Page 1 of 8 Disclaimer: This algorithm has been developed for MD Anderson using a multidisciplinary approach considering circumstances particular to MD Anderson’s specific patient population, services and structure, and clinical information. This is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. This algorithm should not be used to treat pregnant women. Note: Consider Clinical Trials as treatment options for eligible patients.

INITIAL EVALUATION CONSULTATIONS PRE-TREATMENT EVALUATION

● Confirm outside ● If no /pathology, consider ● History examination under anesthesia (EUA), ○ Chief complaint direct (DL), biopsy, ○ History of present illness and previous treatment esophagoscopy ● Past medical history including but not limited to: ● Radiation ○ Social history (including and use) ● Thoracic/Head and Neck Medical Glottic See Page 2 ○ Previous – head and neck, Oncology (THNMO) for patients thoracic, breast (for previous primary or benign with stage III or IV diagnosis) ● Dental Oncology for dentulous Supraglottic: ● patients except those receiving Patient information Node negative (based ○ Full head and neck examination narrow field radiation See Page 3 presented at on clinical and/or ○ Fiberoptic exam ● Speech Pathology for all patients multidisciplinary radiographic imaging) ○ Videostroboscopy (optional) and videostroboscopy, if indicated planning conference ○ General medical examination ● Consider esophagoscopy or barium ● Stage T and N (AJCC) swallow Supraglottic: ● Imaging studies ● Perioperative Evaluation and Node positive (based 1 See Page 4 ○ CT head and neck with contrast or MRI with Management (POEM) on clinical and/or contrast ● Plastic for patients who radiographic imaging) ○ Consider PET-CT scan for stage III/IV will require major reconstruction ○ Modified barium swallow/esophagoscopy (pharyngeal reconstruction) ○ Chest imaging (PET-CT preferred, but CT chest ● Nutritional assessment with contrast acceptable) ● Smoking cessation for active 2 ● Lifestyle risk assessment smokers only

1 CT is tailored to oncologic imaging: high-resolution, bone and soft tissue window, 90-100s contrast delay for optimal opacification of mucosa and soft tissues 2 See Physical Activity, Nutrition, and Tobacco Cessation algorithms; ongoing reassessment of lifestyle risks should be a part of routine clinical practice

Department of Clinical Effectiveness V8 Approved by the Executive Committee of the Medical Staff on 09/21/2021 Larynx Cancer Page 2 of 8 Disclaimer: This algorithm has been developed for MD Anderson using a multidisciplinary approach considering circumstances particular to MD Anderson’s specific patient population, services and structure, and clinical information. This is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. This algorithm should not be used to treat pregnant women. Note: Consider Clinical Trials as treatment options for eligible patients. EVALUATION PRIMARY TREATMENT ADJUVANT TREATMENT SURVEILLANCE

Severe / ● Endoscopic removal (stripping/laser) or in situ ● Radiation therapy as clinically indicated for patients who may have poor functional surgical outcome

● Radiation therapy or Is Yes ● Radiation to primary tumor or ● Neck dissection(s) Primary tumor nodal status ● Endoscopic partial or most T1-2, any N positive? ● Open partial laryngectomy No Observe

1,2 17● Total laryngectomy and neck ● Radiation therapy Yes 4 dissection(s) as indicated, and Presence of ● Consider chemoradiation ipsilateral thyroidectomy pathological risk ● For recurrent or persistent 3 disease, see Page 5 Glottic ● Consider primary tracheoesophageal features ? puncture (TEP) No Observe ● Surveillance (see Page 6) ● Consider THNMO consult Primary tumor for chemoprevention trials most T3, any N Yes Neck dissection(s) Residual nodal ● Consider Yes disease? induction Complete No Observe 3 Pathological risk features include: response at ● Primary pathology ● Concurrent primary 1,2 ○ Any T1 or T2 with perineural invasion chemoradiation site? No Total laryngectomy and neck dissection(s), or as clinically indicated ○ Any T3 or T4 ● Regional pathology ○ Multiple lymph nodes (any N2, N3) 4 ● Total laryngectomy and neck dissection(s) as ● Radiation therapy Pathological risk factors for addition of Primary tumor 4 chemotherapy include: clinically indicated, and ipsilateral thyroidectomy ● Consider chemoradiation T4 disease, any N ● Positive margins (re-excision to clear ● ● Consider primary TEP Supportive Care margins is preferred) 1 Primary tumors requiring total laryngectomy not amenable to partial surgery ● Extracapsular extension 2 Total laryngectomy to be considered for patients with significant pretreatment laryngopharyngeal dysfunction or are medically unable to tolerate organ preservation therapy Department of Clinical Effectiveness V8 Approved by the Executive Committee of the Medical Staff on 09/21/2021 Larynx Cancer Page 3 of 8 Disclaimer: This algorithm has been developed for MD Anderson using a multidisciplinary approach considering circumstances particular to MD Anderson’s specific patient population, services and structure, and clinical information. This is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. This algorithm should not be used to treat pregnant women. Note: Consider Clinical Trials as treatment options for eligible patients. EVALUATION PRIMARY TREATMENT ADJUVANT TREATMENT SURVEILLANCE

