CETUXIMAB PLUS RADIOTHERAPY FOR THETREATMENT OF LOCALLY ADVANCED SQUAMOUS CELL CARCINOMA OF HEAD AND NECK Dr Salim Chaib-Rassou Radiotherapy department American Hospital Dubai
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, Rami pril, 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 QuestionWhat 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
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 effectiveHead to Head comparison Data is Lacking.
Combined Options Cisplatin CetuximabP Huguenin, KT Beer, A Allal et al. Concomitant Cisplatin Significantly Improves Locoregional Control in Advanced head and Neck Cancers Treatedwith Hyperfractionated Radiotherapy. J Clin Oncol 22: (2004)4665-4673.J.A. Bonner, P.M. Harari and J. Giralt et al., Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival datafrom a phase 3 randomised trial, and relation between cetuximab-induced rash and survival, Lancet Oncol 11 (2010), pp. 21–28.
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 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.
MRI pre-treatment Follow up: MRI 8 WEEKS POST TRT MRI8 weeks post treatmentSignificant improvement with no residual mass at the right floor of mouth/BTAnterior to right sternocleidomastoid muscle partially enhancing residuallymph node significantly decreased in size when compared to prior study.Previously described right level III lymph nodes significantly decreased in sizewith one remaining lymph node which restricts on diffusion weighted imagesmeasuring 0.7 x 0.9cmNo other size-significant lymphadenopathy identified.
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
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• 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) HNC Can Now Be Divided Into 2 Large and Distinct SubtypesHPV-Related Cancers Environment-Related Cancers• Caused by high-risk HPV • Caused by environmental – HPV 16 mutagens – Driven by viral oncogenes – Smoking, alcohol• Restricted to oropharynx • Throughout oral mucosa• Distinct molecular markers • Distinct molecular markers• “Good” prognosis • “Poor” prognosis, comorbidity• Young, good general health • Second cancersHPV = human papillomavirus.Goon et al, 2009; Rodriguez et al, 2010.
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 improvethe results of chemo-radiation and modify the needfor pelvic irradiation?These questions and others remain activeareas of clinical investigation.