DR:- OMAR HASHIMCANCER OF LARYNX

Anatomy of the larynx

the larynx is consists of a cartilaginous skeleton with ligaments,which carries the muscles and mostly is covered by mucous membrane .

skeleton of the larynx ;-1)Thyroid cartilage ;- consist of tow lateral

laminae which are fused in front (bow ship). At the tip of bow is a notch (Adam apple) . The superior and inferior horn arise from the posterior edge of each laminae

2) Caricoid cartilage ;-it is ship is like signet ring .it is lamina is 2-2.5 cms lies posterior .the upper edage of the lamina has tow articular surface for the arytenoid cartilage .the lateral surface on each side has articular surface for the inferior horn of the thyriod cartilage .

Arytenoid cartilage ;-pair of cartilage sited on the upper edge of the lamina of the cricoid cartilage .it has the shap of triangular pyramid .

The vocal cord are two thickened uppper end of the conus attached posterior to the vocal process of both arytenoids cartilage and interiorly to the inner surface of the angle of the thyroid cartilagecricoarytenoid muscles .

Epiglottis ;-lies against the middle of the thyroid cartilage

Laryngeal ligaments ;-is a membrane composed of a dense elastic fiber net which lies below the mucous memberane of the larynx and has different sickness in different region (conus elasticus-vocal cord –median cricothyroid ligament l-quadrangular membrane –vestibular ligament …)

Epidemiology & etiology

New case in 2009 is 12,290 with ca larynx .with men affected four time more than female .deaths from ca larynx is 3,660 . With modern care the deaths dropped from 2,97 per 100,000 to 2,24 per 100,000 .

Risk factors ;-1) Age > 55 yrs .2)Gender male to female ratio 4:13)Cigarette smoking (2-25X increase)

4) Alcohol consumption (2-6 increase ) the .The combination of cigarette and alcohol

↑(40-100) .5) Race African –American are more affected .6) Past medical history of head and neck

cancer ↑risk of ca larynx .7) Genetic factors ;- e.g fanconia anemia and

dyskeratosis congenita (condation→aplastic anemia ↑ risk of ca larynx .

8) Condition → ↓ immunity (AIDS –organ transplant ) .↑risk of ca larynx .

Pathology of the ca larynx

Ca larynx sub site

percent

supraglottic 35%

glottic 65%

subglottic 1%

The majority of ca larynx which arise from the mucosal surface is squamous cell carcinoma .

The most are well to mode differentiated .

Route of spread

spread occur by one of the three ;-A) Local extension ;- the most common ,spread

to cartilages→ sclerosis then by additional growth causes cartilage erosion → destruction and penetration of cartilages .

B) Lymph nodes met- Occur less common .the lymphatic drainage depend on the origin of the 1ry sites .

C) Distant mets- ;-the most common site of hematogenous spread is the bones then less common to the lungs .

1supr

11 111

1v v 1 11 111

1v v

1% 39% 26%

8%

5%

O%

12%

5%

3%

3%

ipsilateral nodes

contralateral nodes

lymph nodes involved in the ca larynx (supraglottic)

diagnosis Clinical presentation ;-Early presentation is hoarseness of the voice Change in the quality of the voice . While advance presentation is difficulty in the

swallowing . Cervical adenopathy . Weight loss . Throat pain . Referred pain . Air way obstruction .

Head and neck examination :- inspection of the scalp,ears,

Nose, and mouth . Palpation of the neck, mouth, tongue

Mobility, base of the tongue, and floor of mouth.Endoscope to nasal cavity,nasopharynx,oropharynx,Hypopharynx and larynx . Carefully cranial nerve

examination

Staging

Diagnosis and clinical staging depends on finding from history ,physical examination ,imaging and lab tests . Pathological staging depends on finding from surgical resection and histological examination .

