Laryngeal Cancer

Laryngeal Cancer Anh Q. Truong MS-4 University of Washington, SOM

Vaezi, MF . Nature Clinical Practice Gastroenterology & Hepatology (2005) 2 , 595-603 Anatomy – cont’

Anatomy – subdivision Source: AJCC Cancer Staging Manual, 6 th Ed (2002)

Most common head and neck CA (excluding skin) 12,250 new cases/yr Male : Female = 4 : 1 > 90% squamous cell cancer Glottic CA more common in Caucasian (in US) Glottic CA = supraglottic in African American (in US) Variation of ratio around world Epidemiology American Cancer Society: Cancer Facts and Figures 2008. Atlanta, Ga: American Cancer Society, 2008. Incidence by Site Supraglottic 40% Glottic 59% Subglottic 1%

Tobacco smoking, bidi smoking, alcohol. MJ smoking correlation HPV, GERD implicated Possibly perchloroethylene Risk Factors

Signs and symptoms Mass effect: hoarseness, dysphagia, hemoptysis, neck mass, airway compromise (difficulty breathing), aspiration Throat pain, ear pain (referred through CN X branch) Suggests advanced stage Hoarseness = allow for early detection of glottic cancer Supraglottic CA = tend to present later Usually present w/bulkier tumors before Si/Sx present More likely to present w/node mets d/t richer lymphatics Weight loss Clinical Presentation

Clinical Presentation – cont’ Physical Exam Complete head and neck exam Palpation for nodes; restricted laryngeal crepitus. Quality of voice Breathy voice = cord paralysis Muffled voice = supraglottic lesion Laryngoscopy Laryngeal mirror Fiberoptic exam (lack depth perception) Note: contour, color, vibration, cord mobility, lesions. Stroboscopic video laryngoscopy Highlights subtle irregularities: vibration, periodicity, cord closure

Differential Diagnosis Infectious Inflammatory Granulomatous disease (TB, sarcoidosis) Papillomatosis Lymphoma

Imaging CT or MRI Evaluate pre-epiglottic or paraglottic space Laryngeal cartilage erosion Cervical node mets PET Role under investigation, currently not standard of care Specific application Identifying occult nodal mets Distinguish recurrence vs radionecrosis or other prior tx sequalae Ultrasound In Europe: used to identify cervical mets and laryngeal abn.

Biopsy and Histology Direct laryngoscopy with biopsy Histologic subtypes Squamous cell carcinoma > 90% of causes Characterized by nl  hyperplasia  dysplasia  CIS  invasive CA Invasive CA characterized by: well, moderately, or poorly differentiated Nest of malig epi cells, desmoplastic & inflammatory stroma, keratin pearls (in well and mod dif CA). Linked to tobacco and excessive alcohol Variance: verrucous, spindle cell carcinoma, & basaloid.

Biopsy and Histology – cont’ Histologic subtypes - cont’ Salivary gland Adenoid cystic carcinoma Mucoepidermoid carcinoma Surgery is preferred w/guidelines for adjuvant XRT Sarcomas (mainly chondrosarcoma) Most commonly from cricoid cartilage Nonaggressive, preferably tx with partial laryngeal surgery XRT viewed as ineffective Others: carcinoid tumors, lymphoma, mets.

Supraglottis Tis: CA in-situ T1: limited to subsite of supraglots w/normal cord mobility T2: invade mucosa of > 1 subsite of supraglottis, glottis, or outside of supraglottis w/out fixation of the larynx T3: limited to larynx w/vocal cord fixation and/or invades postcricoid area, pre-epiglottic tissues, paraglottic space, and/or minor thyroid cartilage erosion T4a: invades thyroid cartilage and/or tissues beyond larynx T4b: invades prevertebral space, encases carotid artery, or invades mediastinal structures Glottis Tis: CA in-situ T1: limited to cord; T1a : one cord; T1b : two cords T2: extends to supraglottis, and/or subglottis, and/or w/impaired cord mobility T3: limited to larynx w/vocal cord fixation and/or invades paraglottic space, and/or minor thyroid cartilage erosion T4a: invades thyroid cartilage and/or tissues beyond larynx T4b: invades prevertebral space, encases carotid artery, or invades mediastinal structures Subglottis Tis: CA in-situ T1: limited to subglottis T2: extends to vocal cord with normal or impaired mobility T3: limited to larynx w/vocal cord fixation T4a: invades cricoid or thyroid cartilage, and/or invades tissues beyond the larynx T4b: invades prevertebral space, encases carotid artery, or invades mediastinal structures Staging Source: AJCC Cancer Staging Manual, 6 th Ed (2002)