2 Surgery Yes Radiation or chemoradiation ● Endoscopic resection with Presence of Consider neck dissection(s) or pathological risk Yes ● Open partial laryngeal surgery features1 ? radiation therapy No Pathologic Primary tumor with neck dissection(s) N1? most T1-2, N0 No Observe Definitive radiation

● Radiation therapy 4,5 Yes 2 ● Total laryngectomy and neck ● Consider chemoradiation dissection(s) as indicated, and Presence of ● For recurrent or persistent pathological risk disease, see Page 5 ipsilateral thyroidectomy 1 Yes Radiation therapy features ? ● Surveillance (see Page 6) ● Consider primary TEP No Pathologic ● THNMO consult (optional) Supraglottic N1? No Observe node Primary tumor for chemoprevention trials ● T3, N0 negative 3 ● Selected T4 , N0 Residual Yes Neck dissection(s) Yes nodal ● Consider induction Complete disease? No Observe chemotherapy response at primary ● Concurrent chemoradiation site? Laryngectomy and neck dissection(s), No as clinically indicated

● Total laryngectomy and neck dissection(s), ● Radiation therapy Primary tumor 2 as indicated, and ipsilateral thyroidectomy ● Consider chemoradiation T4, N0 ● Consider primary TEP ● Supportive Care 1 Pathological risk features include: 2 Pathological risk factors for addition 4 Primary tumors requiring total laryngectomy not amenable to partial surgery ● Primary pathology 5 ○ Any T1 or T2 with perineural invasion or lymphovascular invasion of chemotherapy include: Total laryngectomy to be considered for patients with significant pretreatment ○ Any T3 or T4 ● Positive margins (re-excision to clear margins is preferred) laryngopharyngeal dysfunction or are medically unable to tolerate organ preservation therapy ● Extracapsular extension ● Regional pathology 3 ○ Multiple lymph nodes (any N2, N3) Low-volume base-of-tongue involvement Department of Clinical Effectiveness V8 Approved by the Executive Committee of the Medical Staff on 09/21/2021 Larynx Cancer Page 4 of 8 Disclaimer: This algorithm has been developed for MD Anderson using a multidisciplinary approach considering circumstances particular to MD Anderson’s specific patient population, services and structure, and clinical information. This is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. This algorithm should not be used to treat pregnant women. Note: Consider Clinical Trials as treatment options for eligible patients. EVALUATION TREATMENT SURVEILLANCE N1 Yes Observe Complete (initial stage) Primary tumor Yes response of nodal ● T1-2, N+ and Complete disease? Neck Concurrent No N2-3 ● Selected T3 1 response at primary chemoradiation dissection (not requiring total site? laryngectomy) No Salvage surgery as clinically indicated

● Radiation therapy 3 Yes 1 ● Total laryngectomy and neck ● Consider chemoradiation ● For recurrent or persistent Presence of dissection(s) as indicated, and disease, see Page 5 pathological risk ipsilateral thyroidectomy ● Surveillance (see Page 6) Supraglottic features4? node ● Consider primary TEP No Radiation therapy ● THNMO consult (optional) positive for chemoprevention trials Primary tumor 2 ● Most T3, N+ or 2 Yes Observe ● Selected T4 Complete ● Consider induction Yes response of nodal Complete chemotherapy disease? No Neck dissection response at primary ● Concurrent site? chemoradiation ● Salvage surgery as clinically indicated No ● Supportive care

● Total laryngectomy and neck 1 Primary tumor dissection(s) as indicated, and ● Radiation or chemoradiation T4, N+ ipsilateral thyroidectomy ● Supportive care ● Consider primary TEP

