A. Tfayli - Head and neck - Guidelines and clinical case presentation (2-3 cases)


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  • As you know concomitant chemoradiation has become the standard of care
  • Conclusion Severe late toxicity after CCRT is common. Older age, advanced T-stage, and larynx/hypopharynx primary site were strong independent risk factors. Neck dissection after CCRT was associated with an increased risk of these complications. These data suggest that the CCRT has reached the limits of acceptable long-term toxicity. Dose intensity can not be easily increased without some new and effective technique(s) of protection against late effects. In the future, these may include modern techniques in radiation therapy technology27,28 or biopharmacologic radioprotectors.29-31 Presently, however, these techniques have only succeeded in reducing xerostomia, not severe late dysphagia
  • (LOOK UP) But there is one thing we should never forget: Don’t focus on the disease - Focus on the human being !
  • A. Tfayli - Head and neck - Guidelines and clinical case presentation (2-3 cases)

    1. 1. Squamous cell carcinoma of the head and neck (SCCHN) General Features and Treatment Guidelines Arafat Tfayli, MD Associate Professor of Clinical Medicine American University of Beirut Medical Center [email_address]
    2. 2. SCCHN <ul><li>Objectives: </li></ul><ul><ul><li>Basic anatomy of oral cavity, pharynx, and larynx </li></ul></ul><ul><ul><li>Impact of disease (incidence, mortality) </li></ul></ul><ul><ul><li>Risk factors </li></ul></ul><ul><ul><li>Principles of staging </li></ul></ul><ul><ul><li>Treatment guidelines </li></ul></ul>
    3. 3. Anatomic sites <ul><li>Lip and oral cavity </li></ul><ul><li>Pharynx </li></ul><ul><li>Larynx </li></ul><ul><li>Nasal cavity and paranasal sinuses </li></ul><ul><li>Major salivary glands </li></ul><ul><li>Thyroid </li></ul>
    4. 4. Oral cavity <ul><li>Extends to the junction of the hard and soft palate above and to the line of circumvallate papillae below </li></ul><ul><li>Subsites: </li></ul><ul><ul><li>Mucosal lip </li></ul></ul><ul><ul><li>Buccal mucosa </li></ul></ul><ul><ul><li>Upper and lower alveolar ridges </li></ul></ul><ul><ul><li>Retromolar trigone (mucosa overlying the ascending ramus of the mandible) </li></ul></ul><ul><ul><li>Floor of mouth </li></ul></ul><ul><ul><li>Hard palate </li></ul></ul><ul><ul><li>Oral tongue (anterior 2/3) </li></ul></ul>
    5. 6. Pharynx <ul><li>Subsites: </li></ul><ul><ul><li>Nasopharynx (from skull base to soft palate) </li></ul></ul><ul><ul><ul><li>Vault </li></ul></ul></ul><ul><ul><ul><li>Lateral wall (fossae of Rosenmuller and eustachian tube orifices) </li></ul></ul></ul><ul><ul><ul><li>Posterior wall </li></ul></ul></ul><ul><ul><li>Oropharynx (from soft palate to hyoid bone) </li></ul></ul><ul><ul><ul><li>Base of tongue </li></ul></ul></ul><ul><ul><ul><li>Uvula </li></ul></ul></ul><ul><ul><ul><li>Anterior and posterior tonsillar pillars </li></ul></ul></ul><ul><ul><ul><li>Phayngeal tonsils and their fossae </li></ul></ul></ul><ul><ul><ul><li>Lateral and posterior walls </li></ul></ul></ul><ul><ul><li>Hypopharynx (from hyoid bone to cricoid cartilage) </li></ul></ul><ul><ul><ul><li>Pyriform sinuses </li></ul></ul></ul><ul><ul><ul><li>Postcricoid region </li></ul></ul></ul><ul><ul><ul><li>Lateral and posterior walls </li></ul></ul></ul>
