1. CHEMORADIOTHERAPY IN HEAD AND NECK CANCER
Dr David Boote
Consultant in Clinical Oncology
Portsmouth Oncology Centre
May 2007

2. MANAGEMENT OF THE PRIMARY TUMOUR
Most T1 and T2 tumours controlled equally well by surgery or RT
Choice of treatment influenced by:- tumour site, accessibility, histological grade, fitness and patient preference
Surgery preferable when tumour involves bone

3. MANAGEMENT OF THE PRIMARY TUMOUR
Most T3 and T4 tumours require combinations of radiotherapy, chemotherapy and surgery
Chemoradiotherapy becoming more popular for inoperable tumours

4. RADIOTHERAPY
Primary treatment – typical dose 66Gy in 33 fractions over 6½ weeks
Post-operative (adjuvant) – indications include close or involved resection margins, poorly differentiated tumours, extensive lymph node involvement
Palliative e.g. bleeding, pain

5. RADIOTHERAPY CONSIDERATIONS
Unhealthy teeth in the radiotherapy treatment volume need to be removed before starting radiotherapy
Treat in a plastic mask (shell) to ensure accuracy and to avoid ink marks on skin
A mouth-bite can be used when treating e.g. Ca tongue, floor of mouth, to dispace the upper jaw out of the field

6. CLINICAL CHALLENGES Excess alcohol/tobacco intake
Poor nutrition, ? Need PEG
Medically unfit e.g. COPD
Poor social support
May need dental extractions
RT planning is complex and time-consuming

7. TREATMENT OPTIONS IN ADVANCED DISEASE
Surgery ± Radiotherapy ± Chemotherapy

8. CHEMOTHERAPY OPTIONS IN HEAD AND NECK CANCER
Can use chemo in 4 main ways:-
Neoadjuvant (Induction) chemotherapy
Concurrent (Concomitant) chemotherapy
Adjuvant (Post-op) chemotherapy
Palliative chemotherapy

9. 1. INDUCTION CHEMOTHERAPY
Given prior to radiotherapy or surgery
“gold standard” Cisplatin + 5-FU for 2-3 courses
Leads to a major response in 60 – 90% patients
Until recently, no significant effect on overall survival
Can be used for organ sparing e.g. as alternative to laryngectomy
? Use dropped after Pignon meta analysis (Lancet 2000)

10. EFFECTS OF CHEMOTHERAPY ON SURVIVAL AT 5 YEARS: FROM THE META-ANALYSIS
Trial No. of No. Difference Category Trials Patients (%) P value
All trials <0.0001
Adjuvant
Induction PF
Other Chemo
Concomitant <0.0001

11. ADVANTAGES INDUCTION CHEMOTHERAPY
survival
organ preservation
distant mets
Prompt symptom relief
Use whilst waiting for RT

12. DISADVANTAGES INDUCTION CHEMOTHERAPY
Toxicity e.g. neutropenia
Toxic deaths
Delays (C)RT

13. 2. CONCURRENT CHEMOTHERAPY
Most commonly single agent Cisplatin for 2–3 courses
Pignon meta-analysis showed an 8% absolute survival benefit when chemo added to RT
Several randomised trials in unresectable disease show significant improvement in local control and survival
Regarded by most clinicians as the best time to give chemotherapy
Increased toxicity (especially mucositis) means only suitable for fit patients

14. ADVANTAGES/DISADVANTAGES CONCURRENT CHEMOTHERAPY
Advantages   survival
  local control
Disadvantages • Toxicity
•  RT mucositis

15. EORTC 24971/TAX 323 - Study Design
Induction CT + Locoregional RT
Neck Dissection
Surgery for Residual Disease
TPF arm (n=177)
 Docetaxel (75 mg/m²)
 Cisplatin (75 mg/m²)
 5-FU (750 mg/m²/dx5)
Q 3 weeks x 4 cycles
Inoperable
SCCHN
Stage 3-4.
Radiotherapy
(~70 Gy over 7 weeks)
Follow up R
Stratification: 1º tumor site
Institution
PF arm (n=181)
 Cisplatin (100 mg/m²)
 5-FU (1000 mg/m²/dx5)
Q 3 weeks x 4 cycles
Primary Objective: PFS
Treatment arms were well balanced in baseline characteristics
Remenar E, et al. ASCO 2006, abstract Bernier J, et al. ASCO 2006, abstract Vermorken JB, et al. ASCO 2004, abstract 5508.

