Transcript CHEMORADIOTHERAPY IN HEAD AND NECK CANCER

CHEMORADIOTHERAPY IN
HEAD AND NECK CANCER
Dr David Boote
Consultant in Clinical Oncology
Portsmouth Oncology Centre
May 2007
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
MANAGEMENT OF THE
PRIMARY TUMOUR
• Most T3 and T4 tumours require
combinations of radiotherapy,
chemotherapy and surgery
• Chemoradiotherapy becoming more popular
for inoperable tumours
RADIOTHERAPY
a) Primary treatment – typical dose 66Gy in
33 fractions over 6½ weeks
b) Post-operative (adjuvant) – indications
include close or involved resection
margins, poorly differentiated tumours,
extensive lymph node involvement
c) Palliative e.g. bleeding, pain
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
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
TREATMENT OPTIONS IN
ADVANCED DISEASE
Surgery ± Radiotherapy ± Chemotherapy
CHEMOTHERAPY OPTIONS
IN HEAD AND NECK
CANCER
Can use chemo in 4 main ways:1.
2.
3.
4.
Neoadjuvant (Induction) chemotherapy
Concurrent (Concomitant) chemotherapy
Adjuvant (Post-op) chemotherapy
Palliative chemotherapy
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)
EFFECTS OF CHEMOTHERAPY ON
SURVIVAL
AT 5 YEARS:
FROM THE META-ANALYSIS
Trial
Category
All trials
Adjuvant
Induction
PF
Other Chemo
Concomitant
No. of
Trials
No.
Patients
65
8
31
15
16
26
10850
1854
5269
2487
2782
3727
Difference
(%)
P value
+4
+1
+2
+5
0
+8
<0.0001
0.74
0.10
0.01
0.91
<0.0001
ADVANTAGES INDUCTION
CHEMOTHERAPY
•
•
•
•
•
survival
organ preservation
distant mets
Prompt symptom relief
Use whilst waiting for RT
DISADVANTAGES INDUCTION
CHEMOTHERAPY
• Toxicity e.g. neutropenia
• Toxic deaths
• Delays (C)RT
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
ADVANTAGES/DISADVANTAGES
CONCURRENT CHEMOTHERAPY
Advantages
  survival
  local control
Disadvantages • Toxicity
•  RT mucositis
EORTC 24971/TAX 323 - Study Design
Induction CT + Locoregional RT
Neck
Dissection
Inoperable
SCCHN
Stage 3-4.
Stratification:
1º tumor site
Institution
TPF arm (n=177)
 Docetaxel (75 mg/m²)
 Cisplatin (75 mg/m²)
 5-FU (750 mg/m²/dx5)
Q 3 weeks x 4 cycles
Surgery for
Residual
Disease
Radiotherapy
(~70 Gy over
7 weeks)
Follow up
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 5516. Bernier J, et al. ASCO 2006, abstract 5522.
Vermorken JB, et al. ASCO 2004, abstract 5508.
EORTC 24971/TAX 323
Overall Survival
100
90
80
Median OS, mo
70
Hazard ratio (95% CI)
60
P-value
PF
TPF
14.2
18.6
0.71 (0.56, 0.90)
0.0055
50
40
30
Treatment
20
PF
TPF
10
0
0
6
12
18
24
30
36 42
(months)
48
54
60
66
72
Remenar E, et al. ASCO 2006, abstract 5516. Bernier J, et al. ASCO 2006, abstract 5522.
Vermorken JB, et al. ASCO 2004, abstract 5508.
EORTC 24971/TAX 323
Toxicity
NCIC-CTC Grade 3-4
Toxicity
Anemia/thrombocytopenia
Neutropenia
Nausea/vomiting
Diarrhea
Stomatitis
Infection
Febrile neutropenia
PF (n=179)
TPF (n=173)
patient percentage
patient percentage
13/18
53
7/4
3
11
6
3
9/3
77
<1/<1
3
5
7
5
Primary prophylactic antibiotics were given
per protocol for TPF
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
Results
End of Follow-up
(difference in least
square mean)
(difference in least
square mean)
Normal diet
TPF vs PF
+ 5.5
+ 16.8
0.0064
Speech
TPF vs PF
+ 3.7
+ 3.9
<0.0001
Public eating
TPF vs PF
+ 6.6
+ 17.3
0.0002
P-value
Bernier et al. ASCO 2006; Abstract 5522.