    6. 8. Larynx <ul><li>Subsites: </li></ul><ul><ul><li>Supraglottis </li></ul></ul><ul><ul><ul><li>Epiglottis </li></ul></ul></ul><ul><ul><ul><ul><li>suprahyoid </li></ul></ul></ul></ul><ul><ul><ul><ul><li>infrahyoid </li></ul></ul></ul></ul><ul><ul><ul><li>Aryepiglottic folds </li></ul></ul></ul><ul><ul><ul><li>Arytenoids </li></ul></ul></ul><ul><ul><ul><li>False vocal cords </li></ul></ul></ul><ul><ul><li>Glottis </li></ul></ul><ul><ul><ul><li>True vocal cords </li></ul></ul></ul><ul><ul><ul><li>Anterior and posterior commisures </li></ul></ul></ul><ul><ul><li>subglottis </li></ul></ul>
    7. 10. Nasal cavity and paranasal sinuses <ul><li>Subsites: </li></ul><ul><ul><li>Nasoethmoidal complex </li></ul></ul><ul><ul><ul><li>Nasal cavity </li></ul></ul></ul><ul><ul><ul><li>Ethmoidal sinuses </li></ul></ul></ul><ul><ul><li>Maxillary sinus (divided by Ohngren’s line) </li></ul></ul><ul><ul><ul><li>Infrastructure (anteroinferior) </li></ul></ul></ul><ul><ul><ul><li>Suprastructure (superoposterior) </li></ul></ul></ul><ul><ul><li>Sphenoid and frontal sinuses </li></ul></ul>
    8. 11. Major salivary glands <ul><li>Parotid </li></ul><ul><li>Submaxillary </li></ul><ul><li>Sublingual </li></ul>
    9. 12. Lymph zones of the neck Level I: submental, submandibular Level II: upper jugular Level III: mid jugular Level IV: lower jugular Level V: posterior triangle (including spinal accessory or posterior cervical chain) Level VI: prelaryngeal (Delphian), pretracheal, paratracheal Other groups: sub-occipital retropharyngeal parapharyngeal buccinator (facial) preauricular periparotid intraparotid
    10. 13. Regional lymph node involvement <ul><li>Lymphatic spread from some subsites follow a rather predictable course </li></ul><ul><li>Cervical node involvement has major prognostic significance </li></ul><ul><li>Survival is significantly worse when metastases extend beyond the first echelon of lymphatic drainage </li></ul><ul><li>Lower neck nodal involvement carries worse prognosis as compared to upper neck involvement, hence “L” and “U” designations (does not change stage, but has prognostic significance) </li></ul><ul><li>Extranodal extension implies worse prognosis (MRI, pathology) </li></ul><ul><li>Masses of 3 cm or larger are usually confluent nodes or tumor in the soft tissue </li></ul><ul><li>N staging is uniform for all mucosal subsites, except for nasopharynx (and well differentiated thyroid) cancers. </li></ul>
    11. 14. Incidence and Mortality <ul><li>In 2002, there were 139,000 cases of H&N cancers in Europe </li></ul><ul><li>More than 90% are squamous cell cancers </li></ul><ul><li>Five year survival of 42% </li></ul><ul><li>Survival is higher in females (51 vs. 39%) and in younger patients (54 vs. 34%) </li></ul>
