marshall r. posner, md dana-farber cancer institute
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
New Paradigms to Improve Outcomes in Head and Neck Cancer
The Evolving Roles of Induction Chemotherapy, Chemoradiotherapy, and Sequential Therapy
Marshall R. Posner, MDDana-Farber Cancer Institute
Case 1: T3N1 Supraglottic TumorNo 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 TumorNo 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 BAlternative 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 BAlternative 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. Cetuximab plus radiotherapy
2. Concurrent carboplatin
3. Carboplatin plus cetuximab
4. Carboplatin plus paclitaxel plus cetuximab
5. Other
Case 2: T3N2b Tumor of the OropharynxNo 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 OropharynxNo 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 HypopharynxNo 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 HypopharynxNo Significant Co-Morbidities
• This patient has unresectable stage IVB hypopharynx cancer, good performance status, and minimal co-morbidities– 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 HypopharynxNo Significant Co-Morbidities
• This patient has unresectable stage IVB hypopharynx cancer, good performance status, and minimal co-morbidities
• 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, MDDana-Farber Cancer Institute
Effects of Chemotherapy on Survival at 5 YearsFrom 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
Domenge C, et al. Br J Cancer. 2000;83:1594-1598.
Overall SurvivalGETTEC
Patients at risk
161157
137138
101105
6586
4859
2833
1619
77
Per
cen
t
Years
No chemotherapy Chemotherapy
0
40
20
60
80
100
0 1 2 3 4 5 6 7 8
Calais Chemoradiotherapy Regimen
1 2 3 4Weeks
Carboplatin 70 mg/m2 /day x 4 days
QD Radiotherapy200 cGy/ Fx
5-FU 600 mg/m2/days x 4 days
5 60 7
J Natl Cancer Inst. 1999;91:2081-2086.
Denis, F et al. JCO. 2004.
Conclusions: Borderline statistically
significant (P = .05) better overall survival with CRT (22% vs 16%)
Absolute 6% improvement Better LRC (48% vs 25%),
No change in DM (20%) CRT is better then XRT
alone for oropharynx cancer
Calais Chemoradiotherapy Study5-Year Survival
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48 54 60 66 72
Su
rviv
al
(%)
Months
CRT
XRT
RTOG 91-11Phase III Trial of Larynx Preservation
Forastiere, NEJM, 2003
Forastiere AA, et al. ASCO 2006. Abstract 5517
RANDOMIZE
A
P
P
XRT
F
B
C
XRT
XRT Surgery
± Surgery
547 pts
Stage III/IV glottic,
supraglottic intermed.
stage
± Surgery
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%* P
< .0016
Survival 59.2% 54.6% 53.5%1. PF was equivalent to CRT for LFS
2. CRT had better LRC than PF
3. DFS was identical but overall survival favored PF
4. Did patients fare better with PF because they had subtle improvements in function
Forastiere AA, et al. ASCO 2006. Abstract 5517
Induction Chemotherapy
• Pros– 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 post-induction therapy
• Cons– 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
RANDOMIZE
P
P
F
F Daily Radiotherapy: STD or ACB
Response
T
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
Surgery
No Response
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
TPF (%) PF (%) P Value
Larynx preserved (current rate)
63.2 41.4 .036
Response• CR• PR
82.843.439.4
60.830.430.4
.0013
• 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)
Calais G, et al. ASCO 2006. Abstract 5506
Induction TPF (n=108)
Induction PF (n=112)
P (Log-rank test) = 0.036
0 6 12 18 24 30 36 420
20
40
60
80
100
Pe
rce
nt (
%)
Larynx Preservation (Months)
GORTEC Phase III Larynx Preservation Trial Comparing TPF and PF Induction Therapy for Hypopharynx and
Larynx Cancer
Calais et al. ASCO, 2006. Oral Presentation.
