Transcript NEW PARADIGMS TO IMPROVE OUTCOMES IN HEAD AND …

New Paradigms to Improve Outcomes in
Head and Neck Cancer
The Evolving Roles of Induction Chemotherapy,
Chemoradiotherapy, and Sequential Therapy
Marshall R. Posner, MD
Dana-Farber Cancer Institute
Case 1: T3N1 Supraglottic Tumor
No Significant Co-Morbidities
• Patient is a 56 year old male
– Presents with hoarseness, left ear pain, 3 months duration,
treated with antibiotics for 1 month
•
•
•
•
•
40 pack-year smoking history, quit 3 years ago
Wine on weekends
Bank mortgage officer
MI with stent 3 years ago
Mild hypertension well controlled
– Exam shows tumor of the left supraglottic larynx, paralyzed left
vocal cord, 2.5 cm left level 2 lymph node T3N1, stage III
Case 1: T3N1 Supraglottic Tumor
No Significant Co-Morbidities
•
This patient has resectable stage III larynx cancer, good
performance status, and minimal co-morbidities
•
Which treatment option would you recommend?
1. Total laryngectomy
2. Organ preservation – chemoradiotherapy
3. Organ preservation – induction chemotherapy followed by
radiotherapy
4. Organ preservation – sequential therapy: induction chemotherapy
followed by chemoradiotherapy
Estimated 5-year survival is 50%-60%
Case 1 B
Alternative Patients with the Same Tumor
• The patient has the same presentation, but now has a
heavy, active alcohol and smoking history with cirrhosis
and minimal ascites
– In this circumstance laryngectomy would be favored because of
the underlying risk of severe toxicity from chemotherapy
• The patient is 85 years old with moderate congestive
heart failure and hypertension and is on diuretics
Case 1 B
Alternative Patients with the Same Tumor
•
The patient is 85 years old with moderate congestive
heart failure and hypertension and is on diuretics
•
Which treatment option would you recommend?
1.
2.
3.
4.
5.
Cetuximab plus radiotherapy
Concurrent carboplatin
Carboplatin plus cetuximab
Carboplatin plus paclitaxel plus cetuximab
Other
Case 2: T3N2b Tumor of the Oropharynx
No Significant Co-Morbidities
• Patient is a 52 year old male
– Presents with a painless right neck mass of 4 months duration
• 5 pack-year smoking history, quit 30 years ago
• Wine on weekends
• A malpractice litigation lawyer
– Exam shows tumor of the right base of tongue and a 5 cm right,
cystic level 2 mass of lymph nodes
• T3 n2b - stage IVA
• The tumor abuts the midline of the tongue base and is not adjacent to
the larynx
• It is resectable with a total glossectomy and might be resectable with
a partial glossectomy
Case 2: T3N2b Tumor of the Oropharynx
No Significant Co-Morbidities
• This patient has marginally resectable stage IV
oropharynx cancer, good performance status, and
minimal co-morbidities
• Which treatment option would you recommend?
1. Total or partial glossectomy (indeterminate until surgery is
performed)
2. Organ preservation – chemoradiotherapy
3. Organ preservation – induction chemotherapy followed by
radiotherapy
4. Organ preservation – sequential therapy: induction chemotherapy
followed by chemoradiotherapy
Estimated 5-year survival is 35%-50% with standard surgery and radiotherapy
Case 3: T3N3 Tumor of the Hypopharynx
No Significant Co-Morbidities
• Patient is a 63 year old male
– Presents with hoarseness, left ear pain and a left neck mass for 2
months
•
•
•
•
65 pack-year smoking history, quit 3 months ago
Wine on weekends
Retired malpractice attorney
Hypertension, mild COPD
– Exam shows tumor of the left pyriform sinus with extension into
the larynx, a paralyzed left vocal chord, and a 7.5 cm right, cystic
level 2 mass of lymph nodes fixed to the neck
• T3N3, stage IVB
• On CT imaging the tumor surrounds the internal carotid
• It is unresectable
Case 3: T3N3 Tumor of the Hypopharynx
No Significant Co-Morbidities
• This patient has unresectable stage IVB hypopharynx
cancer, good performance status, and minimal comorbidities
– Surgery is not an option
– Estimated 5 year survival is 20%-30% with radiotherapy and there
is a high rate of distant metastases
Case 3: T3N3 Tumor of the Hypopharynx
No Significant Co-Morbidities
•
This patient has unresectable stage IVB hypopharynx
cancer, good performance status, and minimal comorbidities
•
Which treatment option would you recommend?