    12. 15. Achievements <ul><li>Organ preservation without adversely affecting survival in advanced resectable disease </li></ul><ul><li>Improved local and regional control with adjuvant chemoradiation in advanced resectable disease with modest improvement in survival </li></ul><ul><li>Improved surgical and radiation therapy techniques (laser ablation of early lesions, IMRT) </li></ul><ul><li>Evolving role of targeted therapies. </li></ul><ul><li>The major weakness is in control and treatment of distant recurrence </li></ul>
    13. 16. Risk factors <ul><li>Tobacco and alcohol are the most important risk factors (except for nasopharyngeal cancer) </li></ul><ul><ul><li>Alcohol potentiates tobacco carcinogenesis, in addition to being an independent risk factor </li></ul></ul><ul><ul><li>Somkeless tobacco is strongly associated with oral cancer </li></ul></ul><ul><ul><li>Prevalence and spectrum of p53 mutations are significantly greater among users of tobacco and alcohol </li></ul></ul><ul><li>Viruses </li></ul><ul><ul><li>EBV </li></ul></ul><ul><ul><li>HPV </li></ul></ul><ul><li>Genetic predisposition: sporadic occurrence in young adults, nonusers of alcohol and tobacco </li></ul><ul><li>Other less important and controversial risk factors include occupational exposures, dietary factors </li></ul><ul><li>Race: chinese ancestry (nasopharyngeal cancer) </li></ul>
    14. 17. Viruses <ul><li>HPV </li></ul><ul><ul><li>>50% of oropharyngeal tumors, especially those arising in BOT or palatine tonsil, harbor oncogenic HPV DNA </li></ul></ul><ul><ul><li>Less significant p53 mutations </li></ul></ul><ul><ul><li>Better prognosis </li></ul></ul><ul><li>EBV </li></ul><ul><ul><li>Strongly associated with nasopharyngeal cancer (rare in the US, but the commonest form in China) </li></ul></ul><ul><ul><li>EBV DNA can be found in nasopharyngeal cancers of all histologic types </li></ul></ul><ul><ul><li>Elevated IgA and IgG titers are found in almost all patients </li></ul></ul><ul><ul><li>Detection of EBV genomic material by PCR in tumor obtained from cervical lymph nodes in the case of occult primary strongly suggests nasopharyngeal primary </li></ul></ul>
    15. 18. Figure 2. Human Papillomavirus (HPV) in Oropharyngeal Cancers. Recent studies confirm that oropharyngeal tumors are often HPV-positive and compose a distinct clinical and pathologic disease entity. In Panel A, a typical large tonsillar lesion (arrows) is shown. Panel B shows the typical basaloid appearance often seen in HPV-positive tumors. In Panel C, the same tissue section was subjected to in situ hybridization with an HPV-E7-specific probe. The dark brown spots indicate the presence of HPV DNA in virtually all the neoplastic cells. (Courtesy of Wayne M. Koch and William H. Westra.).
    16. 20. TNM Staging <ul><li>Primary tumor (T) </li></ul><ul><li>oral cavity, oropharynx, major salivary glands </li></ul><ul><li>TX: cannot be assessed </li></ul><ul><li>T0: no evidence of primary </li></ul><ul><li>Tis: CIS </li></ul><ul><li>T1: ≤2 cm </li></ul><ul><li>T2: ≤4 cm </li></ul><ul><li>T3: >4 cm </li></ul><ul><li>T4: invasion of adjacent structures </li></ul><ul><ul><li>T4a: resectable </li></ul></ul><ul><ul><li>T4b: unresectable </li></ul></ul>Salivary gland tumors with extraparenchymal extension are at least T3 regardless of size T staging is different for nasopharynx, hypopharynx, larynx subsites, and maxillary sinus, and is dependent on local extension as well as size for early lesions