16. EORTC 24971/TAX 323 Overall Survival PF TPF Treatment PF TPF 10 20 3010 20 30 40 50 60 70 80 90
100 PF
TPF
Median OS, mo
14.2
18.6
Hazard ratio (95% CI)
0.71 (0.56, 0.90)
P-value
0.0055
Treatment PF
TPF 6 12 18 24 30 36 42 48 54 60 66 72
(months)
Remenar E, et al. ASCO 2006, abstract Bernier J, et al. ASCO 2006, abstract Vermorken JB, et al. ASCO 2004, abstract 5508.

17. Primary prophylactic antibiotics were given
EORTC 24971/TAX 323
Toxicity
NCIC-CTC Grade 3-4 Toxicity
PF (n=179) patient percentage
TPF (n=173) patient percentage
Anemia/thrombocytopenia
13/18
9/3
Neutropenia 53 77
Nausea/vomiting
7/4
<1/<1
Diarrhea 3
Stomatitis 11 5
Infection 6 7
Febrile neutropenia
Primary prophylactic antibiotics were given
per protocol for TPF

18. Performance Status Scale – Head & Neck
EORTC 24971/TAX 323
QOL Analysis: PSS-HN
PSS-HN data showed that eating disturbances and disturbances of speech were higher in patients treated with PF vs those treated with TPF
Performance Status Scale – Head & Neck
Parameter
Treatments
Results
End of Treatment
(difference in least square mean)
End of Follow-up
P-value
Normal diet
TPF vs PF
+ 5.5
+ 16.8
0.0064
Speech
+ 3.7
+ 3.9
<0.0001
Public eating
+ 6.6
+ 17.3
0.0002
Bernier et al. ASCO 2006; Abstract 5522.

19. EORTC 24971/TAX 323 Conclusions
Treatment with TPF was superior to PF  Median PFS (primary endpoint; p=.007)  Median overall survival (p=.013)
TPF has a manageable toxicity profile
Health-related QOL and clinical benefit outcomes generally favored TPF

20. Induction CT  CRT  Surgery + Weekly Carboplatin (AUC 1.5 7)
TAX Study Design
Induction CT  CRT  Surgery
N=538
Primary Objective: OS
Stage III/IV
Epidermoid
carcinoma,
no prior surgery,
no hospitalization
for COPD 1y
PF arm (n=246)
 Cisplatin (100 mg/m²/d1)
 5-FU (1000 mg/m²/d 5)
Q 3 weeks x 3 cycles
Radiotherapy (70Gy d1-5)
+ Weekly Carboplatin (AUC 1.5 7)
Surgery is needed R
TPF arm (n=255)
 Docetaxel (75 mg/m²)
 Cisplatin (100 mg/m²d1)
 5-FU (1000 mg/m²/d 4)
Q 3 weeks x 3 cycles
Stratification:
Center
N status
Primary site
Treatment arms were well balanced in baseline demographic and disease characteristics
Posner RM, et al. ASCO 2006, abstract SPS24.

21. Primary Endpoint: Overall Survival Survival Probability (%)
TAX Study Design
Primary Endpoint: Overall Survival
100
TPF significantly improved overall survival vs PF
30% reduction in mortality 90 80 70 60
TPF (n=255)
Survival Probability (%) 50
PF (n=246) 40
2-Year OS TPF 67% PF 54%
3-Year OS TPF 62% PF 48% 30
Log-Rank p = Hazard ratio = 0.70 20 10 6 12 18 24 30 36 42 48 54 60 66 72
Survival Time (months)
Posner RM, et al. ASCO 2006, abstract SPS24.

22. TAX 324 Specific Safety During Chemotherapy TPF (N=251) PF (N=243)
Deaths due to toxicity 1% 2%
Neutropenia Grade 3/4
84%
56%
Febrile Neutropenia
Neutropenic Infection
12% 7% 9%
Primary prophylactic antibiotics were given per protocol for TPF
Posner et al. ASCO 2006.

