New Paradigms in Head & Neck Cancer
Sequential Therapy: Redefining the Role of Induction Chemotherapy
Marshall R. Posner, MDDana-Farber Cancer Institute
Polling Question
• In patients for whom induction chemotherapy is a viable treatment option, I treat the following proportion of patients with induction chemotherapy:1. 0% (don’t use induction chemotherapy)
2. 1%-10%
3. 11%-25%
4. 26%-50%
5. 51%-75%
6. >75%
Polling Question
• The main issue(s) which limits the use of induction chemotherapy is:1. Toxicity
2. Lack of proven benefit for locoregional tumor control and/or overall patient survival
3. Patient/physician preference
4. 1 + 2
5. 1 + 3
6. 2 + 3
7. All of the above (1 + 2 + 3)
8. None (use induction chemotherapy when indicated)
Polling Question
• In patients for whom induction chemotherapy is a viable treatment option, my preferred induction chemotherapy regimen is:1. PF (cisplatin + 5-FU)
2. PT (platinum + taxane)
3. TPF (docetaxel + cisplatin + 5-FU)
4. Other
Case 1: T3N2b Oropharyngeal TumorNo Significant Comorbidities
• Patient is a 50-year old male– Presents with a painless right neck mass
• 5 pack-year smoking history, quit 30 years ago
• Wine on weekends
– Exam shows tumor of the right base of tongue, 5 cm right, cystic level 2 mass of lymph nodes
• T3N2b - stage IVa
• The tumor abuts the midline of the tongue base, does not impair speech or swallowing, and is not adjacent to the larynx
• It is resectable with a total glossectomy and might be resectable with a partial glossectomy
Case 1: T3N2b Oropharyngeal TumorNo Significant Comorbidities
• This patient has resectable stage IVa oropharyngeal cancer, good PS, and minimal comorbidities– Marginally resectable for cure – Risk of swallowing and speech problems with surgery and with
organ preservation– Survival 30-50% at 5 years– Intermediate risk of metastases
Case 1: T3N2b Oropharyngeal TumorNo Significant Comorbidities
• Which treatment option would you recommend?1. Surgery – total or partial glossectomy
2. Organ preservation – chemoradiotherapy (cisplatin + XRT)
3. Organ preservation – induction chemotherapy (TPF) followed by radiotherapy
4. Organ preservation – sequential therapy: induction chemotherapy (TPF) followed by chemoradiotherapy and then surgery as indicated
Case 2: T3N3 Tumor of the HypopharynxNo Significant Comorbidities
• Patient is a 65-year old male– Presents with hoarseness, left ear pain and a left neck mass
• 65 pack-year smoking history, quit 3 months ago
• Wine on weekends
• Hypertension, mild COPD
– Exam shows tumor of the left pyriform sinus with extension into the parapharyngeal wall, 7.5 cm left, 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
CT Image of Neck Mass
Intra-Operative View of Hypopharynx
Pyriform Sinus Tumor
Case 2: T3N3 Tumor of the HypopharynxNo Significant Comorbidities
• This patient has unresectable stage IVb hypopharyngeal cancer, good PS, and minimal co-morbidities– Surgery is not an option – Estimated 5-year survival is 20%-30% with chemoradiotherapy
and there is a high rate of distant metastases
Case 2: T3N3 Tumor of the HypopharynxNo Significant Comorbidities
• Which treatment option would you recommend?1. Chemoradiotherapy – cisplatin/carboplatin + paclitaxel, THFX
2. Induction chemotherapy (TPF) followed by radiotherapy
3. Sequential therapy – induction chemotherapy (TPF) followed by chemoradiotherapy and then surgery as indicated
• What is the natural history of hypopharynx cancer?– Hypopharynx cancer is more aggressive then larynx cancer or
oropharyngeal cancer– Surgery entails laryngectomy in resectable disease– Estimated 5-year survival is 20%-30% with stage III/IV cancer and
there is a high rate of distant metastases
Case 2: T3N3 Tumor of the HypopharynxNo Significant Comorbidities
CT Image of Neck Mass After 3 Cycles of TPF
Case 2: T3N3 Tumor of the HypopharynxNo Significant Comorbidities
• The patient has a CR at the primary site and a PR in the neck
• Which treatment option would you recommend?1. Surgery – perform a total laryngectomy and neck dissection
