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Corey J. Langer MD, FACPDirector, Thoracic OncologyAbramson Cancer CenterProfessor of MedicineHematology-Oncology DivisionUniversity of PennsylvaniaPhiladelphia, Pennsylvania

Recent Advances in the Treatment of Head and Neck Cancer

This program is supported by an educational grant from Bristol-Myers Squibb

clinicaloptions.com/oncologyRecent Advances in the Treatment of Head and Neck Cancer

Head and Neck Cancer

Estimated 39,250 cases in US in 2005*

– 5th leading cancer in US

– 10% of all cancers worldwide

> 11,000 deaths—3% of all cancer deaths

Patients typically aged > 50 yrs, with tobacco and alcohol use

Emerging cohort of HPV-positive cancers in the OP

Histology: > 90% squamous cell carcinoma

Early-stage disease (I, II) curable: > 80%

Locally advanced disease has poorer prognosis

– 5-yr survival rate: < 40%*Oral cavity, pharynx, and larynx.


Outcomes

Stages I and II

– 1/3 of patients

– Curative results: 60% to 80%

– SPTs: greater risk than recurrence

Stages III and IV

– 2/3 of patients

– Multimodal treatment

– 40% to 80% local recurrence

– 10% to 30% distant disease


Head and Neck Cancer: Prognosis

Cases, % 5-Yr Survival, %

Stage I 15 85

Stage II 20 70

Stage III 25 55

Stage IV 25 30

Unresectable 15 10


Historical Perspective: Systemic Therapy in SCCHN 1970s: active cytotoxics identified and studied

– High rates of response in neoadjuvant setting

1980s: randomized trials of neoadjuvant therapy

– Chemosensitivity correlated with radiosensitivity

– No detriment to delay in definitive local therapy

– Decrease in distant metastases

– No sign of improvement in locoregional control or survival

– Coupled with radiation, effective in larynx preservation


Historical Perspective:Systemic Therapy in SCCHN 1990s: randomized trials of chemoradiation

– Improved locoregional control and survival[1-3]

– Increased acute/late toxic effects

– Increased organ preservation rates

– Site-specific benefits[4,5]:

– Oropharynx

– Nasopharynx

– Larynx

– DM predominant recurrence in some trials, where local control appears enhanced

1. Calais G, et al. J. Natl. Cancer Inst. 1999;91:2081-2086. 2. Brizel DM, et al. N Engl J Med. 1998;338:1798-1804. 3. Bourhis J, et al. Hematol Oncol Clin North Am. 1999;13:769-75. 4. Al-Sarraf M, et al. J Clin Oncol. 1998;16:1310-1317. 5. Wolf GT, et al. Head Neck. 1995;17:279-283.


Historical Perspective:Systemic Therapy in SCCHN 2000-2009

– Chemoradiation superior in post-op high-risk setting

– Cetuximab/radiation: improved LRC/survival

– Renewed interest in neoadjuvant therapy[1]

– Taxanes

– Increasing significance of isolated distant failure

– Risk-based approaches (positive N, primary site)

– Randomized trials taxane + PF show increased PFS/OS vs PF[1,2]

– Emergence of HPV as a marker of outcome, particularly in nonsmokers with OP cancer[3]

1. Posner M, et al. N Engl J Med. 2006;354:634-636. 2. Vermorken JB,, et al. N Engl J Med. 2007;357:1695-1704. 3. Gillison ML. Eur J Cancer. 2009;45:383-385.


Case 1

57-yr-old WF minimal past cigarette smoker presents with 4-wk history of sore throat and 10-lb weight loss, as well as pain on swallowing. She notes a lump in the L side of her neck. PE reveals a 3-cm L tonsillar mass extending to the posterior OP and multiple bilateral 1- to 2-cm LN. CT is confirmatory. FNA of L cervical LN shows classical squamous cell carcinoma. Remaining W/U including PET and DL is negative for other sites of disease.


57-Yr- Old WF With OP Cancer

Primary Mass

Lymph nodes


What is the stage of her cancer?

1) III

2) IVA

3) IVB

4) IVC


Head and Neck Tumor Stages

T1: tumor 2 cm or less or confined to the anatomic subsite of origin

T2: tumor 2-4 cm, extending to an adjacent subsite, or impairing vocal cord mobility

T3: tumor > 4 cm or fixing a vocal cord

T4: tumor with massive invasion or involving an adjacent organ


Head and Neck Lymph Node Stages

N1: single node, 3 cm or smaller

N2a: single node > 3 cm but not > 6 cm

N2b: multiple nodes, none > 6 cm

N2c: a contralateral node or bilateral nodes, none > 6 cm

N3: any node > 6 cm


NCCN practice guidelines in oncology: head and neck cancers. Available at: http://www.nccn.org.

TNM Staging in SCCHN

Stage 0 Tis N0 M0

Stage I T1 N0 M0

Stage II T2 N0 M0

Stage III T3T1T2T3

N0N1N1N1

M0M0M0M0

Stage IVA T4aT4aT1T2T3T4a

N0N1N2N2N2N2

M0M0M0M0M0M0

Stage IVB T4bAny T

Any NN3

M0M0

Stage IVC Any T Any N M1


What is the most appropriate therapeutic strategy?1) Concurrent RT and

full-dose cisplatin

2) Induction therapy with TPF followed by radiation and low-dose concomitant chemotherapy

3) Concurrent RT and cetuximab

4) Any of the above

5) None of the above


Nonsurgical Treatment Options for SCCHN

1. Pignon JP, et al. Lancet. 2000;355:949-955. 2. Bonner JA, et al. Lancet Oncol. 2009 Nov 6;[Epub ahead of print]. 3. Vermorken JB, et al. N Engl J Med. 2007;357:1695-1704. 4. Posner MR, et al. N Engl J Med. 2007;357:1705-1715.

