LARYNGEAL CANCER MANAGEMENT

Management of supraglottic and glottic larynx cancer has been revised lately. This presentation gives an overview of guidelines for management of laryngeal cancer. includes latest NCCN guidelines.

1. MANAGEMENT OF CARCINOMA LARYNX DR FARAZ BADAR 23/11/2019 MEDANTA MODERATOR : DR SAUMYA RANJAN/ DR SUSOVAN BANNERJI

2. EPIDEMIOLOGY & RISK FACTORS 2 % of the total cancer burden and 0.3 % of all cancer deaths T he second most common head and neck cancer site after Oral cavity A t diagnosis, 51 %  localized , 29%  regional spread, and 15%  distant metastases. The ratio of glottic to supraglottic carcinoma is approximately 3:1. INDIA : 2.5 % of all cancers. Strongly associated with tobacco smoking .

3. ANATOMY The larynx is divided into the supraglottis , glottis, and subglottis . EXTENT : From cranial border of third to caudal border of sixth cervical vertebrae SUPRAGLOTTIS :Subsites include Epiglottis False vocal cords Ventricles Aryepiglottic folds Arytenoids . (FAVEA)

4. GLOTTIS  Vocal cords and anterior commissure. S UBGLOTTIS  extends from a point 5 mm below the free margin of the vocal cord to the inferior border of the cricoid cartilage .

5. Larynx  9 cartilages. 3 are paired and 3 unpaired. Paired  Arytenoids , Cuneiform and Corniculate Unpaired  Epiglottis , Thyroid, Cricoid Muscles of larynx  Intrinsic and Extrinsic Intrinsic  Control movement of cord Extrinsic  Swallowing

6. All intrinsic muscles of larynx are supplied by RLN except CRICOTHYROID  s/b Superior laryngeal nerve. (Ext branch) EXT ms  1. suprahyoid. 2. Infrahy . 3. Stylopharyngeous Suprahyoid  DSMG  Digastric/Stylohyoid/mylohyoid/ Geniohyoid  elevate larynx Infrahyoid  4 pairs depress larynx  Sternohyoid / sternothyroid /thyrohyoid/ omohyoid

7. LYMPHATIC DRAINAGE SUBSITE DRAINAGE Supraglottis Subdigastric (level II)>> middle internal jugular chain (level III) Glottis No capillary lymphatics of the true vocal cords Subglottis Pretracheal ( Delphian ) lymph nodes Paratracheal (level VI) lymph nodes

8. PATHWAYS OF SPREAD Two major pathways 1. Local. 2. Lymphatic Local spread  Epiglottis : invades vallecula , Base of tongue, false cords, Aryepiglottic folds, medial wall of the pyriform sinus. False cord : U sually submucosal with little exophytic component. E arly involvement of paraglottic fat space and pre- epiglottic space

9. Aryepiglottic Fold/Arytenoid : Early lesions are exophytic. Extend to adjacent sites and eventually cause fixation of the larynx , which is due to involvement of the cricoarytenoid muscle or joint >>invasion of the recurrent laryngeal nerve.

10. Glottic larynx Most lesions of the true vocal cord begin on the free margin and upper surface of the cord. The anterior portion of the cord  most common site . Anterior commissure involvement , is said to occur when no tumor-free cord can be seen anteriorly Extension to the posterior commissure is uncommon.

11. Subglottic Larynx Subglottic cancers are rare. Most involve the inferior surface of the vocal cords by the time they are diagnosed. M ost lesions are bilateral or circumferential on presentation. There is early involvement of cricoid cartilage because there is no intervening muscle layer. Partial or complete fixation of one or both cords is common. Misdiagnosis or diagnostic delay is frequent.

