Radiotherapy and Cetuximab

1. CETUXIMAB PLUS RADIOTHERAPY FOR THE
TREATMENT OF LOCALLY ADVANCED SQUAMOUS
CELL CARCINOMA OF
HEAD AND NECK
Dr Salim Chaib-Rassou
Radiotherapy department
American Hospital Dubai

2. 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

3. 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.

4. 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

5. 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.

6. 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.

7. 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

8. Work up pre-treatment
• Dentistry consultation
• PEG tube insertion
• Nutrition consultation
• Audiology assessment

9. 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

10. Review of literature:
Concurrent Chemotherapy vs. Cetuximab

11. 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

12. 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

13. MACH-NC Meta-analysis

14. MACH-NC Meta-analysis

15. MACH-NC Meta-analysis

16. 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)

17. Combined Options
– Cis platinum effective
– Cetuximab effective
Head to Head comparison Data is
Lacking.

18. Combined Options
Cisplatin Cetuximab
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.
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.

19. 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

20. 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)

21. 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

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

23. 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

24. 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

25. 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

26. 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

27. 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.

28. MRI pre-treatment Follow up: MRI 8 WEEKS POST TRT
MRI
8 weeks post treatment
Significant improvement with no residual mass at the right floor of mouth/BT
Anterior 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.

29. Follow up
MRI pre-treatment MRI 8 weeks post treatment

30. PET/CT : 14 weeks post treatment
• No abnormal FDG accumulation within the tongue
and no hypermetabolic lymphadenopathy.
• No evidence of distant metastases

31. 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

32. 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

33. Acneiform rash

34. 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

35. 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!

36. 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

37. 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

38. Ongoing Trials cont’d
NCIC HN6:

39. 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

40. 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.

41. Molecular and Biological Events in
Head and Neck Cancer (HNC)
HNC Can Now Be Divided Into 2 Large and Distinct Subtypes
HPV-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 cancers
HPV = human papillomavirus.
Goon et al, 2009; Rodriguez et al, 2010.

42. THANKS

43. 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.