TAX 323: TPF vs PF Followed by Radiotherapy A Phase III Study in Unresectable SCCHN
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
RANDOMIZE
P
P
F
F
Daily Radiotherapy
EUA
T
Surgery
Vermoken, ASCO, 2004
TAX 323: Survival Update
Remenar, ASCO, 2006
Log-Rank P = 0.0052 Hazard Ratio = 0.71
Survival Time (months)
Sur
viva
l Pro
babi
lity
(%)
0 6 12 18 24 30 36 42 48 54 60 66 72
0
10
20
30
40
50
60
70
80
90
100
TPF (n=177)
PF (n=181)
Patients at RiskTPF: PF:
177 163 127 91 74 64 60 43 26 16 7181 150 98 77 57 47 39 33 25 15 8 4
TAX 323: Severe Adverse EventsChemotherapy
Vermoken, ASCO, 2004
Toxicity PF (n=179) TPF (n=174)
> 3% of pts N (%) N (%)
Alopecia 0 20 (11.5)
Stomatitis / oral 20 (11.2) 8 (4.6)
Infection 13 (7.3) 15 (8.6)
Nausea 13 (7.3) 1 (0.6)
Vomiting 9 (5.0) 1 (0.6)
Diarrhea 8 (4.5) 5 (2.9)
Dyspnea 8 (4.5) 6 (3.4)
Dysphagia 5 (2.8) 6 (3.4)
Pain 7 (3.9) 11 (6.3)
Death 12 (6.6) 6 (3.4)
An Analysis of Failure in Phase II TPF Induction Trials*
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
Three Cycles of Induction Therapy Followed by BID Radiotherapy
Haddad, Cancer, 2003
An Analysis of Failure in Phase III Chemoradiotherapy Trials*
Trials: INT EORTC RTOG GORTEC
LRF 22% 18% 16% 57%DM 23% 21% 20% 18%DM % of Failure 51% 54% 65% 32%
The Rate of DM Was Not Reduced by CRT
*Excludes Larynx Trial 91-11
Adelstein, JCO, 2003Bernier, NEJM, 2005Cooper, 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
Takimoto & Rowinsky, JCO, 2003
DeathChemotherapy
Treatment B Survival
Treatment A Survival
BA
1012
1011
1010
109
108
107
106
Tu
mo
r C
ell
Nu
mb
er
Time
Critical Time Frame
A Cell Kinetic Model for Response and Survival:The Argument for Timing in Combined Modality Therapy
Sequential Combined Modality Therapy A Phase III Study: TAX 324
TPF vs PF Followed by Chemoradiotherapy
RANDOMIZE
P
P
F
F
Carboplatin - AUC 1.5 Weekly
Daily Radiotherapy
EUA
T
Surgery
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
Treated With Chemotherapy251
(98%)243
(99%)494
(98.6%)
SAFETY PopulationTPF
( n=251)PF
(n=243)ALL
(n=494)
Chemotherapy Treated 251
(100%) 243
(100%) 494
(100%)
Receiving Chemoradiotherapy per Protocol202
(81%)184
(76%)386
(78%)
Not Receiving Chemoradiotherapy per Protocol 49
(19%) 59
(24%)108
(22%)
* ITT excludes 37 patients erroneously randomized and 1 patient with GCP compliance issue
TAX 324: Patients Characteristics (ITT)
TPF (n=255) PF (n=246)
Age (years): Median (Range)
65 years
55 (38 to 82)
34 (13%)
56 (33 to 80)
36 (15%)
Gender Male 215 (84%) 204 (83%)
PS (WHO) 0
1
142 (56%)
113 (44%)
126 (51%)
117 (48%)
Anatomic site Oropharynx
Larynx
Hypopharynx
Oral cavity
132 (52%)
48 (19%)
42 (17%)
33 (13%)
131 (53%)
42 (17%)
34 (14%)
38 (15%)
Clinical Stage III
IV
41 (16%)
214 (84%)
46 (18%)
199 (81%)
Reason Inoperable
Technical Unresectability
Low Surgical Curability
Organ Preservation
92 (36%)
78 (31%)
85 (33%)
84 (34%)
75 (31%)
87 (35%)
TAX 324: SurvivalIntent to Treat Population
TPF (n=255) PF (n=246)
Median Survival (Mo)
95% CI
70.6 +49 – NR
30.120.9 – 51.5
Died * 41% 53%
Kaplan-Meir Survival
1–Year
2–Year
3–Year
80% [ 75.0 – 84.9]
67% [61.5 – 73.2]
62% [55.9 – 68.2]
69% [64.1 – 75.7]
54% [48.2 – 60.8]
48% [41.7 – 54.5]
Hazard Ratio TPF:PF
[95% CI]0.70 [0.54 - 0.90]
Log-Rank P Value 0.0058
*Cut-off: December 3, 2005; The median follow-up is 42 months
TAX 324: Survival
TPF 62%
PF 48%
Log-Rank P = 0.0058 Hazard Ratio = 0.70
TPF 67%
PF 54%
Survival Time (months)
Su
rviv
al P
rob
ab
ility
(%
)
0 6 12 18 24 30 36 42 48 54 60 66 72
0
10
20
30
40
50
60
70
80
90
100
TPF (n=255)
PF (n=246)
Number of patients at riskTPF:PF:
255 234 196 176 163 136 105 72 52 45 37 20 11246 223 169 146 130 107 85 57 36 32 28 10 7 1
Log-Rank P = 0.004 Hazard Ratio = 0.71
TPF 49%
PF 37%
TPF 53%
PF 42%
TAX 324 : Progression-Free Survival
Progression-Free Survival Time (months)
Pro
gre
ssio
n F
ree
Su
rviv
al P
rob
ab
ility
(%
)