12. LYMPHATIC SPREAD : SUPRAGLOTTIC CA. The disease spreads mainly to the level II nodes . The incidence of clinically positive nodes is 55% at the time of diagnosis; 16% are bilateral 1 Stage wise involvement 2 : T1–T2 27%  40%; T3–T4  55 %–65% Lindberg R et al., Cancer 1972 Wang CC, Radiation therapy for head and neck neoplasms, 1996

13. LYMPHATIC SPREAD : GLOTTIC CANCER No capillary lymphatics of the true vocal cords Supraglottic spread  associated with metastasis to the level II nodes . Anterior commissure and anterior subglottic invasion  associated with involvement of the midline pretracheal lymph node (level VI). Stage Perez Wang T1 0%–2% T2 < 2% 2%–7% T3-T4 20%- 30% 15%–30%

14. CLINICAL PRESENTATION SUPRAGLOTTIC CANCER - Pain on swallowing , lump in the throat. Pain referred to ear, N eck mass GLOTTIC CANCER - H oarseness ( very early ) ,s ore throat, ear pai n. P ain localized to the thyroid cartilage and airway obstruction  features of advanced lesions. Late symptoms include weight loss, foul breath, dysphagia, and aspiration.

15. DIAGNOSTIC WORKUP HISTORY : including smoking history (no. of pack years smoked ) PHYSICAL EXAMINATION : including laryngeal mirror examination complimented by Flexible fiberoptic endoscopes. IMAGING STUDIES : CT scan with contrast enhancement is the method of choice for studying the larynx . The CT scan (1-2 mm slice thickness) should be performed before biopsy so that abnormalities that may be caused by the biopsy are not confused with tumor. CT is preferred to magnetic resonance (MR) imaging because the longer scanning time for MR results in motion artifact MRI is useful to detect early cartilage destruction and Base of tongue invasion PET/CT for stage III/IV disease

16. STAGING : SUPRAGLOTTIC CANCER

17. STAGING : GLOTTIC CANCER

18. STAGING SUBGLOTTIC CANCER

19. CLINICAL NODAL STAGING

20. PATHOLOGICAL NODAL STAGING

21. AJCC PROGNOSTIC STAGE GROUPS When T is … And N is … And M is … Then Stage group is.. Tis N0 M0 T1 N0 M0 I T2 N0 M0 II T3 N0 M0 III T 1 , T2, T3 N1 M0 III T4a N0, N1 M0 IVA T 1, T2, T 3 ,T 4 a N2 M0 IVA Any T N3 M0 IVB T4b Any N M0 IVB Any T Any N M1 IVC

22. TREATMENT OF SUPRAGLOTTIC CANCER

23. OVERVIEW Stage Treatment Guidelines T1-T2 N0M0 Definitive RT (preferred) or supraglottic laryngectomy, with or without adjuvant RT T1-T2 N +, T3-T4aN0-N+ Concurrent RT +CT Post treatment ,if residual neck node is there, with a complete response at primary  neck dissection. If the primary does not attain a complete response then the patients should be considered for salvage surgery and neck dissection. T4 a N0-N+ Surgery followed by post-op chemo-RT. If unresectable, definitive concurrent Radiotherapy + Chemotherapy

24. NCCN EARLY STAGE DISEASE  DEFINITIVE RT / SUPRAGLOTTIC PARTIAL LARYNGECTOMY NECK IS ALWAYS TREATED EVEN FOR T1 TUMORS

25. STAGE III  ATTEMPT LARYNX PRESERVATION WITH CONCURRENT CTRT

26. STAGE III/SELECT IVA  CONCURRENT CTRT IS TOC. SURGERY COMES AS A SECOND OPTION

27. TOTAL LARYNGECTOMY+ NECK DISSECTION  TOC. SELECT LESIONS MAY BE TREATED WITH CONCURRENT CTRT WITH TOTAL LARYNGECTOMY RESERVED AS SALVAGE

