CETUXIMAB PLUS RADIOTHERAPY FOR THE TREATMENT OF LOCALLY ADVANCED SQUAMOUS

CELL CARCINOMA OF HEAD AND NECK

Dr Salim Chaib-Rassou

Radiotherapy departmentAmerican Hospital Dubai

بسم الله الرحمن الرحيم

Case Presentation• 79 year old man presents with 1 year history of ‘’on and off ‘’

sore throat and new painless right neck mass

• Past medical History: Coronary artery disease, stent placed in 2001. Hypertension. Hyperlipidemia. Benign Prostatic Hyperplasia.

• Medications: Finasteride, Atorvastatin, Ezetemibe, hydrochlorothiazide, Ramipril, Aspirin

• Habits: quit smoking 30 years ago, 20 pack-year history. Does not drink alcohol

Case continued…• Physical exam:

– ECOG 0. Unremarkable cardiovascular, respiratory and abdominal examinations.

– Good dental hygiene. Oral cavity unremarkable on inspection and palpation. No tongue deviation.

– Palpation of neck: Two right level II lymph nodes 3x4 cm and 2x1 cm, mobile. Left neck clear on palpation.

– Flexible laryngoscopy: fungating ulcerated mass at the right base of tongue, crossing midline, not extending to the vallecula.

– Normal, symmetric, vocal cord movement.

Pathology

• Biopsy of Base of Tongue mass:– Invasive poorly differentiated

squamous cell carcinoma– No evidence of peri-neural or LVI

• FNA right neck node:– Metastatic squamous cell carcinoma

• P16 strongly positive

Staging Investigations: CT neck• Lesion located at right side of floor of mouth, base of

tongue and palatine tonsil, 2.8 x 2.3 cm. • Right Level II b mass of matted nodes 3.7 x 2 x 2.5 cm.• Two other right LN Level III on the 2 x 2.4 cm + 1.5 x 2 cm.

Staging cont’d: MRI Neck• Large primary neoplastic tumor at the right base of tongue involving the right

palatine tonsil 2.8 X 2.7 X 3.1 cm. No bony invasion. • Large right sided necrotic lymph nodes with encasement of right internal

jugular vein and invasion of right SCM , 4.4 X 3.2 X 4.0 cm • More inferiorly in right posterior triangle, two rim-enhancing cystic masses, 1.5

X 1.8 cm and 2 X 1.6 cm. No other significant neck lymphadenopathy noted.

Staging cont’d:

• CT chest: – No evidence of metastatic disease involving the chest.

• Laboratory investigations:– Hb: 143 g/L, Platt: 224, WBC 7.2 – Creatinine: 83 umol/L– Normal liver function tests, TSH, electrolytes and

albumin.

• Final Stage:– T2 N2b M0 : Stage IVA

Work up pre-treatment

• Dentistry consultation • PEG tube insertion• Nutrition consultation• Audiology assessment

Clinical Decision Question

What is your choice of therapy?

1) Surgery plus post-operative chemo-radiotherapy

2) Chemo-radiotherapy

3) Targeted therapy plus radiotherapy

4) Radiotherapy alone

Review of literature:Concurrent Chemotherapy vs. Cetuximab

Standard of care: chemotherapy• Pignon JP et al. Lancet. 2000

– Meta analysis 63 Trials of RT +/- Chemotherapy– Patients treated between 1965-1993 (older RT techniques) 8% benefit with concurrent chemo-RT p<0.0001

MACH-NC Meta-analysis: Pignon et al. Green Journal 2009

• 93 phase III trials, 17,346 patients. • OS benefit (4.5%) at 5 years when chemotherapy added to RT• Greater benefit for concurrent chemo-RT (6.5%) vs. induction • No difference between mono or poly chemotherapy

regimens, but increased benefit with platinum-based compounds

• Decreasing benefit with increasing age, with no benefit observed if ≥71-years old

MACH-NC Meta-analysis

MACH-NC Meta-analysis

MACH-NC Meta-analysis

Summary: Concurrent chemo radiation therapy

• Concurrent chemo radiation is more effective than radiation alone in advanced head and neck cancers.

• Especially for patients with:– Good performance status– Stage III-IV– Young patients <70 years old– Able to tolerate toxicity of platinum based (adequate

renal function, baseline audiology ok)

Combined Options

– Cis platinum effective– Cetuximab effective

Head to Head comparison Data is Lacking.