Rx Regimens HR (95% CI) Absolute Benefit

2-Yr, % 5-Yr, %

RT + concurrent Ctx[1] 0.81(0.76-0.88)

7 8

RT + Cetuximab[2] 0.73(0.56-0.94)

9 10

TPF → RT[3] 0.70(0.54-0.90)

11 NA

TPF → RT + carboplatin[4] 0.74(0.67-0.82)

12 NA


63 randomized trials (1965-1993)

n = 10,717 (excludes NPC trials)

Median follow-up: 6 yrs

ORR: 0.89 (32% vs 36% at 5 yrs)

Pignon JP, et al. Lancet. 2000;355:949-955.

Meta-Analysis of Chemotherapy in HNC (MACH-NC)

Trials N RR P Value Absolute Benefit (5 Yrs), %

Adjuvant 8 1854 0.98 NS 1

Induction 31 5245 0.95 NS 2

Concomitant 26 3727 0.81 < .0001 8


MACH-NC: An Update

24 added trials—93 randomized studies, 17,346 patients

– Median follow-up: 5 yrs

MACH-HN I: 8% abs benefit CMT

MACH-HN II: more homogenous population

Age matters

– Younger than 50 yrs of age: 24% increased survival

– Older than 70 yrs of age: 3% increased survival

Pignon JP, et al. Radiother Oncol. 2009;92:4-14.


Concurrent Chemoradiation in LA-SCCHN: Long-term Survival Results

N F/U, Yrs

RT (Control)

CT/RT P Value Agents Used

French trail 226 3 31 51 .002 Carbo/5-FU

German trial 270 3 24 48 < .0003 cDDP/5-FU/LV

NP intergroup 193 3 47 78 .005 cDDP→DDP/5-FU

Duke U 116 5 28 42 .05 cDDP/5-FU

Intergroup 199 3 23 37 .01 cDDP

Greek 83 3 18 52 < .001 cDDP


Pros and Cons of Chemoradiation

Improves locoregional control

– Facilitates organ preservation

– Beneficial impact on survival

Doubles the rate of severe acute mucositis

Use may be excessive based on stage

Long-term functional deficits in speech, swallowing, mobility


Randomized Trials of PF ± TaxaneInduction Therapy TrialsStudy Eligibility N T + PF

CR/PR, n/N (%)

PF CR/PR, n/N (%)

TPF/PF PFS, Mos

TPF/PF OS, Mos

P Value (HR)

HittJCO 2005

Stage III-IV 382 33/47(80)

14/54(68)

2012

4337

2 yrs: 66%/61%

.035(0.67)

TAX 323 ASCO 2006

Unresectable 358 (68) (54) 118

18.614.23 yrs:

24%/18%

.005(0.71)

Gortec ASCO 2006

L/HPII-IV

205 43/39(82)

30/30(60)

LP:63%/41%

.036

TAX 324ASCO2006

III-IV 501 17/55(72)

15/49(64)

2-yr PFS:53%/42%

7030

3 yrs: 62%/48%

.006(0.7)


Planned sample size: 358 patients

Number of events: 260 progression events needed to show 50% increase in PFS (10-15 months; HR: 0.67)

Unresectable SCCHN

Stratification: Institution Primary Site

R

TPF x 4q3wk

PF x 4q3wk

RadiationCF, AF, or HF

Neck dissection

Neck dissection

Follow

Surgery?

Vermorken JB, et al. N Engl J Med. 2007;357:1695-1704.

Cisplatin/5-FU vs Docetaxel + Cisplatin/5-FU in SCCHN: Study Design


Pts at Risk, nPF 181 112 52 37 25 19 11 5 1TPF 177 129 79 48 23 16 5 3 1

Pts at Risk, nPF 181 149 97 72 49 32 20 13 4TPF 177 163 127 89 57 36 21 9 1

Vermorken JB, et al. N Engl J Med. 2007;357:1695-1704. Copyright © 2007 Massachusetts Medical Society. All rights reserved.

PFS and OS

100908070605040302010

0

PF

S (

%)

Mos0 6 12 18 24 30 36 42 5448

TPFPF

P = .007

100908070605040302010

0

OS

(%

)

Mos0 6 12 18 24 30 36 42 5448

TPF

PF

P = .02

TPFPF


Posner MR, et al. N Engl J Med. 2007;357:1705-1715. Copyright © 2007 Massachusetts Medical Society. All rights reserved.

TAX 324 TPF vs PF: OS

TPF 62%

PF 48%

Log rank P = .006; HR: 0.70

TPF 67%

PF 54%

Survival Time (Mos)

Su

rviv

al P

rob

abil

ity

(%)

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)

Pts at Risk, n

TPF 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


Ongoing Randomized Trials:Definitive ChemoRT ± InductionTrial Eligibility Target N* Control

TxExperimental

Tx

DeCIDE†

U ChicagoN2-3 400

280DHFX TPF x 2

DHFX

ParadigmDFCI

Stages III-IV 300150

CisplatinCB-RT

TPF x 3Carbo-RT or

D-CB-RT

SWOG Oropharynx 400 CisplatinRT

TPF x 1-3surgery or

cisplatin-RT

*All powered to show survival difference of 10% to 15%.†50% accrued as of May 2008.