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
TAX 324 - Study Design
N=538
Stage III/IV
Epidermoid
carcinoma,
no prior surgery,
no hospitalization
for COPD 1y
Stratification:
• Center
• N status
• Primary site
Induction CT  CRT  Surgery
Primary Objective: OS
PF arm (n=246)
 Cisplatin (100 mg/m²/d1)
 5-FU (1000 mg/m²/d 5)
Q 3 weeks x 3 cycles
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
Radiotherapy
(70Gy d1-5)
+ Weekly
Carboplatin
(AUC 1.5 7)
Surgery
is
needed
Treatment arms were well balanced in baseline demographic
and disease characteristics
Posner RM, et al. ASCO 2006, abstract SPS24.
TAX 324 - Study Design
Primary Endpoint: Overall Survival
100
TPF significantly improved
overall survival vs PF
30% reduction in mortality
90
Survival Probability (%)
80
70
60
TPF (n=255)
50
PF (n=246)
40
2-Year OS
TPF 67%
PF 54%
30
20
3-Year OS
TPF 62%
PF 48%
Log-Rank p = .0058
Hazard ratio = 0.70
10
0
0
6
12
18
24
30
36
42
48
54
60
66
72 Survival Time (months)
Posner RM, et al. ASCO 2006, abstract SPS24.
TAX 324
Specific Safety During Chemotherapy
TPF
PF
(N=251)
(N=243)
Deaths due to toxicity
1%
2%
Neutropenia Grade 3/4
84%
56%
Febrile Neutropenia
Neutropenic Infection
12%
12%
7%
9%
Primary prophylactic antibiotics were given per protocol for TPF
Posner et al. ASCO 2006.
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
Phase III Trial PF ± Docetaxel  CRT vs CRT
Study Design
Primary endpoint phase III: TTF
PF
(N=340)
SCHNN
Stage III, IV
(locally advanced)
Unresectable
 3 cycles q 21 days
 Cisplatin
 Infusional 5-FU
TPF
CRT
 3 cycles q 21 days
 Docetaxel
 Cisplatin
 Infusional 5-FU
CRT
Hitt R, et al. ASCO 2006, abstract 5515.
Phase III Trial PF ± Docetaxel  CRT vs CRT
Patient Characteristics
No significant differences between treatments arms in baseline patient
characteristics
TPF
PF
CRT
57 (35-78)
58 (36-85)
55 (25-79)
Age, years
Median (range)
Gender, %
Men
93
92
89
PS (ECOG), %
0
8
13
8
1
92
87
92
Oropharynx
41
43
43
Hyppharynx
19
18
19
Larynx
19
17
18
Oral cavity
21
22
20
T4 N0
19
10
17
T4 N1
18
16
21
T4 N2
43
41
32
T4 N3
0
8
6
Anatomic site, %
Tumor grading, %
Hitt R, et al. ASCO 2006, abstract 5515.
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
TPF
1.000
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.
Phase III Trial PF ± Docetaxel  CRT vs CRT
Toxicity During Chemotherapy
Grade 3/4 Toxicity
Patient Percentage
TPF
PF
CRT
Leucocytes
9
11
11
Granulocytes
Platelets
Febrile neutropenia
Asthenia
Mucositis
Renal
Dermatitis
28
7
6
11
53
2
7
18
6
1
9
58
4
22
18
6
2
5
35
6
13
Hitt R, et al. ASCO 2006, abstract 5515.
GORTEC 2000-01 - Study Design
Induction CT  Larynx Preservation
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
PF arm
 Cisplatin (100 mg/m²)
 5-FU (1000 mg/m²/dx5)
Q 3 weeks x 3 cycles
No
Non-responders:
Total
(P)laryngectomy
+ post-op RT
Response
to
induction
treatment
Yes
Responders:
RT alone
Primary Objective: larynx preservation rate
Calais G, et al. ASCO 2006, abstract 5506.
GORTEC 2000-01
Patient and Disease Characteristics
TPF (n=110)
PF (n=103)
56.6 (38-75)
56.8 (32-75)
101/9
51
59
97/6
51
52
Hypopharynx
61
54
Larynx
49
49
Tumor grading, % T2
15
24
T3
80
63
T4
15
16
Age, years
Gender, %
PS (ECOG), %
Anatomic site, %
Median
(range)
Men/women
0
1
p=(0.14)
Pointreau Y, et al. Cancer/Radiotherapie. 2006:10:493, Abstract C03;
Calais G, et al. ASCO 2006, Abstract 5506.
