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(1)

Head and Neck cancer

Medical Oncologist’s Role in Multidisciplinary Teams

- Focus on Adjuvant & Neo-adjuvant Therapy -

Hye Ryun Kim, M.D.

Yonsei Cancer Center, Medical Oncology

(2)

Contents

I. Introduction

II. Treatment in Locally advanced SCCHN

- Upfront surgery + postop RT/CRT - RT-based treatment

Concurrent chemoradiotherapy (CRT)

Induction CTx  CRT - CRT + cetuximab

III. Summary

(3)

From: Cancer Management: A Multidisciplinary Approach

Oral cavity: 44%

Larynx: 31%

Pharynx: 25%

Anatomy

(4)

Multidisciplinary Team Approach

Symptom palliation Keep voice

Swallowing function Better cosmesis

Maintain mental health Social function

Radiation Oncologist

HN Surgeon

Dietician

Rehab.

Med.

Medical Oncologist

(5)

Contents

I. Introduction

II. Treatment in Locally advanced SCCHN

- Upfront surgery + postop RT/CRT - RT-based treatment

Concurrent chemoradiotherapy (CRT)

Induction CTx  CRT - CRT + cetuximab

III. Summary

(6)

CASE I: Q1, Q2

44세 여자

1년 전부터 있던 Lt. tongue ulceration

2014.11 pathology (biopsy of tongue) squamous cell carcinoma

s/p Lt. partial glossectomy with MRND & Reconstruction (2014.12.04)

(7)

병리

결과 보고서

1) Histology type : Tongue, Lt. SCCa, MD,

2) Size: 3.7x3.4cm, invades intrinsic muscle, invasion depth 1.6cm

3) Lymph nodes: level IA (0/3), level IB (1/4), level IIA (4/11), level IIB (1/2), level III (1/8), level IV (0/12), level VA (0/6) and level VB (0/11); total (7/57) perinodal soft tissue extension (2/7) (maximal diameter: 1.7cm)

- LVI (-), PNI(+)

4) Resection margins: negative

stage IVa pT2N2bM0

(8)

Q1. 이 환자에게 시행해야 하는 postop adjuvant therapy에 대하여 옳은 것을 고르시오.

1) Adjuvant chemotherapy 2) Adjuvant radiotherapy

3) Adjuvant chemotherapy sequential RTx 4) Adjuvant chemoradiotherapy (CCRTx)

5) Observation

(9)

Q2. 수술 후 보조 항암 방사선 요법을 시행 시 병합 요법으로 가장 적절 항암제를 고르시오

1) Cisplatin 2) Cetuximab 3) Taxane

4) Taxol+ carboplatin

5) Cetuximab + Cisplatin

(10)
(11)

Randomize

231 Pts

RT 60-66 Gy/30-33 Fr

228 Pts

RT 60-66 Gy/30-33 Fr Cisplatin 100 mg/m2,

d1,22,43

Primary end point:

Locoregional control

Secondary end points:

Disease-free survival,

Overall survival,

Adverse effects

EORTC Trial: Schema

Unfavorable features: Extranodal spread, RM +, perineural involvement, vascular tumor embolism, oral cavity or oropharyngeal tumor with LN level IV or V

Surgery

(oral cavity, oropharynx, hypopharynx, larynx)

- pT3 or pT4 - N2 or N3

- pT1/T2 and N0/N1 with unfavorable patholgic findings

Oral cavity ~30%

(12)

5-yr PFS 47% vs. 36% 5-yr OS 53% vs. 40%

(13)

Phase III Randomized Trials:

Concurrent Chemo-RT vs. Radiotherapy alone

Treatment

EORTC 22931 (n = 334)

RTOG 9501 (n = 410 )

DDP/RT (%) RT (%) P value DDP/RT (%) RT (%) P value

5 Y-LRF 18 31 0.007 20 29 0.083

5 Y-DFS or PFS

47 36 0.04 37 29 0.098

5 Y-OS 53 40 0.02 45 37 0.19

Acute toxicity ≥ Gr 3

41 21 0.001 77 34 <0.0001

LRF, locoregional failure; DFS, disease-free survival; PFS, progression-free survival;

OS, overall survival.