Combined Options

J.A. Bonner, P.M. Harari and J. Giralt et al., Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival, Lancet Oncol 11 (2010), pp. 21–28.

P Huguenin, KT Beer, A Allal et al. Concomitant Cisplatin Significantly Improves Locoregional Control in Advanced head and Neck Cancers Treated with Hyperfractionated Radiotherapy. J Clin Oncol 22: (2004)4665-4673.

Cisplatin Cetuximab

Bonner et al., NEJM, 2006

• 424 patients with loco-regionally advanced stage III–IV SCC of oropharynx, larynx, or hypo pharynx

• Randomized to: RT Vs. RT + cetuximab given 1 week before RT and weekly during RT.

• RT options included 70 Gy in 35 fractions, 72–76.8 Gy in 60 to 64 fractions BID, or concomitant boost to 72 Gy in 42 fractions.

–Median age was 57–>50% were oropharynx primaries

Bonner et al. • Loco-regional control at 2 years: 41% 50% (p=0.005)• Median overall survival: 29.3 months 49 months (p=0.03)• 3 year overall survival: 45% 55% (p=0.03)

Bonner et al.

• No difference in toxicity for mucositis, dermatitis, dysphagia, xerostomia (unlike concurrent chemotherapy which significantly increases in these toxicities compared to radiation alone)

• Higher rates of acneiform rash and infusion reaction in Cetuximab group– 17% developed grade 3 to 4 acneiform rash

• (87% developed ≥grade 1 rash)

– 3% had grade 3 to 5 infusion reaction

Bonner et al. update Lancet, 2010• Median overall survival: 29.3 months 49 months • 5-year overall survival: 36.4% 45·6%

Bonner et al. update cont’d• Overall survival significantly improved in those who experienced

an acneiform rash of ≥ grade 2 severity compared with patients with ≤ grade 1 rash with a HR 0·49 (p=0·002). – 25.6 months 68.8 months

Our case Radiation Plan: IMRT• 70 Gy in 35 fractions:

– Primary mass and gross adenopathy with margin• 63 Gy in 35 fractions:

– Ipsilateral retropharyngeal nodes, levels Ib to V– Contralateral: retropharyngeal, levels Ib to IV

• 56 Gy in 35 fractions for Contralateral: level V

Concurrent Cetuximab

• Initial loading dose: 400 mg/m2 infused over 2 Hours, 1st week before initiation of RT

• Maintenance dose: 250 mg/m2 infused over 1 Hour weekly during radiation therapy

• He developed grade 3 acneiform rash secondary to Cetuximab

– Treated with minocycline pill and clindamycin cream

Treatment course

• Tolerated treatments fairly well:– Grade 3 dermatitis and grade 3 acneiform rash– Grade 2 mucositis– Grade 2 dysphagia– Grade 2 xerostomia– No hematologic toxicity

• Used PEG as of 4th week of treatment• Lost 2.8 kg overall

Follow up at 8 weeks

• Persistent grade 1 dysphagia, grade 2 xerostomia, and dysgeusia.

• Still using PEG tube. Weight stable.

• Physical examination of neck, oral cavity, and base of tongue revealed no residual palpable mass. Mild sub mental lymphedema.

• Fiber optic laryngoscopy: no evidence of residual disease. Mild to moderate laryngeal edema.

Follow up: MRI

MRI

8 weeks post treatment

Significant improvement with no residual mass at the right floor of mouth/BTAnterior to right sternocleidomastoid muscle partially enhancing residual lymph node significantly decreased in size when compared to prior study.Previously described right level III lymph nodes significantly decreased in size with one remaining lymph node which restricts on diffusion weighted images measuring 0.7 x 0.9cm No other size-significant lymphadenopathy identified.

MRI pre-treatment 8 WEEKS POST TRT

Follow upMRI pre-treatment MRI 8 weeks post treatment

PET/CT : 14 weeks post treatment

• No abnormal FDG accumulation within the tongue and no hypermetabolic lymphadenopathy.

• No evidence of distant metastases

MRI and PET/CT 9 months post treatment

• MRI: No evidence of recurrence of the tumor at the level of the right side of the base of the tongue.