Subglottis Tis: CA in-situ T1: limited to subglottis T2: extends to vocal cord with normal or impaired mobility T3: limited to larynx w/vocal cord fixation T4a: invades cricoid or thyroid cartilage, and/or invades tissues beyond the larynx T4b: invades prevertebral space, encases carotid artery, or invades mediastinal structures Staging Nodes N0: no regional node mets N1: single ipsilateral node, ≤ 3 cm N2a: single ipsilateral node, > 3 cm, ≤ 6 cm N2b: multiple ipsilateral nodes, ≤ 6 cm N2c: bilateral or contralateral nodes, ≤ 6 cm N3: node > 6 cm Mets Mx: unknown M0: no distant mets M1: distant mets Source: AJCC Cancer Staging Manual, 6 th Ed (2002)

Stage Grouping Early stage Advanced stage Stage 0 Tis N0 M0 Stage I T1 N0 M0 Stage II T2 N0 M0 Stage III T3 N0 M0 T1-3 N1 M0 Stage IVA T4a N0-1 M0 T1-4a N2 M0 Stage IVB T4b any N M0 any T N3 M0 Stage IVC any T any N M1

Surgery Microlaryngeal surgery Hemilargyngectomy Supraglottic laryngectomy Near-total laryngectomy Total laryngectomy Photodynamic Therapy Radiation Chemothrapy Cisplatin + 5-fluorouracil Treatments – Options

Current therapeutic options Laser microsurgery (transoral) Open partial laryngectomy Radiation therapy No RCT to compare surgery w/XRT Rate of local control similar between surgery and radiation Current recommendations, XRT with surgery reserved for salvage therapy with local recurrence Treatment – Early Stage (I/II) Mendenhall WM et al., Cancer. 2004 May 1;100(9)

Dose Fractionation Yu et al., 1997 [1] Retrospective study – 5 yr local ctr rate of XRT on T1 glottic CA Daily fx > 2 Gy (50 Gy/2.5Gy QD & 65.25Gy/2.25 Gy QD) had 5 yr local ctr rate of 84% Daily fx = 2 Gy had 5 yr local ctr 65.6% Andy Trotti, RTOG 95-12 – closed [2] Randomized pts with T2 glottic cancer to 70Gy/2Gy QD vs 79.2 Gy/1.2 Gy BID 1 Yu E. et al., Int J Radiat Oncol Biol Phys. 1997 Feb 1;37(3):587-91. 2 www.rtog.org/members/protocols/95-12/95-12.pdf

Dose Fractionation Yamazaki et al., 2006 RTC – 5 yr local ctr rate of XRT on T1 glottic CA 2 Gy/fx (60Gy/30 fx or 66Gy/33fx): 5 yr local ctr rate = 77% 2.25 Gy/fx (56.25Gy/25fx or 63 Gy/28fx): 5 yr local ctr rate = 92% Yamazaki H et al., Int J Radiat Oncol Biol Phys. 2006 Jan 1;64(1):77-82

Treatment – Advanced Stage (III/IV) – VA Study Dept of VA Laryngeal CA Study Group, 1991 RCT: Induction chemo  XRT vs laryngectomy  post-op XRT Chemo arm = cisplatin + 5-FU x 2c  if partial/complete response  3 rd cycle  XRT*, else  salvage surgery Surgery arm = total laryngectomy (partial if poss)  XRT* *XRT = definitive: 66 Gy – 76 Gy; post-op: 50.4Gy (+10Gy if high risk of local recurrence) Department of Veterans Affairs Laryngeal Cancer Study Group, N Engl J Med 1991;324:1685-90.

Treatment – Advanced Stage (III/IV) – VA Study cont’ Department of Veterans Affairs Laryngeal Cancer Study Group, N Engl J Med 1991;324:1685-90. Overall Survival Surg + XRT Chemo + XRT 2 yr OS = 68% in both groups, P = 0.9846 Surg + XRT Chemo + XRT Chem + XRT shorter disease free interval, but dif not significant Disease Free Survival

