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Cetuximab Plus Radiotherapy For Head And Neck Cancer
 

Cetuximab Plus Radiotherapy For Head And Neck Cancer

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    Cetuximab Plus Radiotherapy For Head And Neck Cancer Cetuximab Plus Radiotherapy For Head And Neck Cancer Presentation Transcript

    • Cetuximab plus Radiotherapy for Head and Neck Cancer Rena Callahan Journal Club UCLA Internal Medicine Faculty Discussant: Steven Wong
    • Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck Bonner JA; Harari PM; Giralt J; Azarnia N; Shin DM; Cohen RB; Jones CU; Sur R; Raben D; Jassem J; Ove R; Kies MS; Baselga J; Youssoufian H; Amellal N; Rowinsky EK; Ang KK N Engl J Med. 2006 Feb 9 Volume 354(6):567-78.
    • Objectives
      • Head and Neck Cancer
      • The role of EGFR
      • Cetuximab overview
      • Trial overview
      • Trial Discussion
      • Future prospects
    • Head and Neck Cancer (HNC)
      • 40,000 cases annually in U.S.
      • >60% locoregionally advanced
      • Males>Females
      • African American>Whites
      • Increased Risk: Tobacco and ETOH
    • Head and Neck Anatomy
    • EGFR
      • Cell surface growth regulator expressed by two-thirds of all human cancer cells
      • Upregulated in 98% of HNC
      • EGFR expression has prognostic significance
        • (Ang 2002)
    • EGFR                                                                                            
    • Cetuximab
      • Recombinant human/mouse chimeric Monoclonal antibody vs EGFR
        • Binds EGFR, HER1, c-ErbB-1 on both normal and tumor cells
      • Blocks EGF and other ligand binding
      • Binding to the EGFR blocks phosphorylation and activation of receptor-associated kinases
      • Inhibits cell growth, induction of apoptosis, and decreases matrix metalloproteinase and vascular endothelial growth factor production.
    • Cetuximab Adverse Events
        • Infusion reactions
        • acneform skin rash
        • nail disorder
    • Cetuximab Rash
    • The Approval of Cetuximab
    • Treatment – Locally Advanced HNC
      • Organ preservation
      • Radiation vs.
        • 5-yr survival 10-30%
      • Chemo and Radiation vs.
      • Chemoradiation
        • Increased Survival (Brizel 1998, Wendt 1998, Calais 1999, Budach 2006)
        • Increased Toxicity
          • Severe mucositis 71% vs 39% (Calais 1999)
    • Radiation
      • Short doubling times in HNC
      • Accelerated fractionation
        • Same dose over shorter time
        • Goal=prevent tumor repopulation
      • Hyperfractionation
        • Multiple, smaller doses, daily
        • Increased total dose
        • Goal=reduced toxicity
    • Radiation toxicity
      • Acute
        • mucositis, odynophagia, dysphagia, hoarseness, xerostomia, dermatitis, and weight loss
      • Late
        • Xerostomia, osteoradionecrosis, fibrosis, stricture, thyroid dysfunction, carotid stenosis/rupture
    • Chemoradiation
      • Rationale
        • Radiosensitizers
        • Targeting micrometastases
        • Overcoming radioresistance
        • 5-FU, cisplatin, carboplatin , taxane, MTX, mitomycin
        • cetuximab
    • Chemoradiation-Toxicity
      • Cisplatin
        • Nausea/vomiting
        • Nephrotoxicity
        • Neuropathy
        • Pulmonary fibrosis
        • Myelosuppression
    • Staging
      • TNM
      • Any metastases=Stage IV
      • Mets to lungs>liver>bone
      AJCC 2002
    • Karnofsky Score
      • 100% - normal, no complaints, no signs of disease
      • 90% - capable of normal activity, few symptoms or signs of disease
      • 80% - normal activity with some difficulty, some symptoms or signs
      • 70% - caring for self, not capable of normal activity or work
      • 60% - requiring some help, can take care of most personal requirements
      • 50% - requires help often, requires frequent medical care
      • 40% - disabled, requires special care and help
      • 30% - severely disabled, hospital admission indicated but no risk of death
      • 20% - very ill, urgently requiring admission, requires supportive measures or treatment
      • 10% - moribund, rapidly progressive fatal disease processes
      • 0% - death.
    • Patients
      • Stage III or IV, nonmetastatic
      • Measurable disease
      • Squamous Cell CA
      • Oropharynx, hypopharynx, or larynx
      • Karnofsky score >60%
      • Normal hematopoetic, hepatic, renal function
      • Life expectancy >1 year
    • 424 Patients High dose radiotherapy High dose Radiotherapy + Cetuximab randomized N=213 N=211 Phase III, Randomized, Multicenter Study Design
    • Exclusion Criteria
      • Previous Cancer
      • Chemo within last 3 years
      • Previous surgery
      • Previous radiation
    • Treatment
      • Radiation
        • One of 3 regimens, chosen by investigator
          • Concomitant boost, once-daily, or twice-daily
        • Maximum of two 5-day treatment breaks
      • +/- Cetuximab
        • Started 1 wk prior to RT and continued through end
        • Loading 400 mg/m2, then weekly 250 mg/m2
    • End Points
      • Primary
        • Duration of locoregional control
          • Blinded review by independent committee
      • Secondary
        • Overall survival
        • Progression-free survival
        • Overall response rate