    17. 21. TNM Staging <ul><li>Regional lymph node (N) </li></ul><ul><li>NX: cannot be assessed </li></ul><ul><li>N0: no regional lymph node metastasis </li></ul><ul><li>N1: single ipsilateral lymph node, ≤3 cm </li></ul><ul><li>N2: </li></ul><ul><ul><li>N2a: a single ipsilateral lymph node >3 cm but ≤6 cm </li></ul></ul><ul><ul><li>N2b: multiple ipsilateral lymph nodes, all ≤6 cm </li></ul></ul><ul><ul><li>N2c: bilateral or contralateral lymph nodes, all ≤6 cm </li></ul></ul><ul><li>N3: a lymph node >6 cm </li></ul><ul><ul><ul><li>N staging is different for nasopharyngeal cancer </li></ul></ul></ul>
    18. 22. TNM Staging <ul><li>Distant metastases (M) </li></ul><ul><li>MX: cannot be assessed </li></ul><ul><li>M0: no distant metastasis </li></ul><ul><li>M1: distant metastasis </li></ul>
    19. 23. TNM Staging <ul><li>Early stage disease: </li></ul><ul><ul><li>Stage I T1N0 </li></ul></ul><ul><ul><li>Stage II T2N0 </li></ul></ul><ul><ul><ul><li>For nasopharynx: Stage IIA T2aN0 </li></ul></ul></ul><ul><li>About 40% of patients present with early stage disease </li></ul><ul><li>Treatment generally consists of surgery alone or radiation alone, with generally similar outcomes </li></ul>
    20. 24. TNM Staging <ul><li>Advanced stage disease </li></ul><ul><ul><li>Stage III: any T3, any N1 </li></ul></ul><ul><ul><li>Stage IV: any T4, any N>1, M1 </li></ul></ul><ul><ul><ul><li>For nasopharynx: Stage IIB </li></ul></ul></ul><ul><li>Locally advanced disease refers to T3/T4 </li></ul><ul><li>Regionally advanced disease refers to node positivity </li></ul><ul><li>About 60% of patients present with advanced disease </li></ul><ul><li>Treatment of advanced disease is multidisciplinary (surgery, radiation, chemotherapy) </li></ul><ul><li>Only 45% will be alive after 2 years </li></ul><ul><li>60-70% will develop locoregional recurrence, 20-30% will develop distant recurrence </li></ul><ul><li>Stage IV (except for nasopharynx): </li></ul><ul><ul><li>IVa advanced resectable </li></ul></ul><ul><ul><li>IVb: T4b or N3 advanced unresectable </li></ul></ul><ul><ul><li>IVc: M1 metastaatic </li></ul></ul>
    21. 25. Management of SCCHN <ul><li>Stage I-II: SMT </li></ul><ul><li>Locoregionally advanced stage III-IV: MMT </li></ul><ul><li>Functional organ preservation: </li></ul><ul><li>- cosmetic </li></ul><ul><li>- social </li></ul><ul><li>- communicative </li></ul><ul><li>- nutritional functions. </li></ul><ul><li>the integration of concurrent chemoradiotherapy (CRT) </li></ul>
    22. 26. Multimodality Treatments in LA-SCCHN <ul><li>Historically: Surgery (+/- RT ) or RT alone </li></ul><ul><li>poor outcome for OS and OP </li></ul><ul><li>Currently: </li></ul><ul><li>1- Surgery  adjuvant concurrent CRT </li></ul><ul><li>2- Definitive concurrent CRT +/- Salvage surgery </li></ul><ul><li>3- Induction CT  definitive local therapy </li></ul>Seiwert et al 2007
