Marshall R. Posner, MD Dana-Farber Cancer Institute

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


• 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


• 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


• 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


• 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


CT Image of Neck Mass After 3 Cycles of TPF


• 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



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

/

//

/ /// /

/ // / / / // // //////////// / // /////// //// ////// / //// /

////

/ / //// ///// ////// //////// ///////// / /// //// //

//

/

///

//// // /// / / // / /////

////// // ///// / / // ///


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

///

/ /// /

/// / // ////////////////////// / //////////// //////

///////// // ////// /

////

// / //////////// /// //// //////// / ///////////

/ /// //// ////

//

///

/ //// / / /// /// // / //// //////////// // //////// /// /////

/// //////// ///


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?


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


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


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



Discussion

Marshall R. Posner, MD Dana-Farber Cancer Institute

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