Incidence of EGFR Expression in Solid Tumors

Arteaga C, et al. Semin Oncol. 2003;30:3-14.

Tumor Type EGFR Expression, %

SCCHN ≥ 95

NSCLC 40-80

Colorectal 25-77

Glioblastoma 40-60

Breast 14-91

Esophageal 35-88

Pancreatic 30-50

Gastric 33-74

Bladder 31-72

Prostate 41-100

Ovarian 35-70


Cetuximab (IMC-C225): Properties

IgG1 (chimerized antibody)

Exclusive for EGFR and its heterodimers

Prevents repair and survival of tumor cells damaged by the effects of chemotherapy and radiotherapy

– Potentiates apoptosis

– Inhibits cell cycle progression

– Decreases production of angiogenic factors

– Inhibits invasion/metastasis

88

299

Fab

Fc


A431 Xenografts: Can Certuximab Improve Radiotherapy Results? A431 human tumor xenografts used to test whether

certuximab enhances tumor response to radiotherapy

Certuximab + RT treatment of A431 xenografts substantially delayed tumor growth

– Three certuximab doses with a single 18 Gy RT dose associated with a near 4-fold decrease in tumor growth vs 18 Gy RT alone

Milas L, et al. Int J Radiat Oncol Biol Phys. 2004;58:966-971.


Arm 2 (RT + C)Radiation therapy +

Cetuximab wkly

Phase III Study Design

Stratified by

Karnofsky score: 90-100 vs 60-80

Regional nodes: negative vs positive

Tumor stage: AJCC T1-3 vs T4

RT fractionation: concomitant boost vs once daily vs twice daily

R

A

N

D

O

M

I

Z

E

Arm 1 (RT)Radiation therapy

Bonner JA,, et al. N Engl J Med. 2006;354:567-578.


Patient Characteristics

RT RT + C

Median age, yrs (range) 58 (35-83) 56 (34-81)

Male/female, % 79/21 81/19

Primary tumor site, %OropharynxHypopharynxLarynx

631324

561727

EGFR, %DetectableNondetectableUnknown

801

19

790

21

Bonner JA, et al. N Engl J Med. 2006;354:567-578.


Most Common Adverse Events

Toxicity, %RT (n = 212) RT + C (n = 208)

All Grades Grades 3/4 All Grades Grades 3/4

Skin reaction 91 18 97† 34‡

Mucositis/stomatitis 93 52 91 54

Dysphagia 63 30 64 25

Xerostomia 70 3 64 4

Fatigue/Malaise 50 5 52 4

Infusion reaction* -- – 14‡ 3†

*Listed for its relationship to cetuximab.†P < .05‡P < .001, Fisher’s exact test.



Locoregional Control

Locoregional Control, % RT(n = 213)

RT + C (n = 211)

1 yr*2 yrs*

5948

6956

Log rank P value 0.02

Distant/second primary control 1 yr* 2 yrs*

71

56

77

62


*Kaplan-Meier estimates.


Overall Survival

RT(n = 213)

RT + C (N=211)

Median survival,* mos 29.3 49

95% confidence limits 21-38 36-58+

2 yrs, % 55 62

3 yrs, % 44 57

5 yrs, % 36.4 45.6

Log rank P value .018

HR (95% CI) 0.71 (0.54-0.95)

Bonner JA , et al. Lancet Oncol. 2009 Nov 6;[Epub ahead of print].


Improvement With Cetuximab

Bonner JA , et al. Lancet Oncol. 2009 Nov 6. [Epub ahead of print].

Forest Plot of the HRs by Pretreatment Characteristics: 5-Yr Median Follow-up

Tumor: oropharynx

Tumor: hypopharynx

Tumor stage: T1-T3

Region: other

RT fract: once daily

Overall stage: IV

Nodal stage: N1-N3

Karnofsky 90-100

Sex: male

EGFR unknown

EGFR positive ≤ 50%

Age < 65 yrs

Tumor: larynx

Tumor stage: T4

Region: US

RT fract: twice daily

RT fract: concomitant boost

Overall stage: II-III

Nodal stage: N0

Karnofsky 50-80

Sex: female

EGFR positive > 50%

Age ≥ 65 yrs

0.0 0.6 1.2 1.8


Postoperative stage III or IV SCCHN

Stratified by

Nodal disease

Zubrod score

Prior radiation

PET/CT

Primary site

R

A

N

D

O

M

I

Z

E

Radiotherapy Wks 1-6+

Cisplatin 100 mg/m2 Days 1, 22

Cetuximab 400 mg/m2 Day 1, then 250 mg/m2 Wks 2-8

+ Radiotherapy Wks 2-7

+Cisplatin 100 mg/m2 Days 8, 20

Following chemoradiotherapy, patients with poor response can proceed to surgery.RTOG foundation. Available at: http://www.rtog.org.