23. Conclusions TPF significantly improves survival in 2 phase III trials
 TAX 323: 29% reduction in mortality (p=0.0055)
 TAX 324: 30% reduction in mortality (p=0.0058)
Sequential therapy with TPF is tolerable and safe

24. Phase III Trial PF ± Docetaxel  CRT vs CRT Study Design
Primary endpoint phase III: TTF PF
 3 cycles q 21 days
Cisplatin
Infusional 5-FU
(N=340)
SCHNN
Stage III, IV (locally advanced)
Unresectable
CRT
TPF
 3 cycles q 21 days
Docetaxel
Cisplatin
Infusional 5-FU R
CRT
Hitt R, et al. ASCO 2006, abstract 5515.

25. Phase III Trial PF ± Docetaxel  CRT vs CRT Patient Characteristics
No significant differences between treatments arms in baseline patient characteristics
TPF PF
CRT
Age, years
Median (range)
57 (35-78)
58 (36-85)
55 (25-79)
Gender, %
Men 93 92 89
PS (ECOG), % 8 13 1 87
Anatomic site, %
Oropharynx 41 43
Hyppharynx 19 18
Larynx 17
Oral cavity 21 22 20
Tumor grading, %
T4 N0 10
T4 N1 16
T4 N2 32
T4 N3 6
Hitt R, et al. ASCO 2006, abstract 5515.

26. Phase III Trial PF ± Docetaxel  CRT vs CRT Efficacy Results
Time to Treatment Failure (TTF) favored
the docetaxel-containing (TPF) arm
Time to treatment failure
1.000
TPF PF
CRT
0.875
0.750
0.625
0.500
0.375
0.250
Median: TPF 16 months, PF 12 months, CRT 8 months. Log rank 0.031
0.125
0.000
0.0
3.5
7.0
10.5
14.0
17.5
21.0
24.5
28.0
31.5
35.0
Times (months)
Hitt R, et al. ASCO 2006, abstract 5515.

27. Phase III Trial PF ± Docetaxel  CRT vs CRT
Toxicity During Chemotherapy
Patient Percentage
Grade 3/4 Toxicity
TPF PF
CRT
Leucocytes 9 11
Granulocytes 28 18
Platelets 7 6
Febrile neutropenia 1 2
Asthenia 5
Mucositis 53 58 35
Renal 4
Dermatitis 22 13
Hitt R, et al. ASCO 2006, abstract 5515.

28. GORTEC 2000-01 - Study Design Induction CT  Larynx Preservation R
Larynx or hypopharynx tumors
Resectable tumors or nodes requiring total (pharyngo[P] laryngectomy)
No previous treatment
TPF arm
 Docetaxel (75 mg/m² d1)  Cisplatin (75 mg/m² d1)  5-FU (750 mg/m²/dx5) Q 3 weeks x 3 cycles
Non-responders: Total (P)laryngectomy + post-op RT No
Response to induction treatment R
PF arm
 Cisplatin (100 mg/m²)  5-FU (1000 mg/m²/dx5) Q 3 weeks x 3 cycles
Responders:
RT alone
Yes
Primary Objective: larynx preservation rate
Calais G, et al. ASCO 2006, abstract 5506.

29. Patient and Disease Characteristics
GORTEC
Patient and Disease Characteristics
TPF (n=110)
PF (n=103)
Age, years
Median (range)
56.6 (38-75)
56.8 (32-75)
Gender, %
Men/women
101/9
97/6
PS (ECOG), % 51 1 59 52
Anatomic site, %
Hypopharynx 61 54
Larynx 49
Tumor grading, % T2 15 24 T3 80 63 T4 16
p=(0.14)
Pointreau Y, et al. Cancer/Radiotherapie. 2006:10:493, Abstract C03; Calais G, et al. ASCO 2006, Abstract 5506.

30. GORTEC 2000-01 Larynx Preservation TPF PF Median follow-up: 30 months
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
TPF PF
Larynx preservation, %
Median follow-up: 30 months
Larynx preservation rate higher in TPF group p=0.036
Time from randomization (months) 6 12 18 24 30 36
Pointreau Y, et al. Cancer/Radiotherapie. 2006:10:493, Abstract C03; Calais G, et al. ASCO 2006, Abstract 5506.