1. Chemoradiotherapy
2. Induction chemotherapy, followed by radiotherapy
3. Sequential therapy: induction chemotherapy followed by
chemoradiotherapy
New Paradigms to Improve Outcomes in
Head and Neck Cancer
The Evolving Roles of Induction Chemotherapy,
Chemoradiotherapy, and Sequential Therapy
Marshall R. Posner, MD
Dana-Farber Cancer Institute
Effects of Chemotherapy on Survival at 5 Years
From the Meta-Analysis
Trial Category
No. of Trials
No. Patients
Difference (%)
P value
All trials
65
10,850
+4
<0.0001
Adjuvant
8
1854
+1
0.74
Induction
31
5269
+2
0.10
PF
15
2487
+5
0.01
Other Chemo
16
2782
0
0.91
Concomitant
26
3727
+8
<0.0001
Monnerat, et al. Annals of Oncology, 13: 995-1006, 2002
PF Induction Chemotherapy is Effective for
Improving Survival and Organ Preservation for
Locally Advanced SCCHN
• Meta – Analysis
– 2000, 2004, 2005
• Phase III Trials – Survival
– Studio Trial 1994, 2004
– GETTEC Oropharynx Trial 2000
• Phase III Trials – Organ Preservation
– VA Larynx Trial 1991
– EORTC Hypopharynx Trial 1994, 2004
– Intergroup 91-11 Trial 2003, 2006
Overall Survival
GETTEC
100
Percent
80
60
40
20
0
Patients at risk
0
1
2
3
4
5
6
7
8
48
59
28
33
16
19
7
7
Years
No chemotherapy
Chemotherapy
161
157
137
138
101
105
65
86
Domenge C, et al. Br J Cancer. 2000;83:1594-1598.
Calais Chemoradiotherapy Regimen
Carboplatin
70 mg/m2 /day x 4 days
5-FU 600 mg/m2/days
x 4 days
QD Radiotherapy
200 cGy/ Fx
Weeks
0
1
2
3
4
5
6
7
J Natl Cancer Inst. 1999;91:2081-2086.
Calais Chemoradiotherapy Study
5-Year Survival
100
CRT
80

Survival (%)
XRT
60
Conclusions:
 Borderline statistically
significant (P = .05) better
overall survival with CRT
(22% vs 16%)
40
 Absolute 6% improvement
 Better LRC (48% vs 25%),
20
No change in DM (20%)
 CRT is better then XRT
alone for oropharynx
cancer
0
0
6
12 18 24 30 36 42 48 54 60 66 72
Months
Denis, F et al. JCO. 2004.
RTOG 91-11
Phase III Trial of Larynx Preservation
547 pts
Stage III/IV
glottic,
supraglottic
intermed.
stage
R
A
N
D
O
M
I
Z
E
± Surgery
A XRT
P
B
XRT
C
P
F
XRT
± Surgery
Surgery
Forastiere, NEJM, 2003
Forastiere AA, et al. ASCO 2006. Abstract 5517
RTOG 91-11:Phase III Trial of Larynx
Preservation: 5-Year Update
PF
CRT
XRT
LFS
44.6%
46.6%
33.9%
P < .011
LRC
54.9%*
68.8%*
51%
P < .0018
DM
14.3%
13.2%
22.3%
DFS
38.6%*
39%
27.3%*
Survival
59.2%
54.6%
53.5%
1.
2.
PF was equivalent to CRT for LFS
CRT had better LRC than PF
3.
4.