28. Surgery for supraglottic cancer Supraglottic Laryngectomy Supracricoid Laryngectomy Used for lesions involving the epiglottis, a single arytenoid, the aryepiglottic fold, or the false vocal cord lesions extending from the supraglottis into one or both vocal cords Structures resected Hyoid bone Epiglottis Superior half of thyroid cartilage AE folds, and False cords to arytenoids. Bilateral true and false cords, Paraglottic space Preepiglottic space Epiglottis, and Thyroid cartilage. Containdication Extension of the tumor to the true vocal cord, the anterior commissure, or both arytenoids, fixation of the vocal cord, or thyroid or cricoid cartilage invasion Vocal cord fixation (RELATIVE C/I),Extension to the cricoid and thyroid cartilage

29. Total laryngectomy with or without neck dissection is surgery of choice for advanced lesions. R emoval of the hyoid, thyroid and cricoid cartilage, epiglottis, and strap muscle with reconstruction of the pharynx P ermanent tracheostomy is always needed Speech may be reconstituted with a prosthesis or with an electrolarynx

30. Mould and scan S upine position with hands by side Head immobilized in neutral neck position Head and neck thermoplastic cast (S- frame) Use appropriate head rest Scan limit – Base of skull to sterno - clavicular joint Slice thickness  2mm- 3mm

31. 2D planning The primary lesion and both sides of the neck are treated with opposed lateral portals . 15 degree wedges are used to compensate for the contour of the neck The lower neck nodes are irradiated through a separate anterior portal Field borders: Superior  superior to mandibular angle Inferior  bottom of cricoid cartilage If Subglottic extension is present, shoulders should be pulled down as much as possible . Anterior  0.5–1 cm skin fall-off to neck and one-third of mandible Posterior  Usually spinous processes

32. Portal borders for T3 larynx cancer. Initial lateral field Schematic diagram of the low-neck field

33. Portal borders for T3 larynx cancer. b off-cord lateral c cone down

34. Conformal Planning # T1 GTV- P = All gross primary disease CTV-P1 (yellow) = GTV-P + 5 mm in all directions . CTV-P2(green) = GTV-P + 10 mm in all directions. CTV-P2 includes the pre- epiglottic space and the para-laryngeal space. E xcludes the thyroid cartilage and the air cavity. Ventricle  CTV-P2 extend into the glottic area. A ryepiglottic fold and supra-hyoid epiglottis  CTV-P2 extend into the vallecula . Inter-arytenoid mucosa  it is recommended that the posterior pharyngeal wall is excluded from the CTV-P2 #  GREGOIRE GUIDELINES

35. T2 CTV-P1 = GTV-P + 5 mm margin in all directions. CTV-P2 = GTV-P + 10 mm margin in all directions. CTV-P2 includes the pre- epiglottic space , the para-laryngeal space, thyroid cartilage E xcludes strap muscles and the air cavities Ventricle  CTV-P2 extend into the glottic area. Aryepiglottic fold and supra-hyoid epiglottis  CTV-P2 extend into the vallecula . inter-arytenoid mucosa  it is recommended that the posterior pharyngeal wall is excluded from the CTV-P2

36. T3 CTV-P1 = GTV-P + 5 mm margin in all directions. CTV-P2 = GTV-P + 10 mm margin in all directions . In all cases, CTV-P2 includes part of the thyroid cartilage in relation to the GTV-P and the pre- epiglottic space. D oes not extend outside of the thyroid cartilage except if it is infiltrated. Should not include the posterior pharyngeal wall .

37. T4 CTV-P1 = GTV-P + 5 mm margin in all directions. CTV-P2 = GTV-P + 10 mm margin in all directions . In all cases, CTV-P2 includes the thyroid cartilage in relation to the GTV-P, and the pre- epiglottic space. I t may extend outside of the thyroid cartilage, but does not extend beyond the strap muscles ( sterno -thyroid or thyro -hyoid muscles) unless macroscopically invaded. Also include part of thyroid gland For tumours infiltrating the prevertebral space (i.e. T4b), CTVP2 may extend into the vertebral body.