Phase III Trial of Cisplatin Chemoradiation ± Cetuximab in Advanced SCCHN


Targeted Therapy With an Induction Chemotherapy Platform: TREMPLIN Previously untreated SCC larynx/hypopharynx suitable for TL

Primary endpoint: larynx preservation 3 mos after treatment

Secondary endpoints: larynx function preservation and survival 18 mos after treatment

Total laryngectomy + postop RT

RT 70 Gy +Cisplatin 100 mg/m² on Days 1, 22, 43

RT 70 Gy +Cetuximab 400 mg/m² 1 wk prior to RT

then 250 mg/m² wkly on Wks 1-7

TPF3 cycles, 1 cycle

q3wksT 75 mg/m² on Day 1P 75 mg/m² on Day 15-FU 750 mg/m² on

Days 1-5

R

< PR

≥ PR

Lefebvre J, et al. ASCO 2009. Abstract 6010.


What is the likelihood the patient’s tumor is HPV positive?1) 25% to 35%

2) 40% to 50%

3) 60% to 65%

4) 80% to 85%


What absolute percentage improvement in survival is one likely to see in a patient whose primary tumor is HPV positive compared with HPV negative?

1) 5% to 10%

2) 10% to 15%

3) 15% to 25%

4) 25% to 35%


Is smoking a cofactor in prognosis in patients whose SCCHN is HPV positive?1) Yes

2) No


Emerging Influence of HPV in HNC

Characteristic HPV Positive HPV Negative

Anatomic site OP: tonsil, base of tongue Larynx, OC, hypopharynx

Age Younger Older

Male:female 1:1 3:1

Risk factors Sexual Tobacco/Etoh

Cofactors Marijuana Diet/hygiene

Clinical presentation Unknown or cystic primary Classical

Incidence Increasing Decreasing

Comorbidities Fewer Greater

Prognosis Better Worse

Gillison ML, et al. J Natl Cancer Inst. 2008;100:407-420.


ECOG 2399: Study Design

REGISTER

RESPONSE

RESPONSE

Inductionchemotherapy

Paclitaxel 175 mg/m2

Carboplatin AUC 6

q21days2 cycles

Concurrentchemoradiation

RT 70 Gy/35 fx/7 wksPaclitaxel 30 mg/m2/wk

Fakhry C, et al. J Natl Cancer Inst. 2008;100:261-269.


ECOG 2399: Efficacy by HPV Status

HPV Positive, %

(n = 38; 40%)

HPV Negative, %

(n = 58; 60%)

P Value

Response Induction Protocol

8284

5557

.01

.07

2-yr PFS 86 53 .02

2-yr OS 95 62 .005

Survival, OP cancers 2-yr PFS 2-yr OS

8594

5058

.05.004

Fakhry C, et al. J Natl Cancer Inst. 2008;100:261-269.


Arm 1Standard Fractionation

(SFX) 70 Gy/35 Fx/7 wks +Cisplatin 100 mg/m2

on Days 1, 22, 43

RANDOMIZE

Tumor Site1. Larynx2. Nonlarynx

STRATIFY

Nodal Stage1. N02. N1 or N2a-b3. N2c or N3

Zubrod Performance Status1. 02. 1

Arm 2Accelerated Fractionation

by Concomitant Boost (AFX-C)

72 Gy/42 Fx/6 wks +Cisplatin 100 mg/m2

on Days 1, 22

Gillison ML, et al. ASCO 2009. Abstract 6003.

RTOG 0129


P16 Positive, n (%) P16 Negative, n (%)

HPV positive 192 (96) 7 (4)

HPV negative 22 (19) 94 (81)

433/721 (60%) had oropharynx primary

323/433 (75%) had HPV determination

206 of 323 (64%) were HPV positive

198 of 206 (96%) were HPV16 positive

Kappa = 0.80 (95% CI: 0.73-0.87)


RTOG 0129: Results of Laboratory Analysis


Variable HPV Positive HPV Negative P Value

No. of patients 206 117

Age, median yrs 53.5 57.0 .02

White race, % 92.2 75.2 < .001

Zubrod PS 0, % 68.4 56.4 .03

T stage 2-3, % 75.2 60.7 .008

< 20 pack-yrs, % 51.0 22.2 < .001


Patient and Tumor Characteristics by HPV Status


Variable, % HPV Positive HPV Negative P Value

OS (2 yrs) 87.9 65.8 < .001

PFS 71.8 50.4 < .001

Local-regional failure 13.6 24.8 .004

Distant metastases 9.7 12.9 .26

Second primary tumor 3.9 11.1 .01


2-Yr Outcomes


Tumor HPV, Smoking Status, and OS

Patients, n HR 95% CI

HPV positive, < 20 pack-yrs 105 1.00 --

HPV positive, ≥ 20 pack-yrs 73 1.91 1.20-3.05

HPV negative, < 20 pack-yrs 26 2.25 1.44-3.50

HPV negative, ≥ 20 pack-yrs 62 4.30 2.40-7.71

Adjusted for age, race, T stage, N stage, and treatment assignment



Conclusions

Tumor HPV status is a strong and independent predictor of OS and PFS for patients with oropharynx cancer

Rates for local-regional, but not distant, recurrence events were lower for the HPV-positive patient

P16 IHC is highly correlated with tumor HPV status and is a valid surrogate

Tobacco use appears to modify the biologic behavior of an HPV-positive tumor

Tumor HPV status or P16 must be a stratification factor in clinical trials that include oropharynx patients


Implications

Separate trials for HPV-positive and HPV-negative patients

– HPV positive trials to deintensify Tx, emphasize toxicity mitigation

– HPV negative trials intensifying Tx, adding new agents with new MOAs


Case 1

Patient opts for concurrent RT and cetuximab. She receives 6 wkly doses of cetuximab and > 50 Gy RT, but then develops grade 3 acneiform rash across her face and chest


What should you do next?