Bernier J. N Engl J Med 2004;350:1945-1952; Cooper J. N Engl J Med. 2004

(14)

Conclusion: Postoperative Therapy

Adjuvant concurrent chemoradiation in high-risk disease is standard of care

(“MUST”)

Addition of chemotherapy resulted in a significant increase in local control and DFS, OS (in EORTC)

Cisplatin-based CRT is the current

standard (100 mg/m

2

3-weekly or 30~40

mg/m

2

weekly)

(15)

Q1 이 환자에게 시행해야 하는 보조 치료 ? 1) Adjuvant chemotherapy

2) Adjuvant radiotherapy

3) Adjuvant chemotherapy sequential RTx 4) Adjuvant chemoradiotherapy (CCRTx)

5) Observation

(16)

Q2 수술 후 보조 항암 방사선 요법을 시행 시 병합 요법으로 가장 적절한 항암제를 고르시오

1) Cisplatin 2) Cetuximab 3) Taxane

4) Taxol+ carboplatin

5) Cetuximab + Cisplatin

(17)

Contents

I. Introduction

II. Treatment in Locally advanced SCCHN

- Upfront surgery + postop RT/CRT - RT-based treatment

Concurrent chemoradiotherapy (CRT)

Induction CTx  CRT - CRT + cetuximab

III. Summary

(18)

NCCN Practice Guideline

Risk features: extracapsular nodal spread, positive margins, pT3 or pT4 primary, N2 or N3 nodal disease, nodal disease in levels IV or V, perineural invasion, vascular embolism.

(19)

Role of Chemoradiation in LA-HNSCC

Improved tumor control and OS in HNSCC, compared with RT alone

– MACH-NC: The biggest 5-yr absolute benefit

5.6% & pronounced effect on locoregional control

– Preferred option for organ preservation

Toxicity, both acute and late, is enhanced

Pignon JP, et al. Radiotherapy and Oncol, 2009 Trotti A et al. Radiother Oncol 2003

(20)

CRT is Better than XRT alone for Oropharynx Cancer: 5-year results

Denis, F et al. JCO. 2004

(21)

Organ Preservation Protocol Achieve Similar Locoregional & Overall Control

Rate Compared to Surgery

Soo KC et al. Br J Cancer 2005

(22)

Contents

I. Introduction

II. Treatment in Locally advanced SCCHN

- Upfront surgery + postop RT/CRT - RT-based treatment

Concurrent chemoradiotherapy (CRT)

Induction CTx  CRT - CRT + cetuximab

III. Summary

(23)

Differential Effect on Failure Patterns

Significant improvement in locoregional (LRC) and distant control (DC) with

concomitant chemotherapy

– LRC: HR 0.74 (0.7-0.79; p<0.0001) – DC: HR 0.88 (0.77-1.0; p=0.04)

No improvement in LRC, but significant improvement in DC with induction

chemotherapy

– LRC: HR 1.03 (0.95-1.13; p=0.43) – DC: HR 0.73 (0.61-0.88; p=0.001)

Induction chemotherapy has a more pronounced impact on distant control than concomitant chemotherapy

CRT and Induction chemotherapy may be complementary

Pignon JP, et al. Radiotherapy and Oncol, 2009

(24)

Do Induction Chemotherapy and CRT have Complementary

Effects on Overall Control of Disease?