38. Dose and fractionation # T1-T3,N0-N1  66 to 70 Gy in 2Gy per fraction to High risk PTV and 54 – 63 Gy in 1.8 Gy daily fractions to Low to intermediate risk PTV POST- OPERATIVE  60 – 66 Gy in 2 Gy per fraction to high risk PTV with adverse features such as positive margins and 54 – 63 Gy in 1.8 Gy daily fractions to Low to intermediate risk PTV # NCCN Guidelines v3.2019

39. Indications for postoperative RT pT3 ,pT4 primary N2 or N3 node C lose margins S ignificant subglottic extension (1 cm or more ) C artilage invasion P erineural or vascular invasion E xtension of the primary tumor into the soft tissues of the neck For control of subclinical disease in the opposite neck

40. Indications for postoperative chemoRT Positive margin Extracapsular nodal spread Indications for preoperative RT Fixed neck nodes Have had an emergency tracheostomy through tumor Direct extension of tumor involving the skin

41. Selection of low risk nodal target volumes for laryngeal cancers (GREGOIRE GUIDELINES)

42. CHEMOTHERAPY INDICATION  D efinitive chemoradiation for Stage III–IVB AGENT  C isplatin is standard of care . DOSE  100 mg/m 2 bolus weeks 1, 4, 7 (NCCN Category 1) OR 40 mg/m 2 weekly (NCCN Category 2B). Cetuximab can be used for nonplatinum candidates. DOSE  loading dose of 400 mg/m 2 1 week prior to RT followed by 250 mg/m 2 weekly during RT. Use of induction CHT is controversial but has been used to select pts for laryngectomy versus preservation and consists of docetaxel, cisplatin, 5-fl uorouracil (TPF) q3 weeks X four cycles completed 4 to 7 weeks prior to RT.

43. TREATMENT OF VOCAL CORD CANCER

44. Stage Treatment Guidelines Carcinoma in situ External Beam radiotherapy or Endoscopic removal by laser, stripping of the cord T1-T2 N0M0 External Beam radiotherapy Alone, surgery reserved for salvage after RT failure . Favorable T3 any N Radical External Beam radiotherapy + Concurrent chemotherapy (organ preservation modality) If there is residual neck node, with complete response at primary, to be taken up for neck dissection. If primary does not attain complete response , then should be considered for salvage surgery and neck dissection If primary radical surgery is done, then postoperative Radiotherapy + concurrent chemotherapy. Unfavorable T3- T4 any N Total laryngectomy with ipsilateral (N0-N1) or bilateral(N2-N3)neck dissection. Post operative Radiotherapy

45. NCCN CIS  ENDOSCOPIC RESECTION/RT STAGE I/II RT(PREFERRED)/ SURGERY (PARTIAL LARYNGECTOMY)

46. STAGE III  TOC IS CTRT (LARYNX PRESERVATION) NECK MUST BE TREATED

47. ADVANCED DISEASE  TOTAL LARYNGECTOMY IS TOC

48. Carcinoma in Situ Options of treatment include  S tripping the cord. (Disadvantage : Recurrence, hoarseness) CO 2 laser excision EBRT. (Advantage: better voice preservation) 5-yr Local control rates for glottic CIS  Stripping  72% ; Laser  83% ; RT  88 %–92%

49. Early Vocal Cord Carcinoma Radiation is the initial treatment for T1 and T2 lesions. S urgery reserved for salvage. Although surgery produces comparable cure rates for selected T1 and T2 vocal cord lesions, Radiation is generally preferred . The major advantage of Radiation compared with partial laryngectomy is better quality of the voice .