Treatment – Advanced Stage (III/IV) – VA Study cont’ Department of Veterans Affairs Laryngeal Cancer Study Group, N Engl J Med 1991;324:1685-90. Site of recurrence Surgery (N = 166) Chemotherapy (N=166) Primary 4 (2%) 20 (12%) Regional 9 (5%) 14 (8%) Distant 29 (17%) 18 (11%) All 42 (25%) 52 (31%) No difference in rate of recurrence, significant difference in site of recurrence, significant difference in development of a 2nd primary CA (surg 6%, chemo 2%)

Treatment – Advanced Stage (III/IV) – VA Study cont’ Of the 166 pts in the chemo arms - 107 (64%) patients had preserved larynx - 30 patients (18%)  laryngectomy before definitive XRT - 29 patients (18%)  laryngectomy after definitive XRT Department of Veterans Affairs Laryngeal Cancer Study Group, N Engl J Med 1991;324:1685-90.

Treatment – Advanced Stage (III/IV) – RTOG 91-11 Study Forastiere et al, (RTOG 91-11), 2003 RCT: XRT alone vs induction chemo  XRT vs concurrent chemoXRT, primary endpoint = larynx perservation XRT: 70Gy/35fx in all arms Induction – cisplatin + 5 FU x 2c  if complete or partial response, w/out neck progression  3 rd cycle  XRT; else  laryngectomy  XRT Concurrent – cisplatin x 3c + XRT Forastiere AA et al, N Engl J Med 2003;349:2091-8.

Treatment – Advanced Stage (III/IV) – RTOG 91-11 Study Induction Chemotherapy 173 assigned  168 completed chemo x 2c  144 complete or partial response  134  completed 3 rd chemo cycle 84% of pts received ≥ 67 Gy Concurrent Chemoradiation 172 assigned  120 (70%) completed cisplatin x 3 cycle, 40 (23%) completed cisplatin x 2 cycles. 91% of pts received ≥ 67 Gy Radiation alone 95% of pts received ≥ 67 Gy Forastiere AA et al, N Engl J Med 2003;349:2091-8.

Treatment – Advanced Stage (III/IV) – RTOG 91-11 Study 2 yr 3.8 yr 5 yr update A - induction chemo  XRT: 75% 72% 70.5% - concurrent chemoXRT : 88%* 84%* 83.6% - XRT alone : 70% 67% 65.7% Laryngeal Preservation Forastiere AA et al, N Engl J Med 2003;349:2091-8. A Forastiere AA et al, Journal of Clinical Oncology , Vol 24, No. 18S(June 20 Supplement),2006:5517.

Treatment – Advanced Stage (III/IV) – RTOG 91-11 Study Locoregional Control Forastiere AA et al, N Engl J Med 2003;349:2091-8. A Forastiere AA et al, Journal of Clinical Oncology , Vol 24, No. 18S(June 20 Supplement),2006:5517. 2 yrs 5 yr update A - induction chemo  XRT: 64% 54.9% - concurrent chemoXRT : 80% 68.8% - XRT alone : 58% 51%

Treatment – Advanced Stage (III/IV) – RTOG 91-11 Study A Chemo therapy  significant decreased in dz free survival compared to XRT alone (P =0.02 compared w/induction, P = 0.06 compared w/conccurent Tx) B No significant difference C Difference only significant comparing concurrent chemoXRT vs XRT alone. Forastiere AA et al, N Engl J Med 2003;349:2091-8. Concurrent chemoXRT Induction chemo  XRT XRT alone 2 yrs 5 yrs 2 yrs 5 yrs 2 yrs 5 yrs Dz Free Survival A 61% 36% 52% 38% 44% 27% Overall Survival B 74% 54% 76% 55% 75% 56% Distant mets C 8% 12% 9% 15% 16% 22%

Treatment – Advanced Stage (III/IV) – cont’ Forastiere AA et al, N Engl J Med 2003;349:2091-8.

Hypothyroidism Mucositis Dermatitis Xerostomia Fibrosis Fistulas Dysgeusia Anticipated Toxicities

Take Home Points Most laryngeal CA are SCC Low stage can be tx by different modalities Fraction size ≥ 2.25 Gy/fx may increase local ctr OS similar b/w surgery + XRT vs chemo + XRT in advanced stage, but organ preservation better with chemo + XRT Organ preservation: concurrent XRT > chemo  XRT = XRT alone Don’t smoke or drink too much alcohol

An Actual Picture of a Laryngeal Cancer (L) Source: http://www.medscape.com/content/2002/00/44/25/442595/442595_fig.html (R) Source: http://www.som.tulane.edu/classware/pathology/medical_pathology/New_for_98/Lung_Review/Lung-62.html

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