DFS was identical but overall survival favored PF
Did patients fare better with PF because they had
subtle improvements in function
P < .0016
Forastiere AA, et al. ASCO 2006. Abstract 5517
Induction Chemotherapy
• Pros
• Cons
– High dose treatment, systemic
exposure, transient toxicity
– Improved nutrition and PS
– Reduced tumor volume
• Better preparation for definitive
radiotherapy and IMRT planning
• Improved function
– Established efficacy in resectable
disease and organ preservation
– Improved survival
– Intermediate assessment of
response/prognosis
• Adjusted intensity of postinduction therapy
– Systemic toxicity increased
– Survival improvement may be
site and stage related
– Increased duration of therapy,
change in tumor biology
– No improvement in
local/regional dose intensity
– Cisplatin-based PF was the
only effective chemotherapy
regimen
Chemoradiotherapy
• Pros
– Improved local regional
intensity
– Shortened treatment time
– Efficacy in unresectable
disease
– Efficacy in organ preservation
– Effective post-operative
therapy
• Cons
– Local toxicity increased
• Long-term toxicity not defined
• Esophageal stenosis,
swallowing impaired
• Mortality from unrecognized
toxicity
– Increased systemic toxicity
– Induction of systemic
chemotherapy resistance
– No acceptable standard
– Assessment of
response/prognosis
compromised
– No effect on distant
metastases in advanced
disease
– IMRT planning difficult
TPF Induction Chemotherapy has Proven
Superior to PF in Multiple Phase III Trials
• Organ Preservation
– GORTEC Hypopharynx and Larynx Trial , 2006
• Locally Advanced Resectable and Unresectable
– TAX 324 (2006)
• Unresectable Disease
– TAX 323 (2004, 2006)
GORTEC:2000-01: A Phase III Trial of TPF vs PF
Followed by Radiotherapy for Organ Preservation in
Resectable Larynx and Hypopharynx Cancer
R
A
N
D
O
M
I
Z
E
T
P
F
Surgery
No Response
Response
P
F
Daily Radiotherapy:
STD or ACB
TPF: Docetaxel 75D1 + Cisplatin 75D1 + 5-FU 750CI- D1-5 Q 3 weeks x4
PF: Cisplatin 100D1 + 5-FU 1000CI-D1-5 Q 3 weeks x 3
Calais G, et al. ASCO 2006. Abstract 5506
GORTEC Phase III Larynx Preservation Trial Comparing
TPF and PF Induction Therapy for Hypopharynx and
Larynx Cancer
• Increase in Larynx Preservation with TPF vs PF
– Larynx preservation observed in 80% and 58% of patients following TPF
and PF treatment, respectively (NR)
– Overall survival trend favors TPF over PF (P = .096)
TPF (%) PF (%) P Value
Larynx preserved
(current rate)
63.2
41.4
.036
Response
• CR
• PR
82.8
43.4
39.4
60.8
30.4
30.4
.0013
Calais G, et al. ASCO 2006. Abstract 5506
GORTEC Phase III Larynx Preservation Trial Comparing
TPF and PF Induction Therapy for Hypopharynx and
Larynx Cancer
100
Percent (%)
80
60
P (Log-rank test) = 0.036
40
Induction TPF (n=108)
Induction PF (n=112)
20
0
0
6
12
18
24
30
36
42
Larynx Preservation (Months)
Calais et al. ASCO, 2006. Oral Presentation.
TAX 323: TPF vs PF Followed by Radiotherapy
A Phase III Study in Unresectable SCCHN
R
A
N
D
O
M
I
Z
E
T
P
F
EUA
P
Surgery
Daily Radiotherapy
F
TPF: Docetaxel 75D1 + Cisplatin 75D1 + 5-FU 750CI- D1-5 Q 3 weeks x4
PF: Cisplatin 100D1 + 5-FU 1000CI-D1-5 Q 3 weeks x 4
Vermoken, ASCO, 2004
