Transcript Head and Neck Cancer MD Anderson Board Review Course, Oct

Statements on Head and Neck
Cancer 2006
Primary Radiochemotherapy
Arlene A. Forastiere, M.D.
Johns Hopkins University School of
Medicine
Department of Oncology
Concurrent Chemoradiotherapy as
Standard of Care Based on Phase III Trials
• Organ Preservation
– Larynx
– Oropharynx
Randomized Trials
INT R91-11
GORTEC
• Nasopharynx
Trials in US & Asia
• Unresectable disease
Trials in US & Europe
• Post-operative adjuvant
EORTC & US trials
Standard of Care Options to Preserve
the Larynx for locally advanced disease
• Conservation laryngeal surgery
• Concurrent RT and cisplatin 100 mg/m2 x 3
• RT alone
VA Laryngeal Cancer Study Group
Induction CF - RT versus Surgery + RT
NEJM 1991;324:1685-1690
• No difference in survival
• Larynx preserved in 64%;
2-year LFS rate 41%
• Pattern of failure (CT v S)
– local, 12% v 2%
– distant, 11% v 17%
• Risk factors for surgery
–T4 or N2-3
–56% of T4 eventually
required laryngectomy
INT R91-11 Trial to Preserve the Larynx
Forastiere AA. NEJM 349:2091, 2003
Cisplatin/5-FU*
x2
CR, PR
cisplatin/5-FU
NR
surgery
RT
RT
Radiotherapy + cisplatin 100 mg/m2 x 3
Radiotherapy
•
RT 70 Gy/7 wks, 2 Gy/fx
*cisplatin 100 mg/m2 day 1
5-FU 1000 mg/m2 CIVI days 1-5
Eligibility Criteria
• Resectable SCC of the glottis or supraglottis
requiring total laryngectomy
• Stage III or IV
T1 excluded
T4 excluded if tumor penetrated through
cartilage or invaded > 1cm into base of
tongue
• No distant metastases
Surgery
• Planned neck dissection
– N2 or N3 at initial staging
• Total laryngectomy
– Inadequate response (<PR) of primary to
induction chemotherapy
– Biopsy proven disease after completing RT
– Laryngeal dysfunction or necrosis
Patient Characteristics, in %
Induction Concurrent
RT
N=173
N=172
N=173
Supraglottis
68
66
72
T3
78
78
79
N0-1
72
73
68
Stage III
64
67
64
INT R91-11 Results: Larynx Preservation
Larynx preservation
Intergroup R91-11:
43% absolute
reduction in
laryngectomy rate
with RT/cisplatin
100
% PRESERVED
88%
75%
75
70%
50
Induction vs Concurrent p= 0.0047
Induction vs RT alone p= 0.27
Concurrent vs RT alone p= 0.00012
25
Induction
Conurrent
No difference in
survival
(76% at 2-years)
RT alone
0
0
1
2
3
4
YEARS FROM RANDOMIZATION
5
Local-regional control
100
% L/R CONTROL
78%
75
61%
50
56%
Induction vs Concurrent p =0.0031
Induction vs RT alone p= 0.16
Concurrent vs RT alone p= 0.00002
25
Induction
0
0
1
Concurrent
2
3
YEARS FROM RANDOMIZATION
RT alone
4
5
Induction
Concurrent
100
100
A L I V E & P R E S E R V E D
Disease-free
survival
75
61%
52%
50
44%
%
A L I V E (N E D)
RT alone
25
75
66%
59%
50
53%
25
I + RT vs CRT p= 0.49
I + RT vs RT p= 0.08
CRT vs RT p= 0.01
%
I + RT vs CRT p= 0.64
I + RT vs RT p= 0.017
CRT vs RT p= 0.0053
Laryngectomyfree survival
0
0
0
1
2
3
4
YEARS FROM RANDOMIZATION
5
0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0
YEARS FROM RANDOMIZATION
Response and compliance after two
cycles of induction chemotherapy
• CR 21%, PR 64%, total 85%
• 24 (15%) < PR
–29% had laryngectomy per protocol
–25% other chemo or unknown rx
– 46% had RT with/without third cycle of CT;
all achieved CR post XRT, one failed later
Results
Forastiere AA. N Eng J Med 349:2091, 2003
Weber RS. Arch Otolaryngol Head Neck Surg 129:44, 2003
• Chemotherapy suppressed metastasis
– Concurrent 8% vs RT 16%