1 Pathological risk factors for addition of chemotherapy include: 4 Pathological risk features include: ● Positive margins (re-excision to clear margins is preferred) ● Extracapsular extension ● Primary pathology 2 Low-volume base-of-tongue involvement ○ Any T1 or T2 with perineural invasion or lymphovascular invasion ○ Any T3 or T4 3 Total laryngectomy to be considered for patients with significant pretreatment laryngopharyngeal ● Regional pathology ○ Multiple lymph nodes (any N2, N3) dysfunction or are medically unable to tolerate organ preservation therapy Department of Clinical Effectiveness V8 Approved by the Executive Committee of the Medical Staff on 09/21/2021 Larynx Cancer Page 5 of 8 Disclaimer: This algorithm has been developed for MD Anderson using a multidisciplinary approach considering circumstances particular to MD Anderson’s specific patient population, services and structure, and clinical information. This is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. This algorithm should not be used to treat pregnant women. Note: Consider Clinical Trials as treatment options for eligible patients. CLINICAL PRESENTATION RECURRENT TREATMENT

● Consider systemic therapy/phase I clinical trial ● Palliative care as clinically indicated

Yes Restage Consider salvage surgery, ● CT head and neck Recurrent Yes as clinically indicated with contrast1 disease or Presence of ● CT chest or PET-CT Is recurrence persistent distant metastatic to evaluate for resectable? disease disease? ● Consider systemic therapy distant metastatic No ● Clinical trial disease Yes ● Palliative care, as clinically No indicated Primary treatment Surveillance chemoradiation? (see Page 6) ● Consider salvage surgery as clinically indicated No Yes ● Consider postoperative chemotherapy and Is recurrence radiation therapy2 resectable?

No Consider chemotherapy and radiation therapy1

1 CT is tailored to oncologic imaging: high-resolution, bone and soft tissue window, 90-100s contrast delay for optimal opacification of mucosa and soft tissues 2 Pathological risk factors should be taken into consideration when making concurrent treatment decisions

Department of Clinical Effectiveness V8 Approved by the Executive Committee of the Medical Staff on 09/21/2021 Larynx Cancer Page 6 of 8 Disclaimer: This algorithm has been developed for MD Anderson using a multidisciplinary approach considering circumstances particular to MD Anderson’s specific patient population, services and structure, and clinical information. This is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. This algorithm should not be used to treat pregnant women.

Larynx Cancer Surveillance

Year Year Year Year Year Total years for surveillance 1 2 3 4 5

Frequency of surveillance 3 6 9 12 16 20 24 30 36 48 60 by month

Head and neck history and physical exam including flexible x x x x x x x x x x x laryngoscopy

Baseline CT1 x x x x x x x x x x x

Chest x-ray (CT chest, if smoker) x x x x x x x

Thyroid function x x x x x x x

1 For T1 glottic , initial post treatment CT may not be indicated

Department of Clinical Effectiveness V8 Approved by the Executive Committee of the Medical Staff on 09/21/2021 Larynx Cancer Page 7 of 8 Disclaimer: This algorithm has been developed for MD Anderson using a multidisciplinary approach considering circumstances particular to MD Anderson’s specific patient population, services and structure, and clinical information. This is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. This algorithm should not be used to treat pregnant women.

SUGGESTED READINGS

Bradford, C., Wolf, G., Carey, T., Zhu, S., Beals, T., Truelson, J., . . . Fisher, S. (1999). Predictive markers for response to chemotherapy, organ preservation, and survival in patients with advanced laryngeal carcinoma. Otolaryngology-Head and Neck Surgery, 121(5), 534-538. https://doi.org/10.1016/S0194-5998(99)70052-5 Forastiere, A., Goepfert, H., Maor, M., Pajak, T., Weber, R., Morrison, W., . . . Cooper, J. (2003). Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. The New England Journal of Medicine, 349(22), 2091-2098. https://doi.org/10.1056/NEJMoa031317 Fu, K., Pajak, T., Trotti, A., Jones, C., Spencer, S., Phillips, T., . . . Ang, K. (2000). A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell : First report of RTOG 9003. International Journal of Radiation Oncology, Biology, Physics, 48(1), 7-16. https://doi.org/10.1016/S0360-3016(00)00663-5 Fung, K., Lyden, T., Lee, J., Urba, S., Worden, F., Eisbruch, A., . . . Wolf, G. (2005). Voice and swallowing outcomes of an organ-preservation trial for advanced laryngeal cancer. International Journal of Radiation Oncology, Biology, Physics, 63(5), 1395-1399. https://doi.org/10.1016/j.ijrobp.2005.05.004 Hanna, E., Alexiou, M., Morgan, J., Badley, J., Maddox, A., Penagaricano, J., . . . Suen, J. (2004). Intensive chemoradiotherapy as a primary treatment for organ preservation in patients with advanced cancer of the head and neck: Efficacy, toxic effects, and limitations. Archives of Otolaryngology-Head & Neck Surgery, 130(7), 861-867. https://doi.org/10.1001/archotol.130.7.861 Hanna, E., Sherman, A., Cash, D., Adams, D., Vural, E., Fan, C., & Suen, J. (2004). Quality of life for patients following total laryngectomy vs chemoradiation for laryngeal preservation. Archives of Otolaryngology-Head & Neck Surgery, 130(7), 875-879. https://doi.org/10.1001/archotol.130.7.875 National Comprehensive Cancer Network. (2021). Head and Neck Cancers (NCCN Guideline Version 2.2021). Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf The Department of Veterans Affairs Laryngeal Cancer Study Group. (1991). Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The New England Journal of Medicine, 324(24), 1685-1690. https://doi.org/10.1056/NEJM199106133242402 Weber, R., Berkey, B., Forastiere, A., Cooper, J., Maor, M., Goepfert, H., . . . Ensley, J. (2003). Outcome of salvage total laryngectomy following organ preservation therapy: The Radiation Therapy Oncology Group trial 91-11. Archives of Otolaryngology-Head & Neck Surgery, 129(1), 44-49. https://doi.org/10.1001/archotol.129.1.44