    23. 27. CRT: Answered questions <ul><li>Concurrent CRT is superior to radiotherapy alone in both the definitive and adjuvant setting </li></ul><ul><li>Concurrent CRT results in superior laryngeal preservation compared with sequential CRT or RT alone </li></ul><ul><li>Concurrent CRT is associated with increased toxicity compared with RT alone </li></ul><ul><li>Cetuximab added to RT increases overall survival in the definitive treatment of locoregionally advanced HNC </li></ul>Salama et al. JCO VOL 25 NUM 26 SEP 2007
    24. 28. CRT- Unanswered Questions <ul><li>Single agent Vs multi-agent chemotherapy </li></ul><ul><li>The role of induction chemo </li></ul><ul><li>Integration of altered fractionation and intensity-modulated RT (IMRT) </li></ul>Salama et al. JCO VOL 25 NUM 26 SEP 2007
    25. 29. Concurrent CRT Is Superior to Radiotherapy Alone in Both the Definitive and Adjuvant Setting Salama et al. JCO VOL 25 NUM 26 SEP 2007
    26. 30. Meta-analysis of HNC (MACH-NC) Bourhis J: J Clin Oncol 24:489s, 2004 (suppl; abstr 5505)
    27. 31. Salama et al. JCO Vol 25 Num 26 Sep. 10 2007
    28. 32. Postoperative irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer Bernier et al: 350:1945-1952, 2004
    29. 33. Postoperative irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer NEJM 350:, 2004
    30. 34. Epidermal growth factor receptor
    31. 35. Study design Stage III and IV nonmetastatic SCCHN (n=424) RT (n=213) Erbitux + RT (n=211) Erbitux initial dose (400 mg/m 2 ) Erbitux (250 mg/m 2 ) + RT (wks 2–8) Bonner J et al. N Engl J Med 2006;354:567 –578 a Investigators’ choice R Primary endpoint: Duration of locoregional control Secondary endpoints: OS, PFS, RR, QoL, and safety <ul><li>Stratified by: </li></ul><ul><li>KPS </li></ul><ul><li>Nodal involvement </li></ul><ul><li>Tumor stage </li></ul><ul><li>RT regimen a </li></ul>
    32. 36. Erbitux + RT: Locoregional control Hazard ratio=0.68 (95% CI: 0.52–0.89); p=0.005 Time (months) Erbitux + RT (n=211) Locoregional control (%) 100 80 60 40 20 0 0 10 20 30 40 50 60 70 RT (n=213) 14.9 months 24.4 months 47% (3-year control rate) 34% (3-year control rate) Bonner J et al. N Engl J Med 2006;354:567 –578
    33. 37. Erbitux + RT: Overall survival 5-year update Bonner J et al. Int J Radiat Oncol Biol Phys 2008; 72 (Suppl):Abs LB3 Hazard ratio=0.73 (95% CI: 0.56–0.95); p=0.018 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 10 20 30 40 50 60 70 Time (months) Probability of overall survival 29.3 months 49.0 months Erbitux + RT (n=211) RT (n=213) 36% (5-year survival rate) 46% (5-year survival rate)
    34. 38. Erbitux + RT: Relevant grade 3–5 adverse events Bonner J et al. N Engl J Med 2006;354:567 –578 p<0.001 a p=0.01 a Patients (%) a Fisher’s exact test b Listed for its relationship to Erbitux <ul><li>Median duration of any mucositis or dysphagia in the overall population was 12 – 13 weeks and similar in both treatment groups </li></ul>b 0 10 20 30 40 50 60 Mucositis/stomatitis Dysphagia Radiation dermatitis Xerostomia Fatigue/malaise Acne-like rash Infusion reactions RT (n=212) Erbitux + RT (n=208)
    35. 39. Concurrent CRT Results in Superior Laryngeal Preservation Compared With Sequential CRT or RT Alone
    36. 43. The VA Trial : Conclusion Induction chemotherapy and definitive radiation therapy are effective in preserving the larynx in a high percentage of patients, without compromising overall survival .