1) Suspend both RT and cetuximab

2) Suspend cetuximab only

3) Tx rash with topical clindamycin ointment and oral doxycycline, but continue RT and cetuximab

4) Apply topical steroids


Cetuximab

Rash

– Ubiquitous, ~ 70% to 80%, but grade 3 in 10%

– Acneiform to start

– Rx: clindamycin ointment or gel; oral doxycycline or minocycline; steroids; emollients

– Over time

– Recedes from face and chest to hands and feet and hairline

– Nail dystrophy, fissures (antifungals, superglue!!)

HSR: 3% to 5%

– Worse in the HSR belt: Carolinas, Tennessee (20%)

Cardiotoxicity: < 5%

Hypomagnesemia: persistent, often quite severe, clinical effects uncertain

Diarrhea: far less than seen with oral EGFR TKIs


Reassess after 2 wks; if reactions do not improve,

proceed to next step

MildContinue EGFR inhibitor at current dose and monitor

for change in severity

No treatmentTopical hydrocortisone 1% or 2.5% cream and/or Clindamycin 1% gel

or

Reduce EGFR inhibitor dose per label and monitor for change in severity; continue treatment of skin reaction

Treat as above plus Methylprednisolone dose pack

Reassess after 2 wks; if reactions worsen, dose

interruption or discontinuation may be

necessary

Severe

Continue EGFR inhibitor at current dose and monitor for change in severity; continue treatment of skin reaction

Hydrocortisone 2.5% cream or Clindamycin 1% gel or Pimecrolimus 1% cream plus Doxycycline 100 mg BID or Minocycline 100 mg BID

Moderate

Reassess after 2 wks; if reactions do not improve,

proceed to next step

Lynch TJ Jr, et al. Oncologist. 2007;12:610-621.

A Sample Skin Reaction Algorithm


Case 2: Laryngeal Cancer

68-yr-old WM smoker (80 pack-yrs) presents with hoarseness and a nodule in the right side of his neck. PE reveals a 2.5-cm supraglottal mass on the right and a 1.5-cm ipsilateral LN. CT of the HNC confirms these findings. Bx of both node and primary demonstrates keratinzing squamous cell cancer. Remaining workup is negative.


Case 2: Imaging and Endoscopy Results

CT neck

– R SGL mass

– 1.5-cm posterior triangle rt neck node

CT chest and CT brain: negative

Laryngoscopy and bx-

– Large tumor involving rt false vocal cord extending to true vocal cord and medial wall of pyriform sinus on the same side

– Mobile vocal cord

– No contralateral spread

Becker M, et al. Eur Radiol. 1998;8:1541-1551. Graphic reproduced with permission.


What is the stage of this patient’s cancer?

1) II

2) III

3) IVA

4) IVB


NCCN practice guidelines in oncology: head and neck cancers. Available at: http://www.nccn.org.

TNM Staging in SCCHN

Stage 0 Tis N0 M0

Stage I T1 N0 M0

Stage II T2 N0 M0

Stage III T3T1T2T3

N0N1N1N1

M0M0M0M0

Stage IVA T4aT4aT1T2T3T4a

N0N1N2N2N2N2

M0M0M0M0M0M0

Stage IVB T4bAny T

Any NN3

M0M0

Stage IVC Any T Any N M1


Which of the following is considered standard treatment for this patient?1) Supraglottal laryngectomy

followed by LND

2) RT with low-dose concurrent cisplatin and wkly cetuximab

3) Primary RT and concurrent full-dose cisplatin, with salvage surgery reserved for recurrence

4) Any of the above

5) 1 and 3


Forastiere AA, et al. N Engl J Med. 2003;349:2091-2098.

RTOG 9111: Larynx Preservation Trial

RANDOMIZE

Location1. Glottic2. Supraglottic

STRATIFY

T Stage1. T22. T3, fixed cord3. T3, no cord fixation4. T4, with base of tongue ≤ 1 cm

N Stage1. N0, N12. N2, N3

ChemotherapyArm 1: cisplatin 100 mg/m2/5-FU 1 gm/m2/24 hrs CVI x 120o q3wks x 3 Arm 2: cisplatin 100 mg/m2 Days 1, 22, 43 of RT

Phase III larynx preservation trial: induction chemotherapy and radiation therapy vs concomitant chemotherapy and radiation therapy vs radiation therapy alone

Arm 1:

Arm 2:

Arm 3:

CR, PR x 3 d cycle RT

CDDP/5-FUx 2 cycles

NR surgery RT

Radiation therapy + CDDP

Radiation therapy


RTOG 9111: Larynx Preservation Trial

The median follow-up among surviving patients, 3.8 years

Demographics: median age 59 yrs; 94% KPS 80; 50% N0; 68% SGL; 28% N2-3

Conclusions

– RT/cDDP: stat signif in LFS (P = .01)

– No SS diff in survival

Forastiere AA, et al. N Engl J Med. 2003;349:2091-2098.