Department of Clinical Effectiveness V8 Approved by the Executive Committee of the Medical Staff on 09/21/2021 Larynx Cancer Page 8 of 8 Disclaimer: This algorithm has been developed for MD Anderson using a multidisciplinary approach considering circumstances particular to MD Anderson’s specific patient population, services and structure, and clinical information. This is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. This algorithm should not be used to treat pregnant women.

DEVELOPMENT CREDITS

This practice algorithm is based on majority expert opinion of the Head and Neck Center Faculty at the University of Texas MD Anderson Cancer Center. It was developed using a multidisciplinary approach that included input from the following:

Ŧ Gregory Chronowski, MD (Radiation Oncology) Carol M. Lewis, MD (Head and Neck Surgery) Ed Diaz, Jr., MD (Head and Neck Surgery) Charles Lu, MD (Thoracic/Head and Neck Medical Oncology) Renata Ferrarotto, MD (Thoracic/Head and Neck Medical Oncology) Amy Moreno, MD (Radiation Oncology) Steven J. Frank, MD (Radiation Oncology) William H. Morrison, MD (Radiation Oncology) Clifton Fuller, MD, PhD (Radiation Oncology) Frank E. Mott, MD (Thoracic/Head and Neck Medical Oncology) Wendy Garcia, BS♦ Jeffrey N. Myers, MD, PhD (Head and Neck Surgery) Adam S. Garden, MD (Radiation Oncology) Marc-Elie Nader, MD (Head and Neck Surgery) Paul W. Gidley, MD (Head and Neck Surgery) Jack Phan, MD, PhD (Radiation Oncology) Ann M. Gillenwater, MD (Head and Neck Surgery) Kristen B. Pytynia, MD (Head and Neck Surgery) Maura Gillison, MD, PhD (Thoracic/Head and Neck Medical Oncology) David Rosenthal, MD (Radiation Oncology) Lawrence E. Ginsberg, MD (Neuroradiology) Komal Shah, MD (Neuroradiology) Bonnie S. Glisson, MD (Thoracic/Head and Neck Medical Oncology) Shalin J. Shah, MD (Radiation Oncology) Ryan P. Goepfert, MD (Head and Neck Surgery) Michael Spiotto, MD, PhD (Radiation Oncology) Neil Gross, MD (Head and Neck Surgery) Shirley Y. Su, MBBS (Head and Neck Surgery) Brandon Gunn, MD (Radiation Oncology) Molly K. Tate, MSN, APRN (Radiation Oncology) Ehab Y. Hanna, MD (Head and Neck Surgery) Rui Jennifer Wang, MD (Head and Neck Surgery) ♦ Amy C. Hessel, MD (Head and Neck Surgery) Mary Lou Warren, DNP, APRN, CNS-CC Ŧ Jason Michael Johnson, MD (Neuroradiology) Mark Zafereo, MD (Head and Neck Surgery) Stephen Y. Lai, MD, PhD (Head and Neck Surgery)

Ŧ Core Development Team ♦ Clinical Effectiveness Development Team

Department of Clinical Effectiveness V8 Approved by the Executive Committee of the Medical Staff on 09/21/2021