TAX 323: Survival Update
100
Survival Probability (%)
90
80
Log-Rank P = 0.0052
Hazard Ratio = 0.71
70
60
50
40
30
20
TPF (n=177)
PF (n=181)
10
0
0
6
12
18
24
30
36
42
48
54
60
66
16
15
7
8
4
72
Survival Time (months)
Patients at Risk
TPF: 177
PF: 181
163
150
127
98
91
77
74
57
64
47
60
39
43
33
26
25
Remenar, ASCO, 2006
TAX 323: Severe Adverse Events
Chemotherapy
Toxicity
> 3% of pts
Alopecia
Stomatitis / oral
Infection
Nausea
Vomiting
Diarrhea
Dyspnea
Dysphagia
Pain
Death
PF (n=179)
N (%)
0
20 (11.2)
13 (7.3)
13 (7.3)
9 (5.0)
8 (4.5)
8 (4.5)
5 (2.8)
7 (3.9)
12 (6.6)
TPF (n=174)
N (%)
20 (11.5)
8 (4.6)
15 (8.6)
1 (0.6)
1 (0.6)
5 (2.9)
6 (3.4)
6 (3.4)
11 (6.3)
6 (3.4)
Vermoken, ASCO, 2004
An Analysis of Failure in Phase II
TPF Induction Trials*
Three Cycles of Induction Therapy Followed by BID Radiotherapy
Trials:
TPF, TPFL5, TPFL4, op-TPFL
Entered:
84*
Local/Regional Failure:
26 (31%)
Local/Regional and DM
5 (6%)
DM only
0
*Excludes 17 Patients with NPC
Haddad, Cancer, 2003
An Analysis of Failure in Phase III
Chemoradiotherapy Trials*
Trials:
LRF
DM
DM % of Failure
INT
22%
23%
51%
EORTC
18%
21%
54%
RTOG
16%
20%
65%
GORTEC
57%
18%
32%
The Rate of DM Was Not Reduced by CRT
*Excludes Larynx Trial 91-11
Adelstein, JCO, 2003
Bernier, NEJM, 2005
Cooper, NEJM, 2005
Denis, JCO, 2005
Induction Chemotherapy and Chemoradiotherapy
in Locally Advanced SCCHN
• PF induction chemotherapy results in a significant 5%
(P <.01) improvement in 5-year survival in meta-analysis
(Monnerat, annals of oncology, 2002)
– PF was the only induction regimen that was effective, TPF is
better
– After induction chemotherapy and radiotherapy, failure is
frequently local/regional (Haddad, cancer, 2003)
• CRT results in a significant 8% (P <.0001) improvement in
5 year survival in meta-analysis (Monnerat, Annals of Oncology, 2002)
– There is less local/regional failure, but relatively more distant
metastases (Adelstein, JCO, 2003; Bernier, NEJM, 2005; Cooper, NEJM, 2005;
Denis, JCO, 2005)
Sequential Therapy
for Head and Neck Cancer
Induction Chemotherapy
Chemoradiotherapy
Surgery
Sequential Therapy for Head and Neck Cancer
• Induction chemotherapy
– High response rates, organ preservation, improved survival,
systemic treatment
– Reduced tumor volume, better IMRT planning, improved
functional outcome
– An intermediate assessment of response
• Chemoradiotherapy
– Increased local/regional dose intensity
– Adjustment based on response to induction therapy, potential
toxicity, prognostic factors, and/or planned surgery
• Surgery
– Remove areas of initial bulk disease
– Preserve primary site
A Cell Kinetic Model for Response and Survival:
The Argument for Timing in Combined Modality Therapy
Treatment A Survival
Treatment B Survival
Chemotherapy
Death
AB
Tumor Cell Number
1012
1011
1010
109
108
107
106
Critical Time Frame
Time
Takimoto & Rowinsky, JCO, 2003
Sequential Combined Modality Therapy
A Phase III Study: TAX 324
TPF vs PF Followed by Chemoradiotherapy
R
A
N
D
O
M
I
Z
E
T
Carboplatin - AUC 1.5
Weekly
P
F
EUA
P
Surgery
Daily Radiotherapy
F
TPF: Docetaxel 75D1 + Cisplatin 100D1 + 5-FU 1000CI- D1-4 Q 3 weeks x3
PF: Cisplatin 100D1 + 5-FU 1000CI-D1-5 Q 3 weeks x 3
