marshall r. posner, md dana-farber cancer institute

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


• 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



• 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


• 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)




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


• 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


• 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


• 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


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


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%


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


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


• 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


• 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


• This patient has resectable stage III larynx cancer, good performance status, and minimal co-morbidities

• Which treatment option would you recommend?1. Total laryngectomy




Estimated 5-year survival is 50%-60%


• 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


• 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




• 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


• 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


• 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


• 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)




Estimated 5-year survival is 35%-50% with standard surgery and radiotherapy


• 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


• 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


• 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


• 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


• 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


• 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

marshall r. posner, md dana-farber cancer institute

Documents

year old malepresents

years old

year survival

years agowine

resectable stage

minimal comorbidities

t3n2b tumor

left neck mass