0 6 12 18 24 30 36 42 48 54 60 66 72
0
10
20
30
40
50
60
70
80
90
100
TPF (n=255)
PF (n=246)
Number of patients at riskTPF:PF:
255 198 150 135 121 100 73 50 39 35 26 16 5246 183 125 104 92 72 57 38 30 25 14 8 2
TAX 324: Toxicity During Chemotherapy
Number of PatientsTPF
(n=251)PF
(n=243)
NCIC-CTG Classification Grade 3/4 Grade 3/4
Any Event 65% 62%
StomatitisNauseaLethargyVomitingDiarrheaAnorexia
21% 14% 5% 8% 7%
12%
27% 14% 10% 10% 3%12%
TAX 324: Specific Safety During Chemotherapy
TPF
(n=251)
PF
(n=243)
Neutropenia Grade 3/4 84% 56%
Febrile Neutropenia
Neutropenic Infection
12%
12%
7%
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)
Treatment Delays 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%)
** Logistic, Personal, Vacation
TAX 324: Exposure to Induction Chemotherapy
TPF
(n=251)
PF
(n=243)
Median Cycles 3 3
Cumulative Dose (mg/m2)
T P* F P* F
224 299 11944 299 14760
Relative Median Dose Intensity
.98 .99 .98 .90 .88
*6 Patients in each Arm received carboplatin to replace cisplatin
TAX 324: Toxicity During Chemoradiotherapy
Number of PatientsTPF
(n=203)
PF
(n=184)NCIC-CTG Grade 3/4 Grade 3/4
Any Event
Stomatitis
Dysphagia
Mouth/Nose Dryness
Nausea
Rash/itch
65%
37%
23%
5%
6%
5%
66%
38%
24%
4%
6%
2%
TAX 324: Exposure to Study Treatment
TPF(n=202)
PF(n=184)
Median Dose Radiotherapy (Gy)
Median Dose Carboplatinum (AUC)
Median Duration CRT (Wks)
70
9.9
7.1
70
9.9
7.1
Chemoradiotherapy (CRT)
Chemoradiotherapy toxicity was not enhanced by prior doxetaxel in TPF
TAX 324: Analysis of Failure
TPF (n=251) PF (n=243) All (n=494)
Total Failures/Treated 88 (35%) 110 (45%) 198 (40%)
LRF* 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%)
Distant Metastases** 14 (6%) 21 (9%) 35 (7%)
Distant Only 11 (4%) 17 (7%) 28 (6%)
Distant and LRF 3 (1%) 4 (2%) 7 (1%)
Second Primaries 9 (4%) 7 (3%) 16 (3%)
*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 carboplatin-based 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 StudySequential Therapy vs Chemoradiotherapy
A Phase III Study of TPF/C-XRT vs P-ACBXRT
RANDOMIZE
P
P
F
XRT
C
Daily Radiotherapy
3 Cycles of Chemotherapy
T
Surgery
Q 3 Weeks Surgery
ACB Radiotherapy
*T + ACB for Non-Responders
T*ACB
NR
PR,CR
SWOG Phase III Oropharynx Trial: S0427
RANDOMIZE
P
P
F
XRT
P
Daily Radiotherapy
T
Surgery
Q 3 Weeks
Surgery
Daily Radiotherapy
<50% ResponseSurgery
Q 3 Weeks
>50% Response2 Cycles
* Cisplatinum (P); Docetaxel (D); 5-Fuorouracil (F)
Italia Phase II/III TPF vs CRT Trial
RANDOMIZE
P
P
F
CRT
P
Daily Radiotherapy
T
Daily Radiotherapy
F
F
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 TumorNo 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 TumorNo 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 TumorNo 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 BAlternative 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 BAlternative 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. Cetuximab plus radiotherapy
2. Concurrent carboplatin
3. Carboplatin plus cetuximab
4. Carboplatin plus paclitaxel plus cetuximab
5. Other
Case 1 BAlternative 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 OropharynxNo 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 OropharynxNo 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 OropharynxNo 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 HypopharynxNo 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 HypopharynxNo Significant Co-Morbidities
• This patient has unresectable stage IVB hypopharynx cancer, good performance status, and minimal co-morbidities– 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 HypopharynxNo Significant Co-Morbidities
• This patient has unresectable stage IVB hypopharynx cancer, good performance status, and minimal co-morbidities
• 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 HypopharynxNo 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