2. Surgery – only perform a neck dissection
3. Radiation therapy
4. Chemoradiotherapy – bolus cisplatin
5. Chemoradiotherapy – weekly carboplatin
6. Chemoradiotherapy – weekly carboplatin and paclitaxel
New Paradigms in Head & Neck Cancer
Sequential Therapy: Redefining the Role of Induction Chemotherapy
Marshall R. Posner, MDDana-Farber Cancer Institute
Hear No Induction – See No InductionSpeak No Induction
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 1,854 +1 0.74
Induction 31 5,269 +2 0.10
PF 15 2,487 +5 0.01
Other Chemo 16 2,782 0 0.91
Concomitant 26 3,727 +8 <0.0001
Monnerat, et al. Annals of Oncology, 13: 995-1006, 2002
Studio Induction Chemotherapy Trial:Phase III Study of PF Induction Chemotherapy
Paccagnella A, et al. J Natl Cancer Inst. 1994;86:265-272
RANDOMIZE
P
F
Radiotherapy4 Cycles of Chemotherapy
Surgery
No Surgery
Radiotherapy
Surgery
Radiotherapy
STRATIFY
No Chemotherapy
Chemotherapy
No Surgery(-) Biopsy
Nodal Surgery
(-) Biopsy
Nodal Surgery
A group: initial chemotherapy (cisplatin and infusional fluorouracil) followed by locoregional treatment (n=118).B group: locoregional treatment alone (n=119).
0
0.5
1
0 12 24 36 48
A group
B group
Months from randomization
Ove
rall
surv
ival 27
1915
106
60
28
19
149 6
Conclusion: post-CT surgery did not improve survival in operable patients Surgery may risk of local-
regional recurrence• Surgical Margins Inadequate• Tumor repopulation and
resistance enhanced by delay to XRT
Lack of primary site preservation
Paccagnella A, et al. J Natl Cancer Inst. 1994;86:265-272
Studio Induction Chemotherapy Trial:Overall Survival for Operable Patients
PF group: initial chemotherapy (cisplatin and infusional fluorouracil) followed by locoregional treatment (n=118).XRT group: locoregional treatment alone (n=119).
Conclusion PF induction chemotherapy
improves survival in patients with unresectable disease
Improved LRC, reduced DM
Zorat, P. L. et al. J Natl Cancer Inst 2004
0
20
40
60
80
100
0 20 40 60 80 100 120
Sur
viva
l (%
)
Months
XRT
PF
Studio Induction Chemotherapy Trial: Overall Survival for Inoperable Patients
10-Year Data
Takimoto & Rowinsky, JCO, 2003
A Cell Kinetic Model for Response and Survival:The Argument for Timing in Combined Modality Therapy
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
Induction Chemotherapy and Sequential Therapy – Biological Considerations
• The sequence of chemotherapy CRT should be brisk and uninterrupted– Surgery delays regional therapy
• Neck surgery permits growth at primary site and partial resistance • Surgery leaves an enhanced growth environment• Accelerated tumor repopulation/potential doubling times• Expanded populations with partial resistance
• The choice of chemoradiotherapy regimen can be risk-based– Response
– Toxicity
• A weekly regimen would provide more regional sensitization– Weekly treatment may be more biologically effective and less
systemically toxic then high dose pulsed therapy
Biological Assumptions of Chemoradiotherapy
SCCHN is a local-regional disease• Local-regional failure became the dominant concern
– Local-regional control: persistent disease– Local-regional control: recurrent disease– Local-regional control: new disease– Distant disease
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
Calais G, et al. 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
Sur
viva
l (%
)
Months
CRT
XRT
RANDOMIZE
A
F
B
C
Concomitant Boost XRT
70 cGy
Carboplatin 70 mg/m2/day x 5 days
5-FU 600 mg/m2/day x 5 days
Concomitant Boost XRT
70 cGy
A Phase III Trial of Chemoradiotherapy and Concomitant Boost Radiotherapy in Locally Advanced SCCHN of the
Oropharynx and Hypopharynx
Staar, IJROBP, 2001; 50: 1161-1171
Phase III Trial of Chemoradiotherapy and Concomitant Boost Radiotherapy
Boost -XRT CF-XRT
Patients 127 113
T4 102 (80%) 91 (82%)
N2 + N3 109 (85%) 93 (82%)
5-Year Survival
Oropharynx 13% 26% P < .008
Hypopharynx 22% 22%
Distant Metastases 19% 21%
Mucositis > Grade 3 52% 68% P < .01
Esophageal Stenosis 25% 50% (Survivors at 2 years)
Staar , IJROBP, 2001; 50: 1161-1171. Semrau, IJROBP, 2006.