There are American joint committee on cancer (AJCC)

And Tumor, Node, and Metastasis .(TNM)

Tx primary tumor can not be assessed T0 No evidence of primary tumor T is Carcinoma insitu

AJCC ,TNM classification of carcinoma

Primary tumor ;-

T1 Tumor limited to 1 sub site of supraglottis ,with normal vocal cord mobility

T2 Tumor in more than 1 adjacent sub site of the supraglottis or glottis .with out fixation of the larynx

T3 tumor limited to larynx with vocal cord fixation, or invades following postcricoid area preepiglottic spaceOr inner cortex of thyroid cartilage

T4a

Moderate advanced local disease, tumor invade thyroid cartilage or pre -larynx tissues

T4b

Very advanced local disease ,tumor invade prevertedral space,carotid artery,or invades mediastinal structure

supraglottis ;-

T1 Tumor limited to 1 vocal cord with normal mobility

T1b Tumor involve both vocal cord with normal mobility

T2 Tumor extends to supraglottis or subglottis with impaired vocal cord mobility.

T3 Tumor limited to the larynx with vocal cord fixation Or involve paraglottic space ,or inner cortex of thyroid cartilage .

T4a Moderately advanced local disease ,outer cortex of thyroid cartilage or tissues surrounding the larynx

T4b Very advanced local disease prevertebral space or mediastinal structures .

Glottis

T1 tumor limited to the subglottis

T2 Tumor extend to vocal cord with normal or impaired mobility

T3 Tumor limited to the larynx with vocal cord fixation

T4 Moderately advanced local disease .invading of the cricoid or thyroid cartilage or tissue around the larynx .

T4b

Very advanced local disease ,invading the prevertebral space ,cartoid artery ,meditational structure .

Sub glottis ;-

Nx Can not be assessed

N0 no lymph nodes metastasis

N1 metastasis in the ipsilateral lymph nodes≤3 cm (greater dimension)

N2a Metastasis in single ipsilateral lymph nodes>3cm but≤6cm in greater dimension

N2b Metastasis in multiple ipsilateral lymph nodes none >6 cm

N2c Metastasis in bilateral or contra lateral lymph nodes none > 6cm

N3 Metastasis in lymph nodes >6cm in greater dimension

Regional lymph nodes ;-

Ca larynx suspected

Complete history & physical exam

Endoscopy and biopsy

imaging

study

Labstudy interven

tion

Lesion incapable of regional

met-GLOTTIC

T1-2N0M0

LESION CAPABLE

OF REGIONAL

*Mets-

Advanced lesion

suitable for organ conservati

on**

Advanced lesion

beyond organ

conservation ***

Prognosis ;-

The out come of treatment of ca larynx is varies substantially, from excellent to poor. The most important prognostic factors include extent/stage at diagnosis, the exact site of origin of disease and patient’s performance status /ability to tolerate the desired therapy

Treatment

Localized lesion incapable of regional metastasis ; this include the SCC of glottis (T1 or T2, N0 ) .this treated by radiation therapy to the primary site only . Surgery is second option but radiation is preferable due to subsequent voice quality .

Radiation therapy ;- is indicated for all early stage . The techniques ;- small opposed portals (e.g. 5x5 or 6x6 cm ) treating the primary tumor only .the dose is 63 Gy in 28 fr/ 2.25 CGY/day in 5.6 weeks .

Usually the portals extend from hyoid bone to the bottom of the cricoids cartilage (upper/lower) and from the flash of the skin to the anterior aspect of the vertebral body (anterior/posterior) .

Usually we use tow parallel opposed 4-6 MV photon

Beam field .In recent years arandomized study done

concurring the fraction schaclat for T1N0M0 glottic cancer were treated either with 2,0 or 2.25 Gy ,the 5yrs local control rate favored the group that received 2.25 Gy

(92 versus 77%) . But the cause specific survival rate were similar (100 and 97%) .

Localized lesion capable of regional metastasisLimited extent SCC of the supraglottic larynx (T1N0-smallN1 and most T2N0 . In treatment of

the these type of the lesion the tow type of the treatment can be done radiation and surgery but the radiation is preferable due to less morbid .

Radiation ;- suitable for all case . Specially if the extend of the disease required total laryngectomy to repair the surgery .