Arm cDDP/5-FU RT RT/cDDP RT

Enrolled, n (evaluable) 180 (173) 182 (172) 185 (173)

2-yr laryngectomy FS, % 59 66 53

5-yr DMFS, % 85 88 78

5-yr DFS, % 38 36 27

5-yr OS,% 55 54 56


Advanced Larynx Cancer: PreservationL

aryn

x P

rese

rved

Forastiere AA, et al. N Engl J Med. 2003;349:2091-2098. Copyright © 2003 Massachusetts Medical Society. All rights reserved.

0

20

60

80

100

Mos

0 20 40 60

40Induction CTConcurrent CT (P = .005 vs induction CT; P < .001 vs RT )RT alone


Case 2

Patient feels there is “no cancer like no cancer” and opts to undergo surgery. Pathology confirms ECE in the R cervical node as well as microscopic involvement in 3 adjacent LNs. In total, 4 out of 48 LNs are involved.


What are you going to do next?

1) Post-op XRT

2) Post-op XRT + high-dose platinum

3) Post-op XRT + cetuximab

4) None of the above


Adjuvant Trials: SCCHNRT ± CT (DDP)Trial RT (Gy) F/U,

mosLRC, % DFS, % OS, %

RTOG 9501[1]

≥ 2 LN, ECE, + margins

n = 459 (60-66)

46 81 vs 70(P = .01)

33 vs 25(P = .04)

45 vs 38(P = .19)

EORTC 22931[2]

N2-3, ECE, + margins

n = 350 (66) 60 82 vs 69(P = .007)

47 vs 36(P = .04)

53 vs 40(P = .002)

Bachaud[3]

+ ECE

n = 83 (> 60)

60 70 vs 55(P = .05)

45 vs 23 (P < .02)

36 vs 13(P < .01)

1. Cooper JS, et al. N Engl J Med. 2004;350:1937-1944. 2. Bernier J, et al. N Engl J Med. 2004;350:1945-1952. 3. Bachaud JM, et al. Int J Radiat Oncol Biol Phys. 1991;20:243-246.


Streamlining Adjuvant Therapy

Began to design separate trials for intermediate-risk and high-risk groups

Cooper JS, et al. N Engl J Med. 2004;350:1937-1944. Bernier J, et al. N Engl J Med. 2004;350:1945-1952.Ang KK, et al. Int J Radiat Oncol Biol Phys. 2001;51:571-578.

Risk Stratification

Category Standard of Care

Favorable None

Low 56-60 Gy

Intermediate (ECE-/margin-) 60-66 Gy

High (ECE+/margin+) 60-66 Gy + cisplatin


Postoperative stage III or IV SCCHN

Stratify

Nodal disease

Zubrod score

Prior radiation

R

A

N

D

O

M

I

Z

E



+Cisplatin 30 mg/m2 Wks 2-7

(N = 238)



+Docetaxel 15 mg/m2 Wks 2-7

Kies MS, et al. ASTRO 2009. Abstract 29.

Phase II Adjuvant Chemoradiotherapy + Cisplatin or Docetaxel


Kies MS, et al. ASTRO 2009. Abstract 29. Graphic reproduced with permission.

RTOG H-0234: Locally Advanced Resected

RT + Cetuximab +

Cisplatin Docetaxel

Grade 3/4 reactions, %

Myelosuppression 28 14

Dermatitis 39 39

Mucositis 37 33

Outcome

2-yr OS, % 69 79

2-yr DFS, % 57 66

HR vs 95-01; P value(95% CI)

0.85; .19(0.60-1.21)

0.72; .03(0.50-1.02)


Case 2

2 yrs later, he presents with mild cough. CXR suggests pulmonary nodules; CT confirms multiple lesions in the lungs ranging in size from 5-20 mm. FNA confirms squamous cell carcinoma, identical to the original histology of the HNC.


What is the best therapeutic option for this patient?1) Observation

2) Single-agent chemotherapy

3) Platinum-based chemotherapy alone

4) Platinum-based chemotherapy + cetuximab

5) Single-agent cetuximab


Jacobs C, et al. J Clin Oncol. 1992;10:257-263.

Recurrent/Metastatic SCCHN

Randomized Trials:Combinations vs Monotherapy

Intergroup n RR, % MS, Mos

Cisplatin/5-FU 79 32 5.5

Cisplatin 83 17 5.0

5-FU 83 13 6.1


Forastiere AA, et al. J Clin Oncol. 1992;10:1245-1251.

Recurrent/Metastatic SCCHN

Randomized Trials:Combinations vs Monotherapy

Intergroup n RR, % MS, Mos

Cisplatin/5-FU 87 32 6.6

Carboplatin/5-FU 86 21 5.0

Methotrexate 88 10 5.6


ECOG and SWOG Phase II Trials in Recurrent/Metastatic SCCHN Single-agent therapy (MTX, Pac 96 hr, etc)

– MS: 6 mos

– PFS: 2 mos

Multiple-agent therapy (PF or PPac, etc)

– MS: 9 mos

– PFS: 4 mos


Fan Z, et al. Cancer Res. 1993;53:4637-4642. Graphic reproduced with permission.

Tu

mo

r S

ize

(cm

3)

2

4

Cetuximab

Cisplatin

0 5 15 25 35

Cetuximab+ cisplatin

Days

CetuximabCisplatin

Control (PBS)

A431 cells implanted

A431 xenograft model

Cetuximab + Cisplatin Shows Synergistic Activity

3

1

0302010


Cisplatin 100 mg/m² Day 1 q28days

+

Cetuximab 400 mg/m2 x 1, then 250 mg/m2 wkly

Burtness B, et al. J Clin Oncol. 2005;23:8646-8654.