TAX 324: Analysis Populations
TPF
PF
ALL
All Randomized
280
259
539
INTENT TO TREAT Population*
255
246
501
251
(98%)
243
(99%)
494
(98.6%)
TPF
( n=251)
PF
(n=243)
ALL
(n=494)
251
(100%)
243
(100%)
494
(100%)
Receiving Chemoradiotherapy per Protocol
202
(81%)
184
(76%)
386
(78%)
Not Receiving Chemoradiotherapy per Protocol
49
(19%)
59
(24%)
108
(22%)
Treated With Chemotherapy
SAFETY Population
Chemotherapy Treated
* ITT excludes 37 patients erroneously randomized and 1 patient with GCP compliance issue
TAX 324: Patients Characteristics (ITT)
Age (years):
Gender
PS (WHO)
Median (Range)
 65 years
Male
0
1
Anatomic site
Oropharynx
Larynx
Hypopharynx
Oral cavity
Clinical Stage
III
IV
Reason Inoperable
Technical Unresectability
Low Surgical Curability
Organ Preservation
TPF (n=255)
55 (38 to 82)
34 (13%)
PF (n=246)
56 (33 to 80)
36 (15%)
215 (84%)
204 (83%)
142 (56%)
113 (44%)
132 (52%)
48 (19%)
42 (17%)
33 (13%)
41 (16%)
214 (84%)
126 (51%)
117 (48%)
131 (53%)
42 (17%)
34 (14%)
38 (15%)
46 (18%)
199 (81%)
92 (36%)
78 (31%)
85 (33%)
84 (34%)
75 (31%)
87 (35%)
TAX 324: Survival
Intent to Treat Population
TPF (n=255)
PF (n=246)
Median Survival (Mo)
70.6 +
30.1
95% CI
49 – NR
20.9 – 51.5
Died *
41%
53%
80% [ 75.0 – 84.9]
67% [61.5 – 73.2]
69% [64.1 – 75.7]
54% [48.2 – 60.8]
62% [55.9 – 68.2]
48% [41.7 – 54.5]
Kaplan-Meir Survival
1–Year
2–Year
3–Year
Hazard Ratio TPF:PF
[95% CI]
Log-Rank P Value
0.70 [0.54 - 0.90]
0.0058
*Cut-off: December 3, 2005; The median follow-up is 42 months
TAX 324: Survival
100
90
Survival Probability (%)
80
Log-Rank P = 0.0058
Hazard Ratio = 0.70
70
60
50
40
TPF 67%
PF 54%
30
TPF 62%
PF 48%
20
TPF (n=255)
10
PF (n=246)
0
0
6
12
18
Number of patients at risk
TPF: 255 234 196 176
PF: 246 223 169 146
24 30 36 42 48
Survival Time (months)
54
60
66
72
163
130
45
32
37
28
20
10
11
7
136
107
105
85
72
57
52
36
1
TAX 324 : Progression-Free Survival
Progression Free Survival Probability (%)
100
90
80
Log-Rank P = 0.004
Hazard Ratio = 0.71
70
60
50
40
30
TPF 49%
TPF 53%
PF 42%
20
10
TPF (n=255)
0
PF (n=246)
0
6
12
PF 37%
18 24 30 36 42 48 54 60
Progression-Free Survival Time (months)
Number of patients at risk
TPF: 255 198 150 135
PF: 246 183 125 104
121
92
100
72
73
57
50
38
39
30
35
25
26
14
66
72
16
8
5
2
TAX 324: Toxicity During Chemotherapy
TPF
(n=251)
PF
(n=243)
Grade 3/4
Grade 3/4
Any Event
65%
62%
Stomatitis
Nausea
Lethargy
Vomiting
Diarrhea
Anorexia
21%
14%
5%
8%
7%
12%
27%
14%
10%
10%
3%
12%
Number of Patients
NCIC-CTG Classification
TAX 324: Specific Safety During Chemotherapy
TPF
(n=251)
PF
(n=243)
Neutropenia Grade 3/4
84%
56%
Febrile Neutropenia
12%
7%
Neutropenic Infection
12%
9%
Primary Prophylactic Antibiotics Were Given Per Protocol for TPF
TAX 324: Delays During Induction Chemotherapy
TPF
(n=251)
PF
(n=243)
All
(n=494)
73 (29%)
157 (65%)
230 (47%)
Hematologic
11 (4%)
108 (44%)
119 (24%)
Neutropenia
2 (1%)
95 (39%)
97 (20%)
Non-Hematologic
25 (10%)
22 (9.1%)
47 (10%)
Other**
38 (15%)
40 (17%)
78 (16%)
Treatment Delays
** Logistic, Personal, Vacation
TAX 324: Exposure to Induction Chemotherapy
TPF
(n=251)
PF
(n=243)
3
3
Median Cycles
Cumulative Dose
(mg/m2)