50. Moderately Advanced vocal cord carcinoma

51. Advanced Vocal Cord Carcinoma Advanced lesions usually show extensive subglottic and supraglottic extension , bilateral glottic involvement, and invasion of the thyroid, cricoid, and/or arytenoid cartilages The airway is compromised, necessitating a tracheostomy The mainstay of treatment is total laryngectomy with neck dissection with or without adjuvant RT

52. Voice preserving surgical options for glottic cancer SURGERY TISSUES RESECTED INDICATION CONTRAINDICATION ENDOSCOPIC TECHNIQUES(Mucosal stripping/ TORS/Electrocautery/CO2 laser) MUCOSA OF VOCAL CORD CIS, T1a - Vertical Partial laryngectomy/ Hemilaryngectomy 1 true vocal cord and one-third of contralateral true cord. Vocal cord lesions up to 1 cm anterior and 5 mm posterior subglottic extension Extension to the epiglottis, false cord, or both arytenoids Supracricoid partial laryngectomy True and false cords, paraglottic spaces, thyroid cartilage Tumor extension in supraglottis with sparing of epiglottis Extension to the cricoid and arytenoid cartilages

53. 2D planning Treated with parallel opposed lateral wedged fields 15 degree wedge with heel anteriorly Field borders: T1 lesions  from the thyroid notch superiorly to the inferior border of the cricoid and fall off anteriorly P osterior border  1-1.5 cm posterior to back edge of thyroid cartilage For T2 tumors, the field is extended depending on the anatomic distribution of the tumor. Field size : 4 × 4 cm to 5 × 5 cm (plus an additional 1.0 cm of “flash” anteriorly) and is occasionally 6 × 6 cm for a large T2 lesion

54. T3 and T4 lesions requires larger portals, which include the neck nodes Field borders : S uperior  just above the angle of the mandible ( to include the jugulodigastric lymph nodes) Inferior  bottom of the cricoid cartilage if no subglottic spread. Lowered as per disease extent in subglottic involvement Anterior  Flash Posterior  includes a portion of the spinal cord (for adequate coverage of the midjugular lymph nodes) The level IV lymph nodes are included in a separate low-neck portal

55. Treatment portal for T3-T4N0 glottic carcinoma

56. Conformal Planning # T1 GTV- P = All gross primary disease CTV-P1 = GTV-P + 5 mm in all directions. CTV-P1 include the paraglottic space, the anterior commissure for anterior vocal cord tumour , the anterior part of the contralateral vocal cord for tumour extending to the anterior commissure , and the vocal process of the arytenoid cartilage for tumour extending to the posterior vocal cord, but excludes the thyroid cartilage and the air cavity #  GREGOIRE GUIDELINES

57. T2 CTV-P1 = GTV-P + 5 mm in all directions. CTV-P2 = GTV-P + 10 mm in all directions . CTV-P2 includes the paraglottic space, the anterior commissure, the anterior part of the contralateral vocal cord for tumour extending to the anterior commissure, and the vocal process of the arytenoid cartilage for tumour extending to the posterior vocal cord may include the thyroid cartilage in relation to the GTV-P , but excludes the cricoid cartilage

58. T3 CTV-P1 = GTV-P + 5 mm in all directions. CTV-P2 = GTV-P + 10 mm in all directions . CTV-P2 includes part of the thyroid cartilage in relation to the GTV-P, and most likely part of the cricoid cartilage caudally , the pre- epiglottic space anteriorly and the medial wall of the piriform sinus postero -laterally. D oes not extend outside of the thyroid cartilage, except if it is infiltrated . D oes not extend outside of the larynx into the oropharynx, unless invaded . Should not include the posterior pharyngeal wall.