• No suspicious nodes in the neck.

• PET/CT: no evidence of abnormal radiotracer uptake in the oral cavity, oropharynx or elsewhere in the neck, to suggest the presence of active neoplastic lesions

Follow up 1 year

• Doing overall well• Grade 2 xerostomia • Dysgeusia with altered taste persists• Grade 1 dysphagia • Grade 1 neck fibrosis• Mild submental edema• Weight stable

Acneiform rash

Acneiform rash

• Appears 8-10 days after the initiation of treatment, becomes progressively worse peaking at around 14-21 days and generally resolves completely in the first weeks following the cessation of therapy.

• Recommended treatment:– hydrocortisone 1% cream twice daily– moisturizer twice daily– sunscreen twice daily– minocycline 100 mg once daily

Summary• In patients fit for chemotherapy, concurrent radiation with

platinum based chemotherapy remains one the standard of care. – It is more effective than RT alone in young patients (<70) with good

performance status and advanced stage (III-IV)– But acute and late toxicity is increased (compared to RT alone)

• EGFR inhibition combined with radiotherapy results in enhancement of tumor response compared to radiation alone.– No data yet comparing it to concurrent cisplatin and so the optimal

combination is still unsettled.– Well tolerated with similar toxicity compared to radiation alone

(mucositis, dermatitis, xerostomia)– Special toxicity: acneiform rash, but the more severe the rash the better

the outcome!

Ideal patients for cetuximab

• Stage III-IV head and neck squamous cell carcinomas of the oropharynx, hypo pharynx or larynx

• Not eligible for platinum-based chemotherapy due to either:– Poor renal function– Baseline audiology problems– Multiple comorbidities– Age over 70

• May be as effective as platinum-based concurrent chemo-radiation but final data not yet available

Ongoing Trials

• RTOG 0522: phase 3 trial for stage III and IV randomized to concurrent accelerated radiation (70 Gy in 35 fractions over 6 weeks using IMRT) and:

– Cisplatin vs.– Cisplatin and cetuximab

• Recently closed to patient enrolment. Data will provide definitive information regarding cetuximab in combination with chemo-radiation in the locally advanced disease setting

Ongoing Trials cont’d

NCIC HN6:

Ongoing Trials cont’d

• RTOG 1016:

• Phase III Trial in HPV associated oropharynx cancer (p16+)• Accelerated RT (70Gy in 35 f over 6 weeks) randomized to concurrent:

– Cetuximab weekly VS Cisplatinum day 1 and 22

• RTOG 3501:• Phase II randomized trial of HPV unrelated head and neck cancers (p16 - ) • Accelerated RT (70Gy in 35 f over 6 weeks) + Cis platinum

• Randomized to adjuvant:

– Placebo VS Lapatinib

Conclusions

• Cetuximab is a well tolerated treatment with proven benefit compared to radiation alone in locally advanced head and neck squamous cell carcinomas of the oropharynx, larynx and hypo-pharynx

• Ongoing trials will provide new data regarding the role of cetuximab (and other EGFR inhibitors) instead of chemotherapy or in combination with chemotherapy or in the adjuvant setting for locally advanced disease.

Molecular and Biological Events in Head and Neck Cancer (HNC)

HPV-Related Cancers

• Caused by high-risk HPV– HPV 16– Driven by viral oncogenes

• Restricted to oropharynx• Distinct molecular markers• “Good” prognosis• Young, good general health

Environment-Related Cancers

• Caused by environmental mutagens– Smoking, alcohol

• Throughout oral mucosa• Distinct molecular markers• “Poor” prognosis, comorbidity• Second cancers

HNC Can Now Be Divided Into 2 Large and Distinct Subtypes

HPV = human papillomavirus.Goon et al, 2009; Rodriguez et al, 2010.

THANKS

3. Can we develop more accurate imaging techniques and/or molecular markers to identify patients with positive pelvic nodes to reduce the chance of overtreatment with preoperative therapy?

4. More individualized therapies based on clinical– pathological features and molecular and genetic markers, like the (EGFR) and (VEGF) as promising targets of antitumor treatment.

5. Will more effective systemic agents both improve the results of chemo-radiation and modify the need for pelvic irradiation?

These questions and others remain active areas of clinical investigation.