Relative Median
Dose Intensity
T
P*
F
P*
F
224
299
11944
299
14760
.98
.99
.98
.90
.88
*6 Patients in each Arm received carboplatin to replace cisplatin
TAX 324: Toxicity During Chemoradiotherapy
NCIC-CTG
TPF
(n=203)
Grade 3/4
PF
(n=184)
Grade 3/4
Any Event
65%
66%
Stomatitis
37%
38%
Dysphagia
23%
24%
Mouth/Nose Dryness
5%
4%
Nausea
6%
6%
Rash/itch
5%
2%
Number of Patients
TAX 324: Exposure to Study Treatment
Chemoradiotherapy (CRT)
TPF
(n=202)
70
PF
(n=184)
70
Median Dose Carboplatinum (AUC)
9.9
9.9
Median Duration CRT (Wks)
7.1
7.1
Median Dose Radiotherapy (Gy)
Chemoradiotherapy toxicity was not enhanced
by prior doxetaxel in TPF
TAX 324: Analysis of Failure
TPF (n=251)
PF (n=243)
All (n=494)
88 (35%)
110 (45%)
198 (40%)
77 (31%)
93 (38%)
170 (34%)
Primary
43 (17%)
49 (20%)
92 (19%)
Neck
22 (9%)
33 (14%)
55 (11%)
Both
12 (5%)
11 (5%)
23 (5%)
14 (6%)
21 (9%)
35 (7%)
11 (4%)
17 (7%)
28 (6%)
3 (1%)
4 (2%)
7 (1%)
9 (4%)
7 (3%)
16 (3%)
Total Failures/Treated
LRF*
Distant Metastases**
Distant Only
Distant and LRF
Second Primaries
*Hazard Ratio 0.73 (0.54-0.99), P = .03
**Hazard Ratio 0.60 (0.30-1.18), P = .18
TAX 324: Conclusions
• TPF significantly improves survival compared to PF
– There is a 14% absolute improvement in 3-year survival and a
30% reduction in mortality (P = 0.0058) for TPF
– 62% of TPF patients are alive at 3-years
• TPF significantly reduced local regional failure compared
to PF
– Local regional failure was reduced by 27% (P= .03)
– Distant metastases were reduced 30% compared to PF (P = .18)
• TPF was less toxic than PF
– There were fewer treatment delays with TPF (30% vs 65%)
– More of planned TPF was delivered than PF
TAX 324: Conclusions
• Sequential therapy with TPF is tolerable and safe
– The toxicity of TPF is less than that of PF
– The toxicity of chemoradiotherapy after induction chemotherapy
was acceptable and within expected range
– The toxicity of chemoradiotherapy was the same with TPF or PF
• Sequential therapy with TPF followed by carboplatinbased chemoradiotherapy represents a new, acceptable
standard of care for locally advanced SCCHN
– Sequential therapy makes biological sense and is effective
– Ongoing Phase III trials will determine how TPF-based sequential
therapy compares to chemoradiotherapy
Docetaxel plus PF (TPF) and SCCHN
• TPF is the most effective combination regimen for
induction chemotherapy*
– TPF regimens engender less toxicity and improved survival in
locally advanced SCCHN compared to PF
• TPF is now the standard of care for induction
chemotherapy
• TPF is an appropriate platform for curative therapy to
which new molecularly targeted therapies should be
added
*Remenar, 2006, Posner, 2006, Calais, 2006
Sequential Therapy
for Head & Neck Cancer
• Induction chemotherapy
– High response rates, organ preservation, improved survival, systemic
treatment
– Reduced tumor volume, better function
– An intermediate assessment of response
• Chemoradiotherapy
– Increased local/regional dose intensity
– Adjustment based on response to induction therapy/ potential
toxicity/prognostic factors/planned surgery
– Can chemoradiotherapy rescue non-responders to induction chemotherapy?