59. T4 CTV-P1 = GTV-P + 5 mm in all directions. CTV-P2 = GTV-P + 10 mm in all directions . CTV-P2 includes part of the thyroid cartilage in relation to the GTV-P, part of the cricoid cartilage caudally , and the pre- epiglottic space, anteriorly. E xtends outside of the thyroid cartilage, but does not go beyond the strap muscles ( sterno -thyroid or thyro -hyoid muscles ) unless these muscles are macroscopically invaded

60. Dose and fractionation # Tis,N0  60.75 Gy (2.25 Gy/ fraction) to 66 Gy(2 Gy/fraction) T1, N0  63 Gy ( 2.25 Gy/ fraction, preferred) to 66 Gy(2 Gy/fraction ) T2,N0  65.25 Gy(2.25 Gy/ fraction) to 70 Gy(2 Gy/fraction ) ≥ T2, N1  66 Gy to 70 Gy in 2 Gy/ fraction to High risk PTV and 54 – 63 Gy in 1.8 Gy daily fractions to Low- intermediate risk PTV # - NCCN guidelines v.3 2019

61. Follow-Up

62. Follow-up paradigm History and physical examination + laryngoscopy on each visit. I maging (for signs/Symptoms) TSH (if neck is irradiated ) every 6 to 12 months S peech/hearing evaluation A nnual chest X-ray Counselling for smoking cessation

63. Radiation Therapy Sequelae Tanning or erythema of skin Hoarseness of voice M ild sore throat Edema of the larynx Soft-tissue necrosis leading to chondritis D ry mouth because of Thick saliva Loss of taste S ensation of a lump in the throat Fatigue Dysphagia , odynophagia Weight loss Hypothyroidism

64. SOME LANDMARK TRIALS

65. VA Larynx Study (NEJM 1991) Prospective randomised trial N= 332, III–IV locally advanced SCC of larynx 63 % S upraglottis , 57% vocal cord fixation 2 arms  (a ) induction Chemotherapy followed by Radiation or (b ) Total laryngectomy followed by post-op Radiation. Results : Rate of laryngeal preservation was 64 % at 2 years Conclusion: Induction Chemotherapy followed by definitive Radiation can be effective in preserving larynx in high percentage of pts, without compromising OS.

66. Forastiere , RTOG 91-11 547 patients randomized, 518 evaluable . Median follow up = 3.8 years (Update published with MFU of 10.8 years) Arm A- T hree cycles of induction cisplatin and fluorouracil followed by RT in complete and partial responders (like Veterans affairs study) Arm B- RT and concomitant cisplatin (100 mg/m2 on days 1, 22, and 43 of RT ) Arm C- once-daily RT (70 Gy in 35 fractions over 7 weeks) alone.

67. Results: The rates of larynx presentation were significantly improved for arm B C ompared to induction, chemoradiation improved larynx preservation, Loco regional control but not Laryngectomy free survival (which was the primary end point of study) The 5-year survival rates were similar for the three treatment groups The likelihood of developing distant metastases was lower for the two groups of patients that received adjuvant chemotherapy.

68. RTOG 9003 1076 patients with stage III/IV disease Randomised to 4 arms 1.Standard fractionation  2 Gy/#, once a day, 5 days/week, to a total dose of 70 Gy / 35 #/ 7 weeks 2. Hyperfractionation  1.2 Gy/#, twice daily (≥6 hours apart), 5 days/week, to a total dose of 81.6 Gy in 68 fractions/7 weeks 3. Accelerated fractionation with split  1.6 Gy/#,twice daily (≥6 hours apart), 5 days /week, to a total dose of 67.2 Gy in 42 fractions over 6 weeks, including a 2-week rest after 38.4 Gy 4. Accelerated fractionation with concomitant boost  1.8 Gy/#, once a day, 5 days /week to a large field, plus 1.5 Gy/#once a day to a boost field given 6 or more hours after treatment of the large field for the last 12 treatments days, to a total dose of 72 Gy/ 42 #s over 6 weeks

69. Results The 5-year local-regional failure rates were as follows : Standard fractionation  59% Hyperfractionation  51% Accelerated split course  58% C oncomitant boost  52 %. Both the hyperfractionation and concomitant boost schedules yielded significantly better local-regional control rates T rend toward improved overall survival with hyperfractionation but no difference in cause-specific survival. Acute toxicity was increased with all three altered fractionation schedules; T here was a modest increase in late effects with the concomitant boost schedule

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