• Chemotherapy added toxicity
– Gr 3-4 toxicity: chemotherapy 81%, 82% vs
RT 61%
• Laryngectomy was required in 25% of all
patients (16% chemorad, 28% induction, 32%
RT alone)
Function and QOL Assessments: no
difference in speech at 12 and 24 mos
Moderate impairment: unable to be understood on
the telephone or worse
Induction
Concurrent
RT alone
12 mos
6%
11%
13%
24 mos
3%
6%
8%
Swallowing function at 12 mos: delay in
recovery with concurrent treatment
Swallowing
function
Soft foods,
liquids only
Unable to
swallow
Induction
Concurrent
RT alone
9%
23%
15%
0
3%
3%
No differences between treatment groups at 24 mos
5-Year Update (ASCO 2006)
•
•
•
•
Confirms the 2-year analysis
Survival – no significant difference
Function excellent – no significant difference
Concurrent CRT is significantly better than RT
alone for all endpoints except OS
• Induction was not better than RT alone for
larynx preservation and LR control
• Concurrent CRT and induction were better
than RT alone for laryngectomy-free survival
and DFS
5-year Update
Analysis not yet complete
– Late effects
– Site of first failure
– Cause of death
Implications for Patient
Management
• For larynx preservation of T3 and low volume T4
disease, chemotherapy and RT should be given
concurrently
• For high volume T4 disease
– Glottic cancer or penetration through cartilage into
soft tissues: surgery
– Supraglottic cancer: option for concurrent
chemoradiotherapy
.
Implications for Patient
Management
• RT alone for patients unable to tolerate the
added toxicity of concurrent chemoradiotherapy
• No role for induction chemotherapy outside of a
clinical trial
Concepts in Development
Separate intermediate and advanced stages:
improved survival as primary endpoint
• RT (altered fx or std) + biologic
– Inhibitors of EGFR or angiogenesis
• Standard fx RT + cisplatin + biologic
• Induction followed by cisplatin/RT
Other Questions
• Alternative chemotherapy regimens
• Impact of changing epidemiology
(human papilloma virus) and prevalence
of oropharynx cancer
• Patient selection or therapeutic effect?
ECOG 2399: Schema
Primary endpoints: organ preservation rate, toxicity, assess utility of
organ function instruments
Median follow-up 33 months (11.8 months – 47 months)
TREATMENT DELIVERY (FEASIBILTY)
Larynx (36)
Oropharynx (69) Overall (105)
# Induction Cycles
unknown
1
2
0
0
36 (100%)
2 (4%)
3(4%)
64 (93%)
2 (3%)
3(3%)
100 (95%)
# Concurrent Cycles
unknown
0
4
5
6
7
0
5 (14%)
0
4 (11%)
6 (17%)
21 (58%)
3 (3%)
7 (10%)
7 (10%)
10 (15%)
86% 18 (26%)
24 (25%)
5, 6, or 7 cycles
3 (3%)
12 (12%)
7 (7%)
14 (13%)
24 (23%)
45 (43%)
83 (79%)
Radiation (≥66Gy)
31
59
90 (87%)
SURGICAL INTERVENTIONS
Larynx (n=36)
Oro (n=69) Overall (n=105)
Neck Dissection Only
11 (31%)
18 (26%)
29 (28%)
Primary Site Only
7 (19%)
6 (9%)
13 (13%)
Both
5 (14%)
6 (9%)
11 (11%)
Primary Overall
12 (33%)
12 (18%)
24 (23%)
0.8
p=0.06
0.4
0.6
80%
0.2
58%
Oropharynx
Larynx
0.0
Survival Probability
1.0
Overall Survival by Primary Site
0
10
20
30
Survival Time in Months
40
CONCLUSIONS
• Feasible regimen to deliver
• Surgical salvage rate for larynx cancer, 33%
suggests:
– that weekly paclitaxel concurrent with RT is not
effective for LR control
– Induction chemotherapy does not impact LR
control or allow for a less intense concurrent
chemoRT regimen
• DFS and OS results are excellent for OP
(probable impact of HPV?)