• Surgery
– Remove areas of initial bulk disease
– Preserve primary site
The Paradigm Study
Sequential Therapy vs Chemoradiotherapy
A Phase III Study of TPF/C-XRT vs P-ACBXRT
T*
R
A
N
D
O
M
I
Z
E
T
P
ACB
3 Cycles of
NR
Chemotherapy
Surgery
F
C
PR,C
R
Daily Radiotherapy
P
Q 3 Weeks
Surgery
XRT
ACB Radiotherapy
*T + ACB for Non-Responders
SWOG Phase III Oropharynx Trial: S0427
R
A
N
D
O
M
I
Z
E
T
<50% Response
Surgery
P
P
F
Q 3 Weeks
Surgery
>50% Response
2 Cycles
Daily Radiotherapy
P
Q 3 Weeks
Surgery
XRT
Daily Radiotherapy
* Cisplatinum (P); Docetaxel (D); 5-Fuorouracil (F)
Italia Phase II/III TPF vs CRT Trial
R
A
N
D
O
M
I
Z
E
T
P
F
P
F
Daily Radiotherapy
P
F
CRT
Daily Radiotherapy
TPF: Docetaxel 75D1 + Cisplatin 80D1 + 5-FU 800CI- D1-4 Q 3 weeks x3
CRT PF: Cisplatin 20D1-4 + 5-FU 800CI-D1-4 Weeks 1,6
Pacagnella, ASCO, 2006
Case 1: T3N1 Supraglottic Tumor
No Significant Co-Morbidities
• Patient is a 56 year old male
– Presents with hoarseness, left ear pain, 3 months duration,
treated with antibiotics for 1 month
•
•
•
•
•
40 pack-year smoking history, quit 3 years ago
Wine on weekends
Bank mortgage officer
MI with stent 3 years ago
Mild hypertension well controlled
– Exam shows tumor of the left supraglottic larynx, paralyzed left
vocal cord, 2.5 cm left level 2 lymph node T3N1, stage III
Case 1: T3N1 Supraglottic Tumor
No Significant Co-Morbidities
•
This patient has resectable stage III larynx cancer, good
performance status, and minimal co-morbidities
•
Which treatment option would you recommend?
1. Total laryngectomy
2. Organ preservation – chemoradiotherapy
3. Organ preservation – induction chemotherapy followed by
radiotherapy
4. Organ preservation – sequential therapy: induction chemotherapy
followed by chemoradiotherapy
Estimated 5-year survival is 50%-60%
Case 1: T3N1 Supraglottic Tumor
No Significant Co-Morbidities
• Total laryngectomy is an option
– Other options offer organ preservation with equivalent or better survival
• Bolus cisplatin-based CRT and PF-based induction chemotherapy are
equivalent in terms of laryngectomy free survival
– Both are better than radiotherapy alone
– There is a suggestion that PF-based induction chemotherapy may
improve survival compared to chemoradiotherapy
• TPF-based induction chemotherapy is better for organ preservation
then PF-based induction chemotherapy
• TPF engenders less toxicity than PF
• Better planning for IMRT after induction therapy
Case 1 B
Alternative Patients with the Same Tumor
• The patient has the same presentation, but now has a
heavy, active alcohol and smoking history with cirrhosis
and minimal ascites
– In this circumstance laryngectomy would be favored because of
the underlying risk of severe toxicity from chemotherapy
• The patient is 85 years old with moderate congestive
heart failure and hypertension and is on diuretics
Case 1 B
Alternative Patients with the Same Tumor
•
The patient is 85 years old with moderate congestive
heart failure and hypertension and is on diuretics
•
Which treatment option would you recommend?
1.
2.
3.
4.
5.
Cetuximab plus radiotherapy
Concurrent carboplatin
Carboplatin plus cetuximab
Carboplatin plus paclitaxel plus cetuximab
Other
Case 1 B
Alternative Patients with the Same Tumor
• The patient is 85 years old with moderate congestive
heart failure and hypertension and is on diuretics
– Cetuximab plus radiotherapy would be a reasonable choice here
– Concurrent carboplatin is untested and while less toxic than
cisplatin, is not a standard therapy as sole treatment
– Carboplatin plus cetuximab is untested as a primary therapy
– Carboplatin plus paclitaxel plus cetuximab would be too toxic for
this fragile elderly man at risk for aspiration pneumonia
Case 2: T3N2b Tumor of the Oropharynx
No Significant Co-Morbidities
• Patient is a 52 year old male
– Presents with a painless right neck mass of 4 months duration
• 5 pack-year smoking history, quit 30 years ago
• Wine on weekends
• A malpractice litigation lawyer
– Exam shows tumor of the right base of tongue and a 5 cm right,
cystic level 2 mass of lymph nodes
• T3 n2b - stage IVA
• The tumor abuts the midline of the tongue base and is not adjacent to
the larynx
• It is resectable with a total glossectomy and might be resectable with
a partial glossectomy
Case 2: T3N2b Tumor of the Oropharynx
No Significant Co-Morbidities
• This patient has marginally resectable stage IV
oropharynx cancer, good performance status, and
minimal co-morbidities
• Which treatment option would you recommend?
