1. Head and Neck Cancer
December 6,2016
Uzma Athar, MD

2. Management of LAHNC Induction when and what
Weekly cisplatin vs three weekly cisplatin
Cetuximab vs cisplatin
Radiation dose and fractionation

3. Case
Mr C is a 53 y/o caucasian male with h/o papillary thyroid carcinoma s/p total thyroidectomy and radioactive iodine ablation 20 years ago, who presented with throat discomfort and a 15 lb weight loss. Initially seen by endocrinology who noticed a palpable right level two lymph node ~ 3 cm in size on examination
He had chronic mild dysphagia, hoarseness and chronic aspiration since thyroid surgery
Smoking 1.5 ppd for 30 yrs; presently smokes half ppd
Previous heavy alcohol use but none in over 10 yrs
H/O recurrent pneumonias

4. FNAC of the right submandibular lymph node showed moderately differentiated SC
Direct Laryngoscopy –
An area of ulceration on the posterior right aryepiglottic fold and extending to involve the laryngeal epiglottis
True vocal cords and pyriform sinus were without lesion
Fullness of the BOT was noted without any discrete mass
Rigid esophagoscopy was normal to 36 cm from the incisors

5. Biopsy
Squamous cell carcinoma, well differentiated of right supraglottic region
Lymphoid hyperplasia of right base of tongue
Dysplasia, moderate, of left base of tongue

6. CT Neck
A large matted lymph node in the right level II, measuring
2.0 x 3.0 cm
Prominent soft tissue suspicious for a primary tumor in the left side base of the epiglottis and bilateral lingual tonsils.
PET Scan
Right-sided cervical node level 2 with SUV max 14.9
Left soft tissue mass in the epiglottis/vallecula with SUV max 7.3
Bilateral piriform sinuses with SUV max 6.5
Right aryepiglottic fold with SUV max 15.2

7. Final Stage - IVA (T3N2cM0) Other Studies
Dental Evaluation
Speech/Swallowing evaluation

8. Treatment Options Definitive Concurrent Chemotherapy
Chemoradiotherapy Radiotherapy
Adjuvant Chemoradiotherapy Surgery Chemotherapy
Radiotherapy
Induction Chemotherapy Chemotherapy Chemotherapy
Definitive concurrent CRT Radiotherapy
Induction Chemotherapy Chemotherapy Radiotherapy or
Surgery

9. RCTs of Concurrent CRT
DFS 27-61%, OS 30-50%

10. Concurrent Chemoradiation (CRT)
MACH-NC
87 randomized trials between 1965 and 2000 comparing locoregional treatment and chemotherapy with locoregional treatment alone
Earlier analysis showed survival benefit with chemotherapy was 8% at 5 years
Survival benefit mainly due to improvement in locoregional control and only marginal effect on distant metastasis.
Blanchard P et al. radiotherapy and Oncology2011

11. Benefit of adding chemotherapy is consistent in all tumor locations
Oral cavity %
Oropharynx %
Larynx %
Hypopharynx 4%
Chemotherapy benefit was higher for concomitant administration for all tumor locations
Chemotherapy …. Radiosensitizer ….Early control of micrometastatic disease

12. Neoadjuvant/ Induction Chemotherapy
Organ preservation
Decrease tumor Volume
Response is predictive of subsequent response to RT
Eliminate clinically occult micrometastatic disease
Response is transient and should be followed by definitive treatment
Surgery &/ RT
Response rates 50-75%
Complete response rate 10-15%

13. Neoadjuvant Chemotherapy
Study N
Treatment
Primary End point (Larynx Preservation) OS
VA Study Group
332
Surgery  RT
Cis + 5FU X 3  RT + Surgery
64% at 2 yrs
68%
P= NS
EORTC
24891
202
Cisplatin + 5-FU x 2-3 cycles  RT or Surgery  RT
35% at 5 yrs
35%
30%
P=NS
RTOG 91-11
525
RT alone (70 Gy)
Cis + 5-FU 1000/m2 X 2
CR/PR  Cis/5FU X 1 RT
NR  Surgery  RT
Cis X 3 + RT
70% (65.7%)
75% (70.5%)
88% (83.6%)
56% (53.5%)
55% (59.2%)
54% (54.6%)
RTOG 91-1 Endpoint results 2 yr(5-yr)- Distant mets less with CRT* & I+RT than RT alone (p=0.06)*
VA Study Group- Distant mets less (0.016) and local recurrences (0.0005) more with CRT than RT.
Changed the treatment paradigm
VA laryngeal Ca Study. NEJM 1991;324:
Lefebvre JL et al. JNCI 1996;88: ; Lefebvre. Ann of Oncology 2012;23:2708
Forastiere AA et al. JCO 2013;31: 845