INT-026: A Phase III Trial of Chemoradiotherapy in Unresectable Patients
RANDOMIZE
A
P
P
XRT
F
B
C
XRT
XRT
Surgery
Adelstein, et al: JCO, 2003; 21:92-98
INT-026 – Survival Outcomes
A B C
XRT P-XRT PF-SC-XRT
Evaluable Patients 95 87 89
Dis. Spec. Survival (3-yr) 34% 56%* 42%
Overall Survival (3-yr) 23% 37%* 27%
Median Survival 12.6 Mo 19.1 Mo 13.8 Mo
Rate of DM 18% (30%) 22% (51%) 19% (29%)
“Feeding Tube” 40% 52% 51%
* Significant Difference A vs. B
Adelstein, et al: JCO, 2003; 21:92-98
RTOG 91-11Phase III Trial of Larynx Preservation
Forastiere, NEJM, 2003
Forastiere AA, et al. ASCO 2006. Abstract 5517
547 pts
Stage III/IV glottic,
supraglottic intermed.
stage
RANDOMIZE
A
P
P
XRT
F
B
C
XRT
XRTSurgery
± Surgery
± Surgery
RTOG 91-11 Laryngectomy-Free Survival
Failed / Total
RT + Induction 109 / 173
RT + Concomitant 115 / 171
RT Alone 127 / 171
% A
live
With
out L
aryn
gect
omy
0
25
50
75
100
Years From Randomization0 1 2 3 4 5 6 7 8 9 10
/
//
/ /// /
/ // / / / // // //////////// / // /////// //// ////// / //// /
////
/ / //// ///// ////// //////// ///////// / /// //// //
//
/
///
//// // /// / / // / /////
////// // ///// / / // ///
Forastiere AA, et al. ASCO 2006. Abstract 5517
RTOG 91-11 Overall Survival
Dead / Total
RT + Induction 89 / 173
RT + Concomitant 106 / 171
RT Alone 96 / 171
% A
live
0
25
50
75
100
Years From Randomization0 1 2 3 4 5 6 7 8 9 10
///
/ /// /
/// / // ////////////////////// / //////////// //////
///////// // ////// /
////
// / //////////// /// //// //////// / ///////////
/ /// //// ////
//
///
/ //// / / /// /// // / //// //////////// // //////// /// /////
/// //////// ///
Forastiere AA, et al. ASCO 2006. Abstract 5517
RTOG 91-11ASCO 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
GORTEC: 2000-01: A Phase III Trial of TPF vs. PF Followed by Radiotherapy for Organ Preservation in
Resectable Larynx and Hypopharynx Cancer
Daily Radiotherapy: STD or ACB
RANDOMIZE
P
P
F
F
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
Calais G, et al. ASCO 2006. Abstract 5506
Months
P (Log-rank test) = 0.096
0 6 12 18 24 30 36 42
0
20
40
60
80
100
Per
cent
(%
)
Induction TPF (n=108)Induction PF (n=112)
Overall Survival
GORTEC Phase III Larynx Preservation Trial Comparing TPF and PF Induction Therapy for Hypopharynx and
Larynx Cancer
Calais et al. ASCO, 2006. Oral Presentation.