        • Safety
    • Statistical Analyses
      • Required 208 pts per group for 90% power for primary end point
      • Intention to treat
      • Kaplan-Meier for time-to-event
      • Cox regression methods for hazard ratios
    • Patient Characteristics
    • Results- Patients
      • Balanced between both treatment groups with respect to-
        • Compliance
        • Type of RT chosen
        • Subsequent neck dissections
        • Subsequent salvage surgery
        • Subsequent chemotherapy
    • Results-efficacy
    • Locoregional Control HR=.68; (95% CI .52 to .89)
    • Overall Survival HR=.74; (95% CI .57 to .97)
    • Results- Risk reduction
      • Locoregional control at 3 years 47% in combination arm vs 34%
        • Absolute Risk Reduction 13%
        • NNT = 8
      • Overall survival at 3 years 55% in combination arm vs 45%
        • Absolute Risk Reduction 11%
        • NNT = 9
    • Results-safety
      • 13 patients discontinued cetuximab
        • 4 due to hypersensitivity post 1 st dose
        • 8 due to grade 3 rash
      • Cetuximab did NOT add to radiation toxicities including mucositis, xerostomia, dyphagia, pain, (weight loss), decreased performance status
    • Results-safety
    • Study Limitations
      • Lacked “standard of care” arm
      • Different RT regimens
      • Not site specific
        • Results for hypopharyngeal subgroup
      • Longer term data
      • Quality of Life Data
        • Need for PEG?
      • Concomitant boost vs other RT
      • Late complications
    • So, will this study change practice?
      • Better survival with other chemoradiation regimens (Vokes 2003, Brizel 1998)
      • But, better safety profile with cetuximab+XRT
      • Consider for those with low performance status
    • Chemoradiation Studies Argiris A. Update on chemo radiotherapy for head and neck cancer . Curr Opin Oncol 2002;14:323-329.
    • Future Studies
      • RT+cetuximab vs RT+platinum
      • RT+cetuximab+chemotherapy+neoadjuvant chemotherapy
        • Patterns of failure changing; distant vs local
      • RT + Cetuximab + Chemotherapy
      • Pfister 2006
        • Phase II trial, n=22
        • XRT + Cetuximab + Cisplatin
        • 3 year OS 76%, PFS 56%, LRC 71%
        • But, closed due to adverse events
    • Future studies
      • Which agents are the best to combine with radiation?
      • What is the role of adding targeted therapies?
      • Is combination chemotherapy better than single-agent chemotherapy?
      • Is altered fractionation better than conventional fractionation with CRT?
      • Does induction chemotherapy provide additional benefit?
    • Discussion- Cancer therapy trials
      • Difficulty with true control arms
      • Difficulty with blinding
      • When the “gold standard” keeps changing
    • References
      • Adelstein DJ; Li Y; et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003 Jan 1;21(1):92-8.
      • Al-Sarraf M; LeBlanc M; et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol 1998 Apr;16(4):1310-7.
      • Ang, KK et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 2002; 62:7350.
      • Brizel DM; Albers ME et al. Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 1998 Jun 18;338(25):1798-804.
      • Budach W et al. A meta-analysis of hyperfractionated and accelerated radiotherapy and combined chemotherapy and radiotherapy regimens in unresected locally advanced squamous cell carcinoma of the head and neck. BMC Cancer. 2006 Jan 31;6:28.
      • Calais G; Alfonsi M et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst 1999 Dec 15;91(24):2081-6.
      • Cohen, EE, Lingen, MW, Vokes, EE. The expanding role of systemic therapy in head and neck cancer. J Clin Oncol 2004; 22:1743.
      • Dassonville, O, Formento, JL, Francoual, M, et al. Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer. J Clin Oncol 1993; 11:1873.
      • Denis, F et al Final Results of the 94-01 French Head and Neck Oncology and Radiotherapy Group Randomized Trial Comparing Radiotherapy Alone With Concomitant Radiochemotherapy in Advanced-Stage Oropharynx Carcinoma J Clin Oncol 2004 22: 69-76
      • El-Sayed, S, Nelson, N. Adjuvant and adjuvantive chemotherapy in the management of squamous cell carcinoma of the head and neck region: A meta-analysis of prospective and randomized trials. J Clin Oncol 1996; 14:838.
      • Forastiere, AA et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003; 349:2091.
      • Jeremic, B, Shibamoto, Y, Milicic, B, et al. Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prosepective randomized trial. J Clin Oncol 2000; 18:1458.
      • Kies MS; et al. Induction chemotherapy followed by concurrent chemoradiation for advanced head and neck cancer: improved disease control and survival. J Clin Oncol 1998 Aug;16(8):2715-21.
      • Pfister, DG, Su, YB, Kraus, DH, et al. concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: a pilot phase II study of a new combined-modality paradigm. J Clin Oncol 2006; 24:1072.
      • Pignon JP et al. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 2000 Mar 18;355(9208):949-55.
      • Posner, M et al Cetuximab and Radiotherapy for Head and Neck Cancer N Engl J Med 2006 354: 634-636
      • Wendt TG et al. Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. J Clin Oncol 1998 Apr;16(4):1318-24.