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

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 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

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 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

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 CarcinomaJ 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.