A sequential approach

Induction chemotherapy

Definitive local

therapy (RT or CRT)

Active induction CT improves distant control & further improves locoregional control

Brief dose-dense regimen without compromizing CCRT

Avoiding a long delay of CCRT (selective repopulation of resistant tumor)

Intensive local therapy regimen improves locoregional control

(25)

TAX324 (US)

TPF vs PF Followed by Chemoradiotherapy

R A N D O M

I Z E

P

P F

F

Carboplatin - AUC 1.5 Weekly

Daily Radiotherapy

EUA T

Surgery

TPF: Docetaxel 75D1 + Cisplatin 100D1 + 5-FU 1000 CI- D1-4 Q 3 weeks x3 PF: Cisplatin 100 D1 + 5-FU 1000 CI-D1-5 Q 3 weeks x 3

Posner, NEJM, 2007

(26)

TAX324: Patients Characteristics

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 Inoperability

Technical Unresectability Low Surgical Curability Organ Preservation

92 (36%) 78 (31%) 85 (33%)

84 (34%) 75 (31%) 87 (35%)

(27)

Survival Time (months)

Survival Probability (%)

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

TPF 62%

PF 48%

Log-Rank P = 0.0058 Hazard Ratio = 0.70

TPF 67%

PF 54%

30% reduction in risk of death

TAX324: Overall Survival

(28)

TPF versus PF: Organ Preservation

3-yr LFS: 52% (TPF) vs. 32% (PF)

Posner MR. Ann Oncol 2009; Pointreau Y. JNCI 2009

TAX324 subgroup: Operable laryngeal/

hypopharyngeral cancer

3-yr LP: 70.3% (TPF) vs. 57.5% (PF) P= 0.03

GORTEC phase III

(29)

Study,

population

N Primary endpoint

Regimen Significant outcomes

TAX323, Inoperable

358 PFS PF/RT vs. TPF/RT TPF better in PFS and OS, P < 0.01

TAX324,

locally advanced

501 OS PF/CRT vs.

TPF/CRT

TPF better in 5-year PFS and OS, P= 0.01;

in LFS, P < 0.03 GORTEC 2000-01,

resectable

larynx/hypopharynx

213 Larynx preservation

PF/RT vs. TPF/RT TPF better in LP, P < 0.04

Spanish Head and Neck group,

locally advanced

382 Overall CR rate

PF/Paclitaxel/CRT vs. PF/CRT

PF/Paclitaxel better in CR rate (33% vs. 4%), P <0.001; in OS (43 mo vs. 37 mo), P=

0.03

Summary of Induction Chemotherapy in Four Pivotal Trials

Posner MR, N Engl J Med 2007; 357: 1705–1715; Vermorken JB, N Engl J Med 2007; 357: 1695–1704;

Pointreau Y, J Natl Cancer Inst 2009; 101: 498–506; Hitt R, J Clin Oncol 2005; 23: 8636–8645.

Abbreviation: PF, cisplatin/5-FU; TPF, docetaxel/cisplatin/5-FU; CRT, concurrent chemoradiotherapy; LP, larynx preservation

(30)

Induction Chemotherapy in LA-HNSCC

TAX323/324 demonstrate TPF ICT superior to PF ICT in LA-HNSCC

↑ 3-yr OS ~10%

↓ Risk of death ~30% (HR 0.70-0.74) (vs. CRT > PF induction, Δ 3.5%)

↑ 7~19% Complete response

↑ 10-20% LP or LFS

(31)

Important Questions Raised after TAX Studies

Is induction chemotherapy followed

by definitive local therapy superior to CRT alone?

Dose induction chemotherapy

decrease distant metastasis, thereby

improve OS ? (N2/N3)

(32)

Sequential Therapy vs

Concurrent Chemoradiation only

Group Regimen

Boston (US) (Paradigm)

Chicago (US) (DeCIDE)

TPF x 3  CRT (carboplatin)

CRT (cisplatin)

TPF x 2  THFX THFX

(33)

Results of recent induction study

PRADIGM

DeCIDE

(34)

Overall Conclusion

DeCIDE/PARADIGM/TTCC

Adding TPF to CRT in LA-HNSCC

Did not improve survival

Improved cumulative incidence of

distant failure

(35)

Phase III randomized study of IC followed by CCRT compared with

concurrent chemotherapy alone in patients with N2 or N3 disease (DeCIDE)

All patients

N2a or 2b N2c or N3

J Clin Oncol 32:2735-2743

(36)

Sequential Therapy for HNSCC:

Experimental Therapy

Induction Chemotherapy (TPF-based)

CRT or RT

When and For Whom?