Cisplatin 100 mg/m² Day 1 q28days

+

Placebo

ECOG 5397

Stratified:

New diagnosis vs recurrent

PS 0 vs 1

Cisplatin + Placebo vs Cisplatin + Cetuximab: Design

R

A

N

D

O

M

I

Z

E


Cisplatin + Placebo vs Cisplatin + Cetuximab: ResultsParameter CDDP + Cetuximab

(n = 63 )CDDP + Placebo

(n = 60)P Value

ORR, %Low-mod EGFR, % High EGFR, %

26.3

40.0

11.8

9.8

11.5

5.9

.029

Median PFS, mos 4.2 2.7 .09

Median OS, mos2-yr OS, %

9.3

15.6

8.0

9.2

.21

NS

Data suggest that patients with rash may fare somewhat better

Burtness B, et al. J Clin Oncol. 2005;23:8646-8654.


EndpointsOSPFSResponse rateDisease controlSafetyQuality of life


Recurrent/Metastatic SCCHNStage III/IV

No prior chemotherapy except if given for locally advanced disease > 6 mos prior to

study entryNo nasopharyngeal carcinoma

(N = 442)

Cetuximab 400 mg/m2 then 250 mg/m2/wk until PD or

unacceptable toxicity+

Carboplatin AUC 5 Day 1 or

Cisplatin 100 mg/m2 Day 1 +

5-FU 1000 mg/m2 Days 1-4 every 3 wks, 6 cycles

Carboplatin AUC 5 Day 1 orCisplatin 100 mg/m2 Day 1

+5-FU 1000 mg/m2 Days 1-4

every 3 wks, 6 cycles

EXTREME: Platinum/5-FU With or Without Cetuximab in Recurrent/Metastatic SCCHN

RANDOMIZE


Cetuximab + Platinum/5-FU

(N = 222)

Platinum/5-FU(N = 220)

Median age, yrs (range) 56 (37-80) 57 (33-78)

Male/female, % 89/11 92/8

Recurrence/metastasis, % Loco-regional recurrence Metastasis

54

46

54

46

Primary metastatic disease, % 8 7

Patient and Disease Characteristics

Cetuximab + First-line Platinum in Recurrent or Metastatic SCCHN (EXTREME)



127153

83118

6582

4757

1930

173184

220222

815

13

HR : 0.797 (95% CI: 0.644-0.986)Strat. log-rank test: .0362

CTX onlyCET + CTX

Su

rviv

al P

rob

abil

ity

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18 21 24

| ||||

||

|||| ||||| |||| ||| | |||| | | | | ||| | | | ||| ||

||

| |

|

|

|

| | ||| |||||||||||| || || |||||| | |||||| |||| | | | || | |

10.1 mos7.4 mos

Pts at Risk, nCTX onlyCET + CTX

Survival Time (Mos)

Cetuximab + First-line Platinum in Recurrent or Metastatic SCCHN: OS

Vermorken JB, et al. N Engl J Med. 2008;350:1116-1127. Copyright © 2008 Massachusetts Medical Society. All rights reserved.


Case 2

Patient opts to enroll on the ongoing phase III randomized trial comparing platinum-based chemotherapy with chemotherapy plus bevacizumab


Recurrent/metastatic SCCHN, PS 0-1,no prior chemo

Cisplatin doublet*+ Bevacizumab 15 mg/kg

every 21 days

Cisplatin doublet*every 21 days

Study Chair: A. Argiris

Endpoint: survivalN = 400

*Cisplatin/docetaxel or cisplatin/5-FU

Status: activated 2009

Phase III Randomized Trial of Cisplatin-Based Chemotherapy ± Bevacizumab

RANDOMIZE


Case 2

Patient initially responds to treatment with bevacizumab and 5-FU-DDP, with 60% reduction in lung metastases but then develops new liver metastases during maintenance therapy with bevacizumab


What is the next “proven” treatment option?1) Single-agent cetuximab

2) Erlotinib or gefitinib

3) Docetaxel plus EGFR TKI

4) Single-agent methotrexate

5) Single-agent pemetrexed

6) Combination therapy with capecitabine and lapatinib


Comparison of Cetuximab-Based Therapy and Other Various Second-Line Therapies

Vermorken JB, et al. J Clin Oncol. 2007;25:2171-2177.

Cetuximab approved in platinum-refractory setting

Treatment N ORR(CR + PR),

%

Disease Control (CP + PR + SD), %

Median OS, Mos

Median TTP, Mos

Cetuximab monotherapy 103 13 46 5.9 2.3

Cetuximab + cisplatin or carbo

96 10 53 6.1 2.8

Cetuximab + cisplatin 79 10 56 5.2 2.2

RetrospectiveAll patientsPts with CT alone

15143

30

159

3.43.6

N/AN/A


Gefitinib in SCCHN: Response Data

Gefitinib 500 mg QD PO

N = 47 eligible patients

Half received previous palliative treatments

ORR: 11% (95% CI: 3.5-23.1)

Disease control (CR + PR + SD): 53%

Median survival of 8.1 mos

13% had disease control ≥ 6 mos

Skin toxicity strong predictor of survival

*NCI audited data.

Cohen EE, et al. J Clin Oncol. 2003;21:1980-1987.