    37. 47. Concurrent CRT Is Associated With Increased Toxicity compared With RT Alone
    38. 50. Late toxicity associated with Concurrent CRT Machtay et al, JCO VOL 26 NUM 21 JULY 20 2008
    39. 51. CRT: What Is the Optimal Chemotherapy Regimen? <ul><li>Alternative Cisplatin schedule ( daily, weekly ) </li></ul><ul><li>Multiagent platinum regimens are superior to RT alone </li></ul><ul><li>Whether to use multiagent regimens or single-agent platinum is debatable </li></ul><ul><li>MACH-NC:Concomitant CRT with </li></ul><ul><li>- platinum alone (26%) </li></ul><ul><li>- platinum polychemotherapy (23%) </li></ul><ul><li>- polychemotherapy without platinum (20%) </li></ul><ul><li>- non-platinum/non-5FU (11%) </li></ul>Bourhis J: J Clin Oncol 24:489s, 2004 (suppl; abstr 5505)
    40. 52. What Is the Role of Neoadjuvant Chemotherapy for Patients Treated With Concurrent CRT? <ul><li>Produces high response rates </li></ul><ul><li>Palliate local symptoms </li></ul><ul><li>Predicts sensitivity to Radiotherapy </li></ul><ul><li>Reduces rates of distant metastasis as first site of relapse </li></ul><ul><li>Does not improve locoregional control </li></ul><ul><li>Allows organ preservation </li></ul>
    41. 53. Neoadjuvant Chemotherapy for Patients Treated With Concurrent CRT <ul><li>Some (but not all) induction chemotherapy randomized trials have demonstrated an OS benefit </li></ul><ul><li>Many studies have demonstrated decreased distant metastases </li></ul><ul><li>MACH-NC: patients receiving neoadjuvant cisplatin/FU had a significant absolute 5% OS benefit </li></ul><ul><li>Randomized trials have demonstrated that the addition of taxanes to cisplatin/FU is associated with higher CR rates, decreased toxicity, and improved PFS and OS </li></ul>
    42. 60. Trials are ongoing to determine the role of induction chemotherapy in the setting of highly active CRT
    43. 61. Thank you
    44. 62. Case 1 <ul><li>S.H. is a 69 year old male with PMHx of HTN who presented to our center in March 2011 with a chief complaint of feeling a lump on the right side of his tongue for 1 year. </li></ul><ul><li>Patient is a lifelong non smoker, he drank alcohol lightly in the 1970s. </li></ul>
    45. 63. Case 1 <ul><li>Examination revealed the presence of a mass on the right side of the tongue occupying most of the posterior 2/3 of the tongue, crossing the midline. In addition, there was a 2x2 cm right sided level II cervical lymph node. </li></ul><ul><li>Biopsy of tongue lesion confirmed the presence of moderately differentiated Squamous cell cancer. </li></ul><ul><li>CT scan: </li></ul>
    46. 66. Case 1 <ul><li>Any additional testing you recommend? </li></ul><ul><li>What is the best treatment modality? </li></ul>
    47. 67. Case 1 <ul><li>Patient received concurrent XRT and cisplatinum, completed in June 2011. </li></ul><ul><li>Follow up visit at the end of July 2011, revealed almost complete resolution of the tongue lesion but persistence of the neck lymph node by CT scan. </li></ul><ul><li>How would you further investigate this lymph node ? </li></ul>
    48. 68. Case 1 <ul><li>PET/CT confirmed uptake in the cervical lymph node with an SUV of 4.1. </li></ul><ul><li>How would you manage the patient at this point? </li></ul>
    49. 69. Case 1 <ul><li>Patient neck dissection in August 2011 and pathology confirmed the presence of squamous cell cancer in one lymph node. </li></ul>
    50. 70. Case 2 <ul><li>66 year old male with PMHx of HTN and hypercholesterolemia. He presented in April 2011 with a lump in the right side of the tongue for few months. </li></ul><ul><li>Patient smoked 2 ppd for 35 years, occasional alcohol intake. </li></ul>
    51. 71. Case 2 <ul><li>Examination revealed the presence of a 3x2 cm mass on the right anterolateral aspect of the tongue with an overlying ulcer. No palpable cervical adenopathy. </li></ul><ul><li>Biopsy confirmed the presence of moderately differentiated squamous cell cancer </li></ul><ul><li>What additional testing would you do on this patient? </li></ul>
    52. 72. Case 2 <ul><li>CT scan of neck and chest revealed the presence of a 2 cm ipsilateral level II lymph node. </li></ul><ul><li>What would be your preferred way of management? </li></ul>
    53. 73. Case 2 <ul><li>Patient underwent surgical excision with neck dissection. Final pathology revealed a 3 cm SCC with negative surgical margins and 2 involved lymph nodes where involved with evidence of extracapsular extension. </li></ul><ul><li>Does the patient need any further therapy? </li></ul>
    54. 74. Case 2 <ul><li>Patient received IMRT concurrently with cisplatin. Course complicated by grade III mucositis. </li></ul>