The techniques ;- For small supraglottic include the primary lesion pulse

the upper and mid cervical (level1&11) .For more extensive supraglottic lesion also include

low, anterior cervical (level1v) nodes .If N1 anterior cervical disease the posterior cervical

(level 5) should be treated .Radiation technique ;-usually lateral and parallels op-Posed fields are used . For T1 supraglottic lesion a dose

of 66 GY in 33fr 2fr/day .for T2 supraglottic 70 GY in35 fr .

Advanced lesion suitable for organ preservationT3 –T4 ;- this lesion traditionally treated by

laryngectomy(with or without pharyngectomy) .now these is larynx sparing therapy these is no deferent in the cervival between surgery and the larynx sparing therapy .but not all lesion are suitable for organ preservation therapy (unreliable patients,pts contuse smoking during treatment ,hypertensive,pts who cannot tolerate discomfort

of the surgery)

The treatment modal which used for organ preservation;-

Indicated for advanced lesion that have not penetrated cartilage .(cord fixation is not contra-

Indication).Techniques ;-the primary tumor and clinical

involvedNodes should receive 70 GY in 35 frs .All anterior and posterior cervical

andsupraclavicular clinically uninvolved are at risk for sub clinical involvement and need to receive minimum of 50 GY

The chemotherapy ;- include cisplatin I.V on day 1,22 &43 of radiotherapy .

Clinical evidence ;-Randomized trials ;-

Department of veteran affairs larynx

pts number= 332 ( stage 111 or 1v ca larynx ). Median fallow up 33 monthsCompared 3 cycles of indication cisplatin + flurouracil chemotherapy Versus laryngectomy postoperative radiation.The survival rate is equal in both arm for 2 yrs =68% ( p=0.098) .there were More local recurrence (p=0.005)and fewer distant metastases (p=0.016)In the chemotherapy group than in the other group

EORTC24891 b

Randomized of patent number202 with ca larynx of the pyriform sinus stage 11-1v follow up to 51 months .Compared cycles of inducation cisplatin chemotherapy and thenradiotherapy verus larngectomy and postoperative radiotherapy median cervival was 44months in inducation chemotherapy arm and 25 months in surgery arm .Local and regional recurrence was similar in both arm

RTOG Randomized care of 520 patients who wise Required laryngectomy . Comparing inducation cisplatin plus fluoro-Uracil and then radiotherapy versus radiotherapy with concurrent administration of cisplatin versus radiotherapy alone .The primary end point of preservation of the larynx significantly favored concurrentTherapy 2yrs-88% while inducation chemo-75% and the radiotherapy 70%.2nd end point of loco regional control significantly Favored concurrent therapy 78% while with inducation chemo-61% and 56% with radiotherapyAlone .overall survival was similar in all groups

Resectable advanced lesions not suitable for organPreservation ;-the important part in preservation is the preservation of the function .once function is Irreparably lost , these is little benefit to preserving The anatomy .in other cases concurrent chemo-may be

toxic due to other diseases or refuse stop smoking /co-morbidities /unreliable who cutting medication /patients who emotionally would prefer

Surgery / cartilage destroyed or extracapssular extension. 2studies show that stage111 loco regional

Control improved by adding cisplatin concurrent with

Radiation therapy tech- ;-the fields include the primary site (tumor +ve LNs) +subclinical LNS

The upper border includes the nodes in the upper jugular region. both the ipsilateral and contra lateral

Posterior are include in the treatment portals if anterior chain +ve.

The primary site &area with↑risk(dissected and has

Altered vascular supply)60-66GY 33fr .While area of low risk(not dissected) will receive50-54 fr .

unresectable advanced lesion not suitable for organ

Preservation ;- in unresectable patients with good general condition with no heamatogenus spread can be approached with curative- intent chemotherapy-enhanced radiation therapy . In very

Fit patients inducation chemotherapy succeeded by

Chemo—enhanced radiation therapy .for patient with

Already distant metastasis role will be palliation

Post-operative radiation therapy .Radiation is indicated for all lesion extent Tech – 60-66 GY to operative bed and

drainageNodes .Chemo- ;-indicated for microscopically

involved mucosal margin /extra capsular extension of nodal

Disease . Tech- I-V ;-cisplatin 1 on day 1 ,22 and 43 of

radiotherapy treatment .