Induction TPF (n=108)
Induction PF (n=112)
P (Log-rank test) = 0.036
0 6 12 18 24 30 36 42
0
20
40
60
80
100
Per
cent
(%
)
Months
Larynx Preservation
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
Remenar, ASCO, 2006
TAX 323: Survival Update
Log-Rank P = 0.0052 Hazard Ratio = 0.71
Survival Time (months)
Sur
viva
l Pro
bab
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=177)PF (n=181)
Patients at RiskTPF: PF:
177 163 127 91 74 64 60 43 26 16 7
181 150 98 77 57 47 39 33 25 15 8 4Remenar, ASCO, 2006
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)
Zorat JNCI 2004
Can TPF Improve Overall Survival?
0.5
0.0
1.0
12010896847260483624120
Log-Rank = 4.04; P = .04
PF
RT
2013
11
469
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 (Monnerat, Annals of Oncology, 2002)
– PF was the only induction regimen that was effective – TPF is better than PF– 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 & Neck Cancer
• Induction chemotherapy– High response rates, organ preservation, improved survival,
systemic treatment– Reduced tumor volume, 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
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: 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)
Sur
viva
l Pro
bab
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 risk
TPF:
PF:
255 234 196 176 163 136 105 72 52 45 37 20 11
246 223 169 146 130 107 85 57 36 32 28 10 7 1
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
Hematologic ToxicityTPF
(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*P < .0001
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 11,944 299 14,760
Relative Median Dose Intensity
.98 .99 .98 .90 .88
*6 Patients in each Arm received carboplatin to replace cisplatin
TAX 324: Exposure to Study TreatmentChemoradiotherapy (CRT)
Chemoradiotherapy (CRT)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 toxicity was not enhanced by prior docetaxel 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 (5%) 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
Experience With Docetaxel-Based Induction in Locally Advanced SCCHN
Study N (Criteria) Primary Endpoint Regimens Result
Remenar 2006 (EORTC 24791/ TAX 323)
358 (Inoperable) PFS
PF RT vs.TPF RT
TPF led to higher PFS and
OS (P <.01)
Posner 2006 (TAX 324)
501 (Advanced) OS
PF CRT vs.TPF CRT
TPF improved OS at 3-years
P (<.01)
Calais 2006* (GORTEC 2000-01)
213 (Resectable) LxP
PF vs.TPF
TPF led to higher LxP, CR
*Preliminary results.
All trials showed that TPF had less significant toxicity and no effect on ability to undergo sequential CRT or RT
TAX 324/323: Questions
• Is 5-FU necessary?– PT and PF are equivalent in recurrent disease (Gibson, 2004)– There is synergism with cisplatin and 5-FU and cisplatin and
docetaxel– TPF is better than PF– Show us that PT is better than TPF!
• Tax 323 and Tax 324 use somewhat different regimens– Dose intensity is greater in Tax 324 for cisplatin and 5-FU than in
Tax 323– Direct evidence for giving 3 or 4 cycles is lacking– Dose intensity may impact on local regional control and distant
metastases
TAX 324: Conclusions
• TPF significantly improves survival compared to PF – In Tax 323 and Tax 324 there is significant improvement in 3-year
survival and a 27-30% reduction in mortality (P < 0.006).
• In Tax 324 TPF significantly reduced local regional failure (P = .03) and showed a trend towards improved DM (P = .18)
• In Tax 323, Tax 324, and GORTEC, TPF was less toxic than PF
• Induction chemotherapy and sequential therapy with TPF are tolerable and safe and represent new, acceptable standards of care for locally advanced SCCHN
• Phase III trials to determine if sequential therapy or aggressive chemoradiotherapy is best
Hear No Induction – See No InductionSpeak No Induction
Hear About The Data Think About The DataSpeak About The Data
Evaluate the Data: Form Your Own
Opinion
New Paradigms in Head & Neck Cancer
Sequential Therapy: Redefining the Role of Induction Chemotherapy
Discussion