cetuximab plus radiotherapy for head and neck cancer
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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 reactionsacneform skin rashnail 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 doseRadiotherapy
+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
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 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
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 chemoradiotherapy 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
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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
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