Good PS; Large or low neck node (+);

Oropharynx, hypopharynx, larynx primary

(37)

Contents

I. Introduction

II. Treatment in Locally advanced SCCHN

- Upfront surgery + postop RT/CRT - RT-based treatment

Concurrent chemoradiotherapy (CRT)

Induction CTx  CRT - CRT + cetuximab

III. Treatment in metastatic SCCHN

IV. Summary

(38)

CASE 2: Q3

62세 남자

8개월간의 odynophagia

Karnofsky performance status: 100%

Comorbidity: HTN

Smoking Hx: current smoker 50pyrs

Laryngoscope 소견

Ulcerative mass on posterior hypopharyngeal wall

No involvement in both arytenoid and pyriform sinus

vocal cord intact

Pathologic diagnosis: squamous cell carcinoma

(39)

Baseline image

PET CT scan 31th Jan, 2013

MRI scan 31th Jan, 2013 Hypopharynx, posterior wall, SCCa, cT4a/bN2bM0, stage IVA

T= Mass infiltrates hyoid bone, Possible invasion of prevertebral fascia.

N= Metastatic LNs in both neck level II-III. (1.5cm)

(40)

Q3. 이 환자에게 시행할 가장 적합한 치료 방법은 ? 1) Operation

2) Operation  post op adjuvant radiotherapy 3) definitive concurrent chemoradiotherapy

4) Induction chemo  operation

5) Chemotherapy

(41)

Multiple molecular target in HNSCC

EGFR pathway

VEGF pathway

Hypoxia

C-MET

IGF-1R pathway

Downstream target of RTK (PI3K)

(42)

Stage III and IV non-metastatic

SCCHN (n=424)

RT (n=213)

Erbitux + RT (n=211)

Erbitux initial dose (400 mg/m2) 1 week before RT

Erbitux (250 mg/m2) + RT (weeks 2–8)

Erbitux + RT in locally advanced SCCHN: Phase III study design

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

*Bonner J, et al. as presented ASTRO 2008

R

3-year locoregional control rate: 47% vs 34%, p<0.01 3-year overall survival rate: 55% vs 45%, p=0.05 5-year overall survival rate: 46% vs 36%, p=0.02

Stratified by

KPS

Nodal involvement

Tumor stage

RT regimen

Oral cavity cancer excluded

(43)

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

ERBITUX + RT: OS 5 year update

0 10 20 30 40 50 60 70

Months

Probability of Overall Survival

Treatment Total Death Alive Median

RT 213 130 83 29.3

Erbitux + RT 211 110 101 49.0

ERBITUX + RT

RT

ERBITUX + RT RT p- value

5-year OS rate 46% 36% 0.02

p = 0.02

ERBITUX + RT improves significantly long term

survival, with nearly half of the patients alive at 5 years

HR=0.73 (0.56–0.95)

Bonner J.A, et al. as presented ASTRO 2008

(44)

Erbitux + RT in LA SCCHN:

- Indirect comparison with CRT -

Levy AR, et al. Curr Med Res Opin 2011;27:2253-2259 1: Pignon et al. meta-analysis

2: All original studies with p-value 0.10 assumed for Forastière et al. (modified from Levy et al. 2011 to correct an error in the publication) 3: All original studies with p-value 0.99 assumed for Forastière et al.

4: Only studies with comparable mortality to Bonner et al. in RT arm 5: All original