The volume delineation ;- The primary tumor site,all nodal beds at risk

of subclinical disease and operative bed . The upper border include the nodes in jugular region .the high

Risk region→ 60-66 GY .low risk→50-54 GY .

RTOG 9501

459 patients . Who ,after definitive surgery , had histologic invasionOf tow or more regional LNs/extra capsular extension of nodal diseaseOr mucosal resection margin.Randomized to radiotherapy alone o(60-66GY) versus identical treatment+concurrent cisplatin on day 1 ,22 &43 .The primary end point of loco regional control favored concurrent chemotherapy at 2 yrs 82% ( with chemotherapy ) versus 72% (no chemotherapy ).The secondary end point of disease free survival also favored concurrentTherapy ( p=0.04) but over all survival not different

Supporting clinical evidence

EORTC22931

Patients number 334 ,who after definitive surgery had histological Evidence of extra nodal spread , + ve margin , per neural involvementOr vascular tumor embolism (median fallow up 60 months )Randomized to radiotherapy alone (66 GY in 33 fr) versus identical treatment +concurrent cisplatin in day 1, 22 &43 .The primary end point of disease free survival favored concurrent therapyAt 5 yr s4% with chemotherapy verus36% (no chemotherapy) p=o.o4Second end point of overall survival(p=0.02) and loco regional control(p=0.007) both significantly favored concurrent therapy

schedule frequency

First follow up 2weeks after radiation →for acute reaction

Yrear0-1 Every month

Year 1-2 Every 2 months

Year2-3 Every 3 months

Year 3+ Every 6 months

From the previous data of RTOG 9501and EORTC 22931

Which concurring the benefit of chemotherapy.

Were the ECE (extra capsular extenation) or +ve SM.

Involvement of2 more LNs by tumor is not predict

Benefit from chemotherapy .

Palliation treatmentThe emis is to controlling thedistressing loco-Regional signs or symptoms of disease for during the

patient remaining alive .For who have one or tow non life threatening

lesion .with good response to chemotherapy ,the radiation

Therapy that approaches the intensity of definitive Treatment. With more advanced metastatic disease The author tends to favor asplit-course( eg;-30GY in

2weeks the tow weeks rest ,followed by another30 GY in 2weeksto smaller field never over lap the

spinal cord.for patient live more we can do quadShot technique

For M0tumor

Multi-institutional phase 111 trial includeing 295 patient with unresectableNondisseminated ,head and neck cancer.Randomized to stander radiation therapy alone (70YG in 30 fr ) versusIdentical radiation +concurrent bolus cisplatin on day 1 ,22 ,34 versus Split-course radiation therapy + bolus cisplatin and continuous –infusionFluorourcil . The with concurrent cisplatin is associated with improve of The survival,at the cost increase the toxicity .the 3yrs overall survival37% .

Supporting clinical evidence ;-

For M0 tumor

166 patients with locally advanced ( 74% operable and 26% unoperable)laryngeal and hypophyaryngealcancer .Randomized to to treatment with docetaxel (taxotere) ,cisplatin And 5-fluorourcil inducation then chemoradiotherapy versus Cisplatin and fluorourcil (pf) then chemoradiotherapy .For inoperable 2 yrs overall survival was 55% with TPF AND 41% In the PF . for inoperable tumor ,the 2 yrs progression free survival was 42%In TPF and 30% in the PF .

For MI TUMOR

30 patients who had advanced head and neck nearly stage 1v With performance score of 2-3 .Quad shot =14 GY in 4fr given twice a day at least 6hours apartOver 2 consecutive days ahd repeated up to twice more every4 weeks .53% objective reponse rate ( complete reponse,2, partial response,4.) .Median progression free survival3,1 months . Median overall survival 57 months .44% patients had measurable improvement in the quality of life

Organ at risk

Dose limitation (GY)

spinal cord 45

brachial plexus

60

mandible 70

posterior neck

<35 (astrip of normal tissue should be left to facilitateDrainge )

Dose limitation gude line in the ca larynx