Response n (%)*

CR 1 (2)

PR 4 (9)

SD 21 (45)

PD 22 (47)


Stewart JS, et al. J Clin Oncol. 2009; 27:1864-1871.

Gefitinib vs Methotrexate in Patients With Recurrent or Metastatic SCCHN: OS No significant difference in OS between treatment arms

Median survival: gefitinib 250 mg (5.6 mos), gefitinib 500 mg (6.0 mos), and methotrexate (6.7 mos)

– Gefitinib 250 mg vs methotrexate: HR = 1.22 (95% CI: 0.95-1.57; P = .12)


Patients with platinum-resistant disease had a survival advantage when given methotrexate




Accrual: N = 271

60% PS 2; 72% prior chemotherapy

RANDOMIZED

Docetaxel 35 mg/m2 Days 1, 8, 15 q28days + Placebo

Docetaxel 35 mg/m2 Days 1, 8, 15 q28days +Gefitinib 250 mg/day x 28 days

Argiris A, et al. ASCO 2009. Abstract 6011.

Docetaxel in PS 2 or Previously Treated Pts With Recurrent or Metastatic SCCHN


Arm Docetaxel Docetaxel + Gefitinib P Value

Patients, n 136 134

Grade 3/4 fatigue, n/% 12/3 11/0

Diarrhea, n/% 2/0 11/1

Grade 5 AEs, % 3 7

OR, % 6 12 .21

MTTP, mos 2.1 3.5 .047

PFS, mos 2.2 3.3 .18

OS, mos 6 6.8 .97

Argiris A, et al. ASCO 2009. Abstract 6011. Graphic reproduced with permission.

E1302: Phase III Trial of Docetaxel + Placebo vs Docetaxel + Gefitinib


Erlotinib in Recurrent or Metastatic SCCHN N = 115 with recurrent/metastatic SCCHN

150 mg daily initial dose

– Dose reductions/escalations allowed based on tolerability of drug

Locoregional recurrence (53%); metastatic disease (23%); both (24%)

EGFR positivity

– 87% had strong EGFR staining intensity

– 50% had EGFR staining on > 80% of cells

99% received previous chemotherapy

Soulieres D, et al. J Clin Oncol. 2004;22:77-85.


Erlotinib in Recurrent or Metastatic SCCHN: Results 5 PR (RR: 4.3%)

44 SD (38%) for median 16 wks

– Range to 90+ wks

Median survival: 6 mos

Improved survival in patients with grade ≥ 2 skin rash

– Skin rash vs no skin rash (7.4 vs 4.0 mos; P = .045)

– No difference on the basis of EGFR expression

Adverse events (mostly mild) included acneiform rash (79%), diarrhea (37%)

Soulieres D, et al. J Clin Oncol. 2004;22:77-85.


Phase II Study of Lapatinib in SCCHN

EGFR-HER2 kinase inhibitor

Arm A: no previous EGFR exposure (n = 27)

Arm B: previous EGFR exposure (n = 15)

42 patients enrolled

Diarrhea (40%)

RR: 37% (arm A) and 20% (arm B)

PFS: 1.6 mos (arm A) and 1.7 mos (arm B)

U. Penn: phase II combination lapatinib with capecitabine

Abidoye OO, et al. ASCO 2006. Abstract 5568.


Erlotinib Plus Bevacizumab in Recurrent/Metastatic SCCHN Phase I/II design: no more than 1 previous chemotherapy

regimen Phase I part escalated bevacizumab at 3 dose levels:

5, 10, 15 mg/kg Phase II dose: erlotinib 150 mg PO QD plus bevacizumab

15 mg/kg IV every 21 days Phase II part (N = 48)

– RR: 15%; SD: 54%

– Median PFS: 3.8 mos

– Median OS: 6.8 mos

– 3 serious bleeding events (1 fatal)Vokes E, et al. ASCO 2009. Abstract 5504.


Recurrent or metastatic SCCHN

No previous chemotherapy

PS 0-1

No invasion of major blood vessels No anticoagulation

Pemetrexed 500 mg/m2 IV on Day 1 +Bevacizumab 15 mg/kg IV on Day 1

every 21 days until progression

Endpoints: TTP (primary), RR, OSSample size: 40 patients

UPCI 05-002: Phase II trial of Pemetrexed/Bevacizumab


Phase II trial of Pemetrexed/Bevacizumab: Preliminary Results 25 patients enrolled in 3 centers

Median number of cycles: 6 (range: 1-11)

Best response in 22 evaluable patients

– 8 patients (36%) had an objective response (3 CRs, 5 PRs)

– 13 patients (59%) had SD

– 1 patient (5%) had PD

With a median follow up of 8 mos, the median TTP was 7 mos (95% CI: 3.7-10.3)

4 (16%) grade 3-5 bleeding events

Protocol amended to exclude all pts with a history of bleeding related to SCCHN in previous 6 mos

Argiris A, et al. ASCO 2008. Abstract 6069.


Conclusions

HPV-positive patients constitute a separate prognostic and therapeutic cohort

Concurrent chemoradiation has yielded improved survival in treatment of LA-SCCHN

Docetaxel approved as component of induction Tx for locally advanced (esp N+)

Cetuximab approved with radiation and in metastatic/recurrent setting (2nd line)

Treatment for metastatic/recurrent SCCHN is still poor, but cetuximab appears to augment the efficacy of standard platinum-based therapy

Other targeted agents are undergoing further investigation

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