31. Grade 3/4 Acute Toxicities
GORTEC
Grade 3/4 Acute Toxicities
% of patients
NCI/CTC Grade 3/4*
TPF PF p
Mucositis
4.6
7.8
0.49
Neutropenia
55.6
37.3
0.01
Febrile neutropenia
13.9
0.24
Thrombocytopenia
1.9
0.09
Deaths
3.6
2.9
0.71
*Among patients treated with RT alone, no differences were observed between the 2 arms in: xerostomia, fibrosis, larynx edema, dysphagia, % of patients with permanent feeding tube.
Pointreau Y, et al. Cancer/Radiotherapie. 2006:10:493, Abstract C03; Calais G, et al. ASCO 2006, Abstract 5506.

32. GORTEC
Relative to Other Studies of PF Induction Followed by RT
Results with PF arm from GORTEC are consistent with those observed in other studies
Study
5-Year LPR (N function)
Veteran (larynx)
39%
EORTC (hypopharynx)
35%
RTOG (larynx)
43%*
GORTEC
41.4% (3-year)
*Endpoint was 5-year laryngectomy-free survival
(45% in the concomitant group).
Calais G, et al. ASCO 2006, Abstract 5506.

33. Adding Targeted Therapies in SCCHN - The Next Step
Potential role in induction, adjuvant treatment, and radiation sensitization
 These agents can be added to induction/sequential therapy and to chemoradiotherapy to improve outcomes
Agents with early experiences for recurrent/advanced disease:
 EGFR-inhibitors
 Combined EGFR/HER2 inhibitors
 Angiogenesis
 Other targets

34. EGFR is an important target for cancer therapy
• EGFR over-expression is associated with a poor prognosis3-7
• Erbitux® specifically targets EGFR, which is over-expressed in SCCHN8,9
References:
1. Baselga J et al. Eur J Cancer 2001;Suppl 4:S16-S22.
2. Wells A. Int J Biochem Cell Biol 1999;31(6):
3. Ang KK et al. Cancer Res 2002;62(24):
4. Rubin Grandis J et al. J Nat Cancer Inst 1998;90:
5. Maurizi M et al. Br J Cancer 1996;74:
6. Magne N et al. Eur J Cancer 2001;37(17):
7. Hitt R et al. Eur J Cancer 2005;41(3):
8. Baselga J et al. J Clin Oncol 2005;23(24):
9. Bonner JA et al. N Engl J Med 2006;354:

35. Erbitux® specifically targets EGFR1
• Erbitux® is an innovative chimeric monoclonal antibody1
• By binding to EGFR, Erbitux® inhibits the signalling cascade leading to multiple effects2,3
• Erbitux® inhibits post-radiation DNA damage repair4
References:
1. Baselga J et al. Eur J Cancer 2001;Suppl 4:S16-S22.
2. Ciardiello F and Tortora G. Clin Cancer Res 2001;7(10):
3. Arteaga CL. J Clin Oncol 2001;19(18 Suppl):32S-40S.
4. Huang SM et al. Clin Cancer Res 2000;6(6):

36. A new approach: Erbitux® + radiotherapy in locally advanced SCCHN
Characteristics
RT (n=213)
Erbitux® + RT (n=211)
Karnofksy performance status: 60– –100 71
141 63
147
Site of primary tumour:
Oropharynx
Larynx
Hypopharynx
135 51 27
118 57 36
Nodal involvement: NO
Nodal involvement: N+ 38
175 42
169
Tumor stage: T1–3
Tumor stage: T4
148 65 62
Fractionation:
RT was administered as: once-daily (26%), twice daily (18%) or concomitant boost (56%)
Reference:
1. Bonner JA et al. N Engl J Med 2006;354:

37. Erbitux® + radiotherapy significantly prolongs locoregional control in SCCHN1
The addition of Erbitux® to RT vs RT alone:
• significantly prolongs the duration of locoregional control by almost 10 months (24.4 months vs months, p=0.005)1
• resulted in a 32% reduction in the risk of locoregional progression (Hazard ratio = 0.68,
95% CI = )1
Reference:
1. Bonner JA et al. N Engl J Med 2006;354:

38. Erbitux® + radiotherapy significantly prolongs survival in SCCHN1
The addition of Erbitux® to RT vs RT alone:
• significantly prolongs median overall survival by almost 20 months (49.0 vs 29.3 months, p=0.03)1
• resulted in a 26% reduction in the risk of death (Hazard ratio = 0.74, 95% CI = )1
Reference:
1. Bonner JA et al. N Engl J Med 2006;354:

39. Frequently observed* adverse events (grades 3–5)1
Erbitux® does not significantly increase radiotherapy-related side effects
Frequently observed* adverse events (grades 3–5)1
RT (%)
Erbitux® + RT (%)
p value‡
Adverse event
n=212
n=208
Mucositis 52 56
0.44
Acneform rash 1 17
<0.001
Radiation dermatitis 18 23
0.27
Weight loss 7 11
0.12
Dry mouth 3 5
0.32
Dysphagia 30 26
0.45
Asthenia 4
0.64
Nausea 2
1.00
Constipation
• Erbitux® does not significantly exacerbate typical radiotherapy- associated toxicities such as mucositis, xerostomia and dysphagia in locally advanced SCCHN1
• The most frequently observed adverse events related to Erbitux® are skin reactions1
* Frequently observed = All grades in ≥30% of subjects
‡ p values were determined with the use of a Fisher’s exact test
Reference:
1. Bonner JA et al. N Engl J Med 2006;354:

40. Erbitux® in practice
• No EGFR testing is required
• An average patient treatment cost for Erbitux® is approximately £5,700
• Erbitux® + RT is associated with an incremental cost per QALY of approximately £6,870 compared to RT alone over the expected patient lifetime1
• Erbitux® + RT is estimated to cost: – £6,558 per extra life year1
– £5,688 per progression-free life year1
Reference:
1. Data on file, UKECRC05020.

41. INDUCTION CHEMOTHERAPY IN PORTSMOUTH
Until 2000 – Cisplatin + 5-FU (“waiting list chemo”)
Nov 1999, JCO, Colevas et al, phase 2 study, TPF (+ leucovorin) induction chemo in H+N Ca 93% RR (63%CR) but 1 toxic death (neutropenic sepsis) and generally toxic. Also needed g-csf and prophylactic antibiotics
Decided to use TPF but lower doses, omitting leucovorin, no g-csf or prophylactic antibiotics

42. DRUG DOSES (mg/m2) T P F
323 75
3750
324
100
4000
Boote 40 80
2800

43. PORTSMOUTH RESULTS Approximately 80 patients treated so far
Have audited results on first 43 patients
Average age 58 (range 44-81)
Male 79%, Female (21%)
Primary:- Tonsil 28%, Base tongue 23%, unknown 13%, Hypopharynx 10%, Larynx 8%, other 18%

44. PORTSMOUTH RESULTS (cont’d)
Stage:- nodes unknown primary 13%, stage II 5%, stage III 38%, stage IV 44%
Majority (70%) received 2 cycles (range 1-3)
39/43 underwent radical RT
2 underwent surgery followed by RT
1 underwent surgery alone
Overall response rate 85% (70% CR, 15%PR)
Average follow-up (first 43 pts) 18 months

45. PORTSMOUTH RESULTS (cont’d)
Of the CR’s 4 patients recurred at an average of 10 months (range 6-15 months)
3 of the PR’s have progressed at an average of 6 months after treatment. One of these PR’s underwent surgery and remains disease free,
All patients who progressed on treatment have died

46. CHEMOTHERAPY TOXICITY
No toxic deaths
No grade 4 toxicity
One grade 3 toxicity (neutropenia)
One grade 2 toxicity (vomiting)
Most patients grade 1 toxicity only
Most toxicity seen in PS2 patients

47. CHEMOTHERAPY TOXICITY (cont’d)
2 patients had impaired renal function after their first cycle and were changed to Carboplatin
1 myocardial infarction ? Treatment related
6 extravasations – no long term complications
1 episode of hypotension ? Cause
No increase in radiotherapy toxicity

48. ACTUAL CASE Mr D.K. age 56 Presented with lump in neck December 2000
Investigations showed carcinoma of base of tongue with bilateral neck nodes (stage T2, N2)
Given 3 courses TPF, well-tolerated (bursitis)
Complete response after chemo
Then had RT (66Gy/33/6½ weeks)
Last seen in clinic July 2006 – alive and well – discharged