14. Conclusions
A larynx preserving approach can be offered to patients without compromising their survival
Surgery can be an option in the salvage setting
Patients with comorbidities and no access to adequate speech and swallowing rehab

15. TPF vs PF Study N Treatment Regimen TPF PF TAX 324 501
Docetaxel 75 mg/m2 D Cisplatin 100 mg/m2
Cisplatin 100 mg/m2 D FU 1000 mg/m2 D1- 5
5-FU 1000 mg/m2 D1-4
Q 3 wks x 3 ->CRT ->Sx Q 3 wks x 3 ->CRT-> Sx
EORTC 24971/ TAX 323
358
Docetaxel 75 mg/m2 D Cisplatin 100 mg/m2
Cisplatin 75 mg/m2 D FU 1000 mg/m2 D1-5
5-FU 750 mg/m2 D1-5
Q 3 wks x 4 -> RT Q 3 wks x 4 -> RT
TAX 324 -> CRT included carboplatin AUC 1.5 wkly x 7 and RT Gy ->>>> surgery in N2+PR, N3, residual disease
EORTC-> RT included convention dose Gy or acc/ hyperfractionated dose of Gy.
Vermorken JB et al. NEJM 2007; 357:
Posner MR et al. NEJM 2007; 357:

16. TPF vs. PF Results Outcome TAX 324 TPF PF p EORTC 24971 TPF PF p RR
0.006
OS (m)
0.02
3-yr OS %
PFS (m)
0.007
2-yr PFS %
Such a difference in responses- 1)Tax 324 resectable+ unresectable LAHNC….. EORTC trial had only unresectable disease. 2) Ind chemo CRT better than RT alone
In EORTC –subgp analysis showed a survival benefit across all subgps but this was not statistically significant.
Vermorken JB et al. NEJM 2007; 357:
Posner MR et al. NEJM 2007; 357:

17. TPF vs PF
Conclusions
As compared with the standard regimen of cisplatin and fluorouracil, induction chemotherapy with the addition of docetaxel significantly improved progression-free and overall survival in patients with unresectable squamous-cell carcinoma of the head and neck.
TPF is the regimen of choice for induction chemotherapy

18. Radiation Conventional Fractionation Altered Fractionation
70 Gy in 2 Gy fractions
Altered Fractionation
Hyper fractionated
1.1 – 1.2 Gy/Fr twice daily (interval of 6 hrs)
74-82 Gy (higher dose but no increase in LT toxicity)
Improved LR disease control; no survival benefit with CRT
Preferred when RT is used alone
Accelerated fractionation
1.5 – 1.6 Gy/Fr daily with an additional 2 Gy Fr/ week
Shorter total radiation course
Total dose is same or lower than conventional RT
Accelerated fractionation attempts to reduce tumor repopulation as a prominent cause of RT failure by decreasing the total time over which the radiation is administered////// IMRT much improved xerostomia

19. IMRT
Focally increase the dose per fraction to the tumor itself while maintaining lower doses to normal tissue/ uninvolved areas
Costly, requires planning
Often used for boost to the primary tumor
Less side effects i.e. xerostomia

20. RTOG 0129 N = 721 with LRAHNC Randomized to No difference in OS
70 Gy in 35 fractions over seven weeks with cisplatin 100 mg/m2 on D1,22,43
Accelerated boost RT (70 Gy in 42 fractions over six weeks) with cisplatin on D1 and 22
No difference in OS
8-year survival rate 48 % percent with both schedules (HR ratio 0.96, 95% CI )
No significant differences in PFS, LRF or rate of distant metastases
Toxicity – increased acute toxicity – skin and mucus membranes// 27% patients in both arms PEG dependent

21. GORTEC 99-02 N = 840 with LRAHNC Treatment Schema
70 Gy in 7 weeks with 3 cycles of carboplatin and 5-FU
Accelerated chemoradiotherapy (70 Gy in 6 weeks with two cycles of carboplatin fluorouracil)
Very accelerated RT alone twice daily (64.8 Gy in 3.5 weeks)
3-yr PFS was 34% in accelerated CRT versus 38% in conventional CRT (p = 0.88)
3-yr PFS was 38% in CRT versus 32% in very accelerated RT alone arm (p = 0.06)
Similar results were observed for overall survival
Acute toxicity- Gr 3/4 mucosal toxicity 69% vs 76% vs 84%

22. Cisplatin dose and frequency
Stage III/IV SCC of the oropharynx, larynx, hypopharynx and oral cavity
Treatment Regimen
Cisplatin 40 mg/m2 IV week 1-4
RT – 1.8 GY on D1-40; 1.5 Gy boost D25-40
Total dose 72 Gy
Stage IV 89% and oropharynx 44%
Medina JA. Radiotherapy and Oncology 2006

