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Head and Neck Grand Rounds Greater Baltimore Medical Center David Zaboli December 3, 2010

Primary Chemoradiation Therapy for Loco-Regionally Advanced HNSCC: Analysis of 105 consecutive patients treated at the Greater Baltimore Medical Center. Head and Neck Grand Rounds Greater Baltimore Medical Center David Zaboli December 3, 2010. Disclosures. None. Overview. Epidemiology

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Head and Neck Grand Rounds Greater Baltimore Medical Center David Zaboli December 3, 2010

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  1. Primary Chemoradiation Therapy for Loco-Regionally Advanced HNSCC: Analysis of 105 consecutive patients treated at the Greater Baltimore Medical Center Head and Neck Grand Rounds Greater Baltimore Medical Center David Zaboli December 3, 2010

  2. Disclosures None

  3. Overview Epidemiology Risk Factors Review of evidence for chemoradiation therapy for primary treatment of HNSCC Results of 105 patients treated with Brizel Regimen at GBMC Future Projects

  4. Epidemiology 620,000 cases of Head and Neck Cancer worldwide in 2009 6th most common cancer 6% of all malignancies worldwide 1,529,560 cases of cancer in the USA 48,000 cases of HNC in USA in 2009 11,300 deaths from HNC

  5. Incidence of HNC varies greatly by region Highest incidence/death rates Rural Georgia 12.5/2.9 Lowest incidence Utah 8.06/1.7 Top 5 states overall deaths DC, MS, LA, SC, TN Bottom 5 states MT, NE, CT, NM, UT

  6. 5-year Survival Source: SEER Cancer Statistics Review 1975-2006 Oral Cavity and Oropharynx • 1975-1977 53.1 • 1978-1980 54.0 • 1981-1983 52.6 • 1984-1986 54.6 • 1987-1989 54.2 • 1990-1992 56.2 • 1993-1995 58.4 • 1996-1998 58.8 • 1999-2005 62.5 Larynx • 1975-1977 66.6 • 1978-1980 66.0 • 1981-1983 68.8 • 1984-1986 65.7 • 1987-1989 66.4 • 1990-1992 66.6 • 1993-1995 63.9 • 1996-1998 65.1 • 1999-2005 63.2

  7. Racial Discrepancy in Survival Source: SEER Cancer Statistics Review 1975-2006

  8. Epidemiology Risk Factors Review of evidence for chemoradiation therapy for primary treatment of HNSCC Results of 105 patients treated with Brizel Regimen at GBMC Future Projects

  9. Risk Factors Tobacco Alcohol Viral Infection (HPV, EBV) Occupational exposures Betel nut chewing Nutritional deficiency Immunodeficiency Previous radiation Poor oral hygiene Mechanical irritation Mouthwash that contains alcohol??? Previous HNC Genetics

  10. Epidemiology Risk Factors Review of evidence for chemoradiotherapy for primary treatment of advanced HNSCC Results of 105 consecutive patients treated at GBMC with the “Brizel” Regimen Future Projects

  11. RATIONALE Combination Chemotherapy and Radiotherapy (CRT) as primary treatment for HNSCC • Improved efficacy • Less morbidity • Organ preservation AND often function • Only option for patients with unresectable disease

  12. Toxicity Associated with CRT Acute -Mucositis -Pain -Swallow -Chemotherapy specific Long-Term -Swallowing dysfunction -Speech -Soft-tissue complications -Vascular complications -Xerostomia, change in sputum -Cosmetic deformities -Change/Loss taste -Hypothyroid -Esophageal fibrosis -Psychological

  13. Cisplatin Mechanism -DNA intercalation> DNA damage> apoptosis -alkylating agent Side Effects -peripheral neuropathy -ototoxicity -nephrotoxicity -electrolytes -myelosuppression

  14. 5-Fluorouracil Mechanism -noncompetitive inhibition of thymidylate synthase -antimetabolite Side Effects -mucositis -myelosuppression -dermatitis -diarrhea -cardiac toxicity Thymine 5-FU

  15. Mechanism • Radioresistance of cancer cells a major problem • Chemotherapy combined with RT to enhance radiosensitivity by • Decreasing tumor vol • Inhibit DNA repair • Inhibit tumor repopulation • Selective kill hypoxic cells “Also provides some adjuvant treatment for potential distant metastatic disease”Brizel J. Clin Oncology 2006

  16. Insert picture of article

  17. MACH-NC Findings CRT improved survival versus surgery alone, surgery + RT Addition of chemotherapy produced absolute survival benefit of 4.5% at 5 years If concomitant CRT, absolute survival 6.5% at 5 years In mono-chemotherapy, platin better than non-platins Concomitant more effective for LRC Induction more effective for distant metastasis Benefit of CRT decreases with age

