cetuximab plus radiotherapy for head and neck cancer
TRANSCRIPT
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Cetuximab plus Radiotherapy for Head and Neck Cancer
Rena Callahan
Journal Club
UCLA Internal Medicine
Faculty Discussant: Steven Wong
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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.
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Objectives
Head and Neck Cancer The role of EGFR Cetuximab overview Trial overview Trial Discussion Future prospects
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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
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Head and Neck Anatomy
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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)
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EGFR
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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.
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Cetuximab Adverse Events
Infusion reactionsacneform skin rashnail disorder
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Cetuximab Rash
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The Approval of Cetuximab
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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)
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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
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Radiation toxicity
Acute– mucositis, odynophagia, dysphagia, hoarseness,
xerostomia, dermatitis, and weight loss
Late– Xerostomia, osteoradionecrosis, fibrosis, stricture,
thyroid dysfunction, carotid stenosis/rupture
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Chemoradiation
Rationale– Radiosensitizers– Targeting micrometastases– Overcoming radioresistance– 5-FU, cisplatin, carboplatin, taxane, MTX,
mitomycin– cetuximab
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Chemoradiation-Toxicity
Cisplatin– Nausea/vomiting– Nephrotoxicity– Neuropathy– Pulmonary fibrosis– Myelosuppression
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Staging
TNM Any metastases=Stage IV Mets to lungs>liver>bone
AJCC 2002
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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.
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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
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424 Patients
High dose radiotherapy
High doseRadiotherapy
+Cetuximab
randomized
N=213 N=211
Phase III, Randomized, Multicenter
Study Design
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Exclusion Criteria
Previous Cancer Chemo within last 3 years Previous surgery Previous radiation
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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
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End Points
Primary– Duration of locoregional control
Blinded review by independent committee
Secondary– Overall survival– Progression-free survival– Overall response rate– Safety
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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
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Results- Patients
Balanced between both treatment groups with respect to-– Compliance– Type of RT chosen– Subsequent neck dissections– Subsequent salvage surgery– Subsequent chemotherapy
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Results-efficacy
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Locoregional Control
HR=.68; (95% CI .52 to .89)
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Overall Survival
HR=.74; (95% CI .57 to .97)
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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
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Results-safety
13 patients discontinued cetuximab– 4 due to hypersensitivity post 1st dose– 8 due to grade 3 rash
Cetuximab did NOT add to radiation toxicities including mucositis, xerostomia, dyphagia, pain, (weight loss), decreased performance status
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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
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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
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Chemoradiation Studies
Argiris A. Update on chemoradiotherapy for head and neck cancer. Curr Opin Oncol 2002;14:323-329.
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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
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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?
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Discussion- Cancer therapy trials
Difficulty with true control arms Difficulty with blinding When the “gold standard” keeps changing
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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
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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-
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