1. Total or partial glossectomy (indeterminate until surgery is
performed)
2. Organ preservation – chemoradiotherapy
3. Organ preservation – induction chemotherapy followed by
radiotherapy
4. Organ preservation – sequential therapy: induction chemotherapy
followed by chemoradiotherapy
Estimated 5-year survival is 35%-50% with standard surgery and radiotherapy
Case 2: T3N2b Tumor of the Oropharynx
No Significant Co-Morbidities
• Total or partial glossectomy is an option but the other 3 options offer
organ preservation and better survival
– Functional organ preservation is an important goal in this setting
• Bolus cisplatin-based chemoradiotherapy has been the standard of
care, carboplatin/5-FU chemoradiotherapy is a standard in Europe and
PF-based induction chemotherapy has been used effectively
– With PF-based induction chemotherapy or chemoradiotherapy 5-year
survival is 20%-50%
• TPF is reasonable treatment for this patient
– Sequential therapy with TPF followed by carboplatin-based
chemoradiotherapy was also better than PF and has a 60% 3-year survival
– Induction chemotherapy with TPF followed by radiotherapy alone improved
survival in unresectable patients compared to PF and was associated with
a significantly improved quality of life
Case 3: T3N3 Tumor of the Hypopharynx
No Significant Co-Morbidities
• Patient is a 63 year old male
– Presents with hoarseness, left ear pain and a left neck mass for 2
months
•
•
•
•
65 pack-year smoking history, quit 3 months ago
Wine on weekends
Retired malpractice attorney
Hypertension, mild COPD
– Exam shows tumor of the left pyriform sinus with extension into
the larynx, a paralyzed left vocal chord, and a 7.5 cm right, cystic
level 2 mass of lymph nodes fixed to the neck
• T3N3, stage IVB
• On CT imaging the tumor surrounds the internal carotid
• It is unresectable
Case 3: T3N3 Tumor of the Hypopharynx
No Significant Co-Morbidities
• This patient has unresectable stage IVB hypopharynx
cancer, good performance status, and minimal comorbidities
– Surgery is not an option
– Estimated 5 year survival is 20%-30% with radiotherapy and there
is a high rate of distant metastases
Case 3: T3N3 Tumor of the Hypopharynx
No Significant Co-Morbidities
•
This patient has unresectable stage IVB hypopharynx
cancer, good performance status, and minimal comorbidities
•
Which treatment option would you recommend?
1. Chemoradiotherapy
2. Induction chemotherapy, followed by radiotherapy
3. Sequential therapy: induction chemotherapy followed by
chemoradiotherapy
Case 3: T3N3 Tumor of the Hypopharynx
No Significant Co-Morbidities
• Chemoradiotherapy
– Bolus cisplatin or carboplatin and 5-FU have been found to improve
survival in unresectable SCCHN
• Induction chemotherapy, followed by radiotherapy
– Several studies have shown improved survival in unresectable tumors
when PF is given followed by radiotherapy
– TPF has been shown to be more active than PF and result in a better
quality of life
• Sequential therapy
– TPF followed by chemoradiotherapy has resulted in improved survival
compared to PF and chemoradiotherapy.
– Sequential therapy and chemoradiotherapy have not been compared in
Phase III trials
• Phase III trials are ongoing, early results suggest that sequential therapy is not
worse than chemoradiotherapy
Head and Neck Cancer - 2006
• Up to 70% of patients with advanced disease and without
significant co-morbidities can be cured
– Sequential chemotherapy, chemoradiotherapy, postoperative
chemoradiotherapy
– Better assessment of risk factors, extent of disease
– New agents to improve survival
• Therapy is long, difficult and requires considerable
physician care and an experienced team
– New agents with reduced toxicity
– Improved interventions during therapy to reduce acute toxicity and
improve late function