  18. Epidemiology Risk Factors Case Presentation Review of evidence for chemoradiotherapy for primary treatment of advanced HNSCC Results of 105 consecutive patients treated at GBMC with the “Brizel” Regimen Future Projects

  19. Study Objectives Primary Endpoints Overall Survival (OS) Date of Death- Date Completion of CRT Loco-Regional Control (LRC) Date of Local OR Regional Recurrence – Date Completion of CRT Disease-Free Survival (DFS) Date of Local OR Regional OR Distant Recurrence – Date Completion of CRT

  20. Study Objectives Primary Endpoints Overall Survival (OS) Date of Death- Date Completion of CRT Loco-Regional Control (LRC) Date of Local OR Regional Recurrence – Date Completion of CRT Disease-Free Survival (DFS) Date of Local OR Regional OR Distant Recurrence – Date Completion of CRT Secondary Endpoints • Short-term Toxicity Mucositis, nephrotoxicity, Neutropenia, • Long-term Toxicity Peg Usage, ORN, Peripheral Neuropathy, Ototoxicity • Unplanned Hospitalizations • Causes of death Cancer of Head and Neck Second Primary Co-Morbidity Treatment-Related Unknown • Second Primary Malignancies

  21. Methods • Retrospective Review • Locally Advanced Head and Neck Squamous Cell Carcinoma (Stage III-IVb) • All patients treated at GBMC between 2000-2007 • N=105 • Medical records reviewed in Milton Dance Center, Radiation Oncology, and Medical Oncology • Exclusion from review • Cancer of sinus, salivary glands • Unknown primary • Recurrent cancer • Previous therapeutic radiation to Head or Neck • Previous systemic chemotherapy

  22. Treatment Regimen Chemotherapy • Cisplatin (12 mg/m2/h) • 5-Fluorouracil (600 mg/m2/20h) • Given as inpatient for five days concomitant with first and last weeks of radiation • CBC, BMP pre-treatment, post week 1, post week 5, post 4 weeks Radiation Therapy • Hyperfractionated 1.25 Gy BID x 28-30 days • Primary total dose 70-75 Gy • Involved Cervical LN 60 Gy • Uninvolved Cervical and Supraclavicular LN 50 Gy • Interruptions minimized • Treatment break one week after 40Gy Prophylactic PEG

  23. Regimen- Continued 6-12 weeks later… • Visit with provider and exam of primary tumor site and neck • PET/CT Neck Dissection • Offered to all patients with Nodal disease of N2 or greater • All but one eligible patient received • Type of neck dissection made on individual basis Follow-Up Years 1-2 • Every 2 months Years 3-5 • Every 3-6 months Years 5+ • Every 6-12 months

  24. Assessment of Treatment Response Clinical Response: Physical Exam and Imaging Complete Primary Total disappearance Neck PE < 1 cm or PET FDG consistent with inflammatory change Partial Primary Partial shrinkage 30-50% longest dimension Neck Palpable LAN or FDG activity suggestive of viable metastatic LN Pathologic ResponseBiopsy of Primary Tumor or Pathology of LN Complete Incomplete Primary Biopsy reveals viable cancer Neck LN reveal viable cancer

  25. Patient CharacteristicsN=105 Mean age (y) 58.7 Range 43-79 <55 40 ≥55 65 Sex -Female 21 -Male 84 Race -Caucasian 90 -African American 15 Site * -Oropharynx 78 -Hypopharynx 15 -Larynx 13 AJCC Stage -III 30 -IV 75 Tumor (T) -T1 6 -T2 36 -T3 45 -T4 18 Nodal (N) -N0 14 -N1 24 -N2 56 -N3 11

  26. Patient Characteristics continued Smoking • No 23 • Yes 82 • <20 PY 21 • 20-40 PY 21 • 40-60 PY 18 • >60 PY 18 • Unknown 4 Alcohol • No 8 • Unknown 7 • Yes 90 • Social 21 • Moderate 21 • Heavy 18 HPV Status (Oropharynx only) • Positive 25 • Negative 20 • Unknown 32 Pre-treatment Hemoglobin • <12 26 • >12 71 • Unavailable 8 KPS • <70 9 • 80 29 • 90 31 • 100 27 • Unknown 9 Self-reported Weight Loss (lbs) • None/less than 10 28 • >10 67 • Unknown 10

  27. Response • Complete clinical response 88% • Partial clinical response 12%

  28. Overall Survival Median F/U surviving patients = 56 months (3-119) 3-year OS 75% • Stage III 77% • Stage IV 72% 5-year OS 60% • Stage III 63% • Stage IV 58%

  29. Causes of death (N=38)

  30. Factors associated with Overall Survival Univariate Analysis Decreased survival • Age • Hypopharynx • T3/T4 • Ever Smoker • > 40 PY Increased survival • Male