• ASCO update in 2006
R99-14: Concomitant Boost RT +
Concurrent Cisplatin
•
72 Gy/42 fx over 6 wks (daily for 3.5 wks then bid for
2.5 wks) + cisplatin 100 mg/m2 day 1 & 22
• 76 analyzable pts
– Median age 57 (range 40-76)
– Stage IV 88%; T3-4 64%, N2-3 78%
– Oral cavity
9 (12%)
– Oropharynx
50 (66%)
– Hypopharynx
8 (11%)
– Larynx
9 (12%)
Overall survival, disease-free survival and
relapse pattern
Ang, K. K. et al. J Clin Oncol; 23:3008-3015 2005
Copyright © American Society of Clinical Oncology
Cumulative incidence of all treatment-related late grade 3 to 5
and grade 4 to 5 toxicity
Late Toxicity
Ang, K. K. et al. J Clin Oncol; 23:3008-3015 2005
Copyright © American Society of Clinical Oncology
R97-03: Randomized Ph II
Concurrent Chemradiation
• RT – 70 Gy/35 fx
• Chemotherapy
– Arm 1: cisplatin 10 mg/m2 + 5-FU 400
mg/m2/d during last 10 days of RT
– Arm 2: hydroxyurea + 5-FU + RT every
other week (U. Chicago FHX)
– Arm 3: cisplatin 20 mg/m2 + paclitaxel 30
mg/m2 weekly
R97-03: Randomized Phase II
Concurrent Chemradiation
•
•
•
•
231 eligible pts randomized
Median age 56 (range 21-83)
T3-4 75%; N2-3 70%
Primary site
– Oral cavity
16%
– Oropharynx
67%
– Hypopharynx
17%
Time to locoregional failure
Estimated 2-yr
LR failure rate
41%
27.5%
Garden, A.S. J Clin Oncol 22:2856-2864, 2004
Copyright © American Society of Clinical Oncology
R97-03: Disease-free Survival
Estimated 2-yr DFS
51%
49%
38%
Garden, A.S. J Clin Oncol; 22:2856-2864, 2004
Copyright © American Society of Clinical Oncology
R97-03: Overall survival
2-yr rate
57%
69%
67%
( R91-14: 2-yr survival 72% )
Copyright © American Society of Clinical Oncology
Randomized trials needed
• RTOG H0129 Stage III/IV OC, OP, HP & Lx
Accelerated fx/concomitant boost + cisplatin x 2
versus
Standard fractionation + cisplatin x 3
• RTOG H0522 Stage III/IV OC, OP, HP & Lx
Accelerated fx/comcomitant boost + cisplatin
100 mg/m2 x 2 +/- cetuximab
E1303: Non-operative rx for resectable
patients (E2399 replacement)
Induction paclitaxel + carboplatin + C225 (PCC)
concurrent PCC + RT 70 Gy
 Response assessment after induction and 50
Gy, surgery if < pCR after 50 Gy
 Endpoints: 90% disease-free at completion of
treatment
Phase II trial of C225 with RT and
cisplatin in unresectable patients
• E3303: RT 70 Gy + C225 weekly + cisplatin 75
mg/m² days 1, 22 & 43
CR, PR, SD continue C225 for 6 mos
• Rationale: INT E1392 – improved 3-yr survival with
RT/CDDP ( 37% vs 23%)
• Endpoints: PFS and survival, toxicity, molecular
correlates
• Accrual: 68 pts to increase 2-yr PFS (35% to 50%)
Chemoradiotherapy
• Mixed site trials are useful for hypothesis
generation and feasibility testing
• Efficacy for local-regional control may differ
by primary site mandating site-specific trials
– e.g. HPV related oropharynx cancer
• Alternative concurrent chemotherapy
regimens to cisplatin 100 mg/m2 or PF should
not be assumed to have equivalent efficacy