy,

ototoxicity, electrolyte disturbances, anorexia Indications: best single-agent against squamous cell carcinoma of the head and neck in recurrentdisease; common combination agent for neoadjuvant, adjuvant, andconcomitant chemotherapy of the head and neck; radiation sensitizer.

Carboplatin• Mechanism of Action: similar to cisplatin (less reactive).• Common Side Effects: better tolerated than cisplatin (less nephrotoxicity,

nausea, neurotoxicity, and ototoxicity)• Indications: not been fully investigated in head and neck cancer, often used

in combination with taxol


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5-Fluorouracil (5-FU)• Mechanism of Action: antimetabolite that binds

to thymidilate synthetase blocking the conversionof uridine to thymidine preventing DNA synthesisin S-phase.

• Common Side Effects: anorexia and nausea,mucositis, diarrhea, alopecia, myelosuppression,cardiac toxicity.

• Indications: similar to cisplatin (cisplatin and 5-FUis the most studied combination chemotherapyregimen in head and neck cancer)



Methotrexate• Mechanism of Action: antimetabolite that binds to dihydrofolate

reductase preventing DNA synthesis in S-phase• Common Side Effects: bone marrow suppression, gastrointestinal

disturbances, mucositis, alopecia, dermatitis, nephrotoxicity,teratogenicity, interstitial pneumonitis

• Indications: “standard” palliative therapy for recurrent or metastaticdisease

Taxanes (Paclitaxel and Docetaxel)• Mechanism of Action: prevent normal microtubular reorganization• Common Side Effects: neutropenia, alopecia, mucositis• Indications: currently being investigated for recurrent disease and as

a potential radiation sensitizer.


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There is a wide variation in sensitivity of various cancers to chemotherapy:

High Intermediate Low

Lymphoma Breast Head and neck

Leukemia Colon Prostate

Small Cell Lung cancer Non-small cell lung cancer

Gastric

Testicular cancer Pancreatic


Chemotherapy Administration and Dosing

• Doses are individualized based upon apatient’s BSA (body surface area).

• Drugs are given in cycles, usually at 3-4 weekintervals

• Chemotherapy is often combined with surgeryand/or radiation


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Modes of Chemotherapy

• Primary Chemotherapy - chemotherapy is used as thesole anti-cancer treatment in a highly sensitive tumortypes– Example – CHOP for Non-Hodgkins lymphoma

• Adjuvant Chemotherapy – treatment is given aftersurgery to eliminate microscopic residual disease– Example – Adriamycin, cyclophosphamide for breast cancer

• Neoadjuvant chemotherapy – treatment is give beforesurgery to shrink tumor and increase chance of successfulresection– Example – Adriamycin, ifosfamide for osteosarcoma

• Concurrent chemotherapy – treatment is givensimultaneous to radiation to increase sensitivity of cancercells to radiation– Example – Cisplatin, 5-fluourouracil, XRT for head and neck

tumors


Chemotherapy toxicity:

• Hematologic-anemia, neutropenia, thrombocytopenia, immunosuppression

• Skin/Mucosa-scaling, mucositis, alopecia

• Cardiac-decreased myocardial contractility, arrhythmias

• Renal/GU-acute tubular necrosis, chronic renal insufficiency, hemorrhagic cystitis, sterility

• Neurologic-hearing loss, peripheral neuropathy

• GIT-Nausea/vomiting, diarrhea

• Osteonecrosis


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Oral Toxicity

• Mucositis

• Xerostomia

• Dental pain

• Osteonecrosis

• Oral mucosal infections

• Dental pulp/periapicalinfections

• Peridontal infection

• Mucosal hemorrhage


Cisplatin/5-FU Regimen for Head and Neck Cancer

1. Prehydrate IV NS

2. Induce diuresis – Lasix, mannitol

3. Antiemetic – Zofran, Decadron

4. Cisplatin over 1 hour IV (based on height and weight)

5. Posthydrate with electrolytes

6. 5-FU – continuous IV infusion 24 hrs x 5 days (dose based on height and weight)

7. Daily antiemetics, IVF

8. Repeat at 3 or 4 week intervals

9. Concurrent radiotherapy


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Summary

• Two broad classes of chemotherapy arecytotoxic drugs and targeted drugs

• Chemotherapy is often used as an adjunct tosurgery and/or radiation therapy (adjuvant,neoadjuvant, concurrent)

• Chemotherapy toxicities can be severe, andare generally specific to a drug’s mechanismof action.


Summary

• Standard therapy for resectable disease remainssurgery followed by radiotherapy, if indicated.

• To date, induction chemotherapy followed bysurgery has not shown a survival benefit in oralcavity cancer.

• Adding chemotherapy following surgery andradiation has been shown to decrease theincidence of distant metastases, but this has notbeen associated with improved survival.


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Chemoprevention

• An additional area of intensive research is development ofchemoprevention agents, which are defined as agents that reverseor suppress premalignant carcinogenic progression to invasivemalignancy.

• The role of such agents would be twofold:(1) To treat premalignant lesions to prevent their evolution to invasive

carcinoma.(2) To prevent development of second primary squamous cell cancers

in patients who have already undergone treatment of cancer.• leukoplakia has been used to monitor responsiveness to certain

chemoprevention agents in clinical trials. including retinoids, betacarotene, and vitamin E derivatives, retinoids have demonstratedthe most efficacy in eliminating leukoplakia.


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