23. ORR was 88% (66% CR and 22% PR) Median OS was 27 months
Est 4-yr OS was 41%
Est 4-yr local control 59%
Toxicity
Acute toxicity- Mucositis (gr III 85%), Pharyngoesophageal (gr III 50%), dermatitis (17%)
Late Toxicity- Bone 2%, larynx 4%, esophagus 2%, skin/ subcutaneous tissue 2%

24. Conclusion
Concomitant boost accelerated radiation plus concurrent weekly cisplatin is a feasible schedule in patients with LA unresectable head neck cancer with acceptable toxicity and survival data

25. Role of Cetuximab as first line agent
Randomized control trial comparing cetuximab and radiation with radiation alone in previously untreated patients with LASCC.
Cetuximab 400 mg/m2  250 mg/m2 weekly
3 different regimens of RT used
Once daily 70 Gy in 35 fractions
Twice daily Gy in fractions
Concurrent boost 72 Gy in 42 fractions
EGFR testing not required for enrollment
Bonner JA et al. NEJM 2006;354:567-78

26. Study End Points Outcome Cetuximab +RT RT P value LR control (m) 24.4
14.9
0.005
OS (m) 49
29.3
0.03
PFS (m)
17.1
12.4
0.006
PFS % (3 yr) 42 31
0.04
LRC % (3 yr) 47 34
<0.01
OS % (3 yr) 55 45
0.05
Check subdivision of responses in each type of HNC- Study not designed to analyse subgroup analysis i.e poor PS/ elderly. Distant mets were similar in 2 gps at 2 yrs.
No difference in RT dose.
Bonner JA et al. NEJM 2006;354:567-78
Bonner et al. Lancet Oncology 2010;11:21-28

27. Updated 5-yr survival data
OS 45.6% in cetuximab arm versus 36.4% in RT arm (HR 0.73 and p value 0.018)
Bonner et al. Lancet Oncology 2010;11:21-28

28. Adverse Events Grade > 3 AE C + RT RT P value Infusion Reaction 3
0.01
Acneiform Rash 17 1
0.001
Mucositis 56 52
0.44
Dermatitis 23 18
0.27
Weight Loss 11 7
0.12
Dysphagia 26 30
0.45
Xerostomia 5
0.32
One third patients had stage III disease and they better prognosis a such. No head to head comparison of CRT vs cetuxRT. Is CRT+targeted therapy better than CRT alone.
Bonner JA et al. NEJM 2006;354:567-78

29. Cetuximab arm with grade 2 or higher rash
OS 68.8 months versus 25.6 months (HR 0.49, p 0.002)
Bonner et al. Lancet Oncology 2010;11:21-28

30. TREMPLIN Study
Phase II study of patients with Stage III/IV larynx/ hypopharynx SCC
N = 153
TPF X 3 cycles
CR/PR CRT with cisplatin 100 mg/m2 X 3
 RT with Cetuximab weekly
NR  surgery  RT

31. Larynx preservation at 3 months was 95% in cisplatin arm and 93% in cetuximab arm
LFP was 87% (cis) vs 82% (cetux) at 18 months
OS was 92% (cis) vs 89% (cetux) at 18 months

32. Local failure was more in the cetuximab arm 21% versus 13%
Surgical salvage was feasible in cetuximab arm
42% received 3 cycles of cisplatin
71% received 7 treatments of cetuximab

33. Acute Toxicity Cisplatin Cetuximab
Mucositis % %
Infield skin toxicity % %
Renal %
Hematologic %
Late Toxicity
Residual renal dysfunction 22% in cisplatin arm

34. Conclusions
There is no evidence that one treatment was superior to the other or could imporve outcomes reported with induction chemotherapy followed by radiation alone.

35. Case
The patient was treated with IMRT to 70 Gy in 35 fractions concurrent with chemotherapy
with cisplatin weekly X 6 weeks
CT Scans done at 3 months showed residual neck disease
2, 1.8, and 1.6 Gy/fraction to PTV1, PTV2, PTV3,
respectively for 35 fractions to a total dose of 70 Gy.

36. Case Underwent salvage b/l neck dissection 4/8 positive lymph nodes
He is now 5 yrs out from neck dissection with no evidence of disease

37. Management of LAHNC Induction when and what
Weekly cisplatin vs three weekly cisplatin
Cetuximab vs cisplatin
Radiation dose and fractionation

38. A Randomized Phase II Trial for Patients with p16 Positive, Non-Smoking Associated, Locoregionally Advanced Oropharyngeal Cancer(NRG-HN002) (CIRB) MSKCC
RT alone versus weekly cisplatin/RT

39. Thank you