  31. Factors associated with Survival Uni and Multivariate Analysis

  32. Loco-regional Control Local or regional recurrence occurred in N=13 patients * 3-year LRC 76% 5-year LRC 68% Of those that had LRC, Mean time to event was 59 weeks Mean survival after LRC was 2.5 years

  33. Factors associated with LRC Univariate Analysis

  34. Disease-Free Survival Local or regional or distant recurrence occurred in N=25 patients, and 16 of these presented with distant recurrence 3-year DFS 64% 5-year DFS 56% Of those that had any recurrence, mean time to event was 49 weeks Mean survival after LRC was 1.3 years

  35. Factors associated with Disease-Free Survival Univariate Analysis Decreased survival • Hypopharynx • T3/T4 • Ever Smoker • Mod-Heavy smoker Increased survival • No significant

  36. Decreased survival Hypopharynx HR 4.06 (1.89-8.72) p=0.0003 T3/T4 HR 2.66 (1.3-5.45) p=0.01 Factors associated with Disease-Free Survival Uni and Multivariate Analysis

  37. Neck Dissection 65 patients underwent either uni or bilateral ND Residual carcinoma identified in 18/65 (28%) patients Pathology status unknown for 2 patients

  38. Neck Dissection- Continued Of the N=13 patients with Loco-regional recurrence, 8 underwent neck dissection 5/8 (63%) had positive LN (versus 28% overall)

  39. Second Primary Malignancies Source: UpToDate: Second primary malignancies in patients with head and neck cancers Patients with HNC at high risk for SPM Estimated to occur at rate of 3%/yr Metachronous > 6 months Synchronous < 6 months Simultaneous Warren-Gates criteria • Both the index and secondary tumors are malignant • At least 2 cm of normal mucosa between the two tumors • However, if the tumors are in same location, should be separated in time by ≥5 years • Not a metastatic tumor

  40. Second Primary Malignancies Total SPM 18 Head and Neck 1 Non-Head and Neck 17 Lung 8 Prostate 2 Colon 2 Renal 1 Pancreatic 1 Thyroid 1 CLL 1 Leukemia 1 Average time to diagnosis of SPM was 31 months (median 29, range 12-62) The median time to occurrence of SPM was 2.4 years (similar to other publications of 2.8 years, Argiris 2004) In a meta-analysis, of the SPM, frequency of most common sites HNC (35%), lung (25%), esophagus (9%)

  41. Toxicity Grade 3 or 4 mucositis: Data available for 66/105 (63%) patients. The rates of grades 3 and grade 4 mucositis were 24 (36%) and 39 (59%) Osteoradionecrosis: N=5 PEG Dependence: Data available for 96/105 patients. The mean duration of PEG use = 255 days (range 31-1570 days), which included patients who died with a PEG in place. 46/96 (48%) patients required PEG use greater than 6 months. 15/96 (16%) of patients required PEG greater than 12 months.

  42. Hypopharynx poorer outcomes

  43. Comparison to Other Cohorts

  44. Study Critiques Weaknesses • Retrospective Review • Heterogenous cohort, mainly oropharynx • HPV unavailable for half of oropharynx, mainly the earlier patients before HPV widely tested • Toxicity not always available, may be underreported Strengths • Large patient cohort • Uniform treatment protocol • Excellent follow-up • Enough time for interval events to occur • Availability of excellent records via electronic and paper charts • Exhaustive review of records from three departments

  45. Conclusions • The CRT regimen described demonstrated excellent outcomes with high rates of great organ preservation • However, loco-regional and distant recurrences continue to cause significant mortality and highlight the need for more effective therapies to prevent and manage these events.

  46. Future Projects Compare Brizel and Gainseville cohorts (efficacy and toxicity and hospitalizations) Compare impact of salivary gland transfer (on xerostomia and dehydration, infection, need for hospitalization) Cetuximab and other biological agents Identify high-risk patients and determine if more intensive treatment plan is reasonable Use of epigenetic salivary markers for diagnosis or prediction of recurrence

  47. Areas of Clinical Interest Management of Neck Decision-making in patients with Complete versus Partial response to CRT Decision-making in patients with positive versus negative neck pathology Tailor treatment in high-risk patients??

  48. Acknowledgements Dr. Patrick K. Ha Dr. Marshall Levine Dr. Mei Tang Dr. Eva Zinreich HrishikeshGogineni Spencer Lake Katherine Fan Dr. Joseph A. Califano Dr. John R. Saunders Dr. Ray G. Blanco Dr. Sara Pai Dr. Simon R. Best Marianna L. Zahurak Barbara Messing Karen Ulmer All staff at Milton Dance Center, Radiation Oncology, Medical Oncology

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