GORTEC 2000-01
Larynx Preservation
1.00
0.90
Larynx preservation, %
0.80
0.70
TPF
0.60
PF
0.50
0.40
0.30
Median follow-up: 30 months
0.20
Larynx preservation rate higher
in TPF group p=0.036
0.10
0.00
0
6
12
18
24
30
36
Time from randomization
(months)
Pointreau Y, et al. Cancer/Radiotherapie. 2006:10:493, Abstract C03;
Calais G, et al. ASCO 2006, Abstract 5506.
GORTEC 2000-01
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
7.8
0.24
Thrombocytopenia
1.9
7.8
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.
GORTEC 2000-01
Relative to Other Studies of PF
Induction Followed by RT
Results with PF arm from GORTEC 2000-01 are consistent with
those observed in other studies
Study
5-Year LPR (N function)
Veteran (larynx)
39%
EORTC (hypopharynx)
35%
RTOG 91-11 (larynx)
43%*
GORTEC 2000-01
41.4% (3-year)
*Endpoint was 5-year laryngectomy-free survival
(45% in the concomitant group).
Calais G, et al. ASCO 2006, Abstract 5506.
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
EGFR is an important target for cancer therapy
•
EGFR over-expression is
associated
with a poor
3-7
prognosis
•
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. 6. Magne N et al. Eur J Cancer 2001;37(17):2169-2177.
2. Wells A. Int J Biochem Cell Biol 1999;31(6):637-643.
7. Hitt R et al. Eur J Cancer 2005;41(3):453-460.
3. Ang KK et al. Cancer Res 2002;62(24):7350-7356.
8. Baselga J et al. J Clin Oncol 2005;23(24):5568-5577.
4. Rubin Grandis J et al. J Nat Cancer Inst 1998;90:824-832.
9. Bonner JA et al. N Engl J Med 2006;354:567-578.
5. Maurizi M et al. Br J Cancer 1996;74:1253-1257.
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):2958-2970.
3. Arteaga CL. J Clin Oncol 2001;19(18 Suppl):32S-40S.
4. Huang SM et al. Clin Cancer Res 2000;6(6):2166-2174.
A new approach: Erbitux® + radiotherapy in locally
advanced SCCHN
RT
(n=213)
Erbitux® +
RT (n=211)
Karnofksy performance status: 60–80
90–100
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
148
62
Characteristics
Fractionation:
Reference:
1. Bonner JA et al. N Engl J Med 2006;354:567-578.
RT was administered as:
once-daily (26%), twice
daily (18%) or
concomitant boost (56%)
Erbitux® + radiotherapy significantly prolongs
locoregional control in SCCHN1
The addition of Erbitux®
to RT vs RT alone:
Reference:
1. Bonner JA et al. N Engl J Med 2006;354:567-578.
•
significantly prolongs the duration
of locoregional control by almost
10 months (24.4 months vs
14.9 months, p=0.005)1
•
resulted in a 32% reduction in the
risk of locoregional progression
(Hazard ratio = 0.68,
95% CI = 0.52-0.89)1
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
•
Reference:
1. Bonner JA et al. N Engl J Med 2006;354:567-578.
resulted in a 26% reduction in the
risk of death (Hazard ratio = 0.74,
95% CI = 0.57-0.97)1
Erbitux® does not significantly increase
radiotherapy-related side effects
Frequently observed* adverse events (grades 3–5)1
RT (%)
Erbitux®
+ RT (%)
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
5
4
0.64
Nausea
2
2
1.00
Constipation
5
5
1.00
Adverse event
Reference:
1. Bonner JA et al. N Engl J Med 2006;354:567-578.
p value‡
•
Erbitux® does not significantly
exacerbate typical radiotherapyassociated 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
Erbitux® in practice
•
No EGFR testing is required
•
An average patient treatment cost
for
Erbitux® is approximately £5,700
Reference:
1. Data on file, UKECRC05020.
•
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
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
DRUG DOSES
2
(mg/m )
323
324
Boote
T
75
75
40
P
75
100
80
F
3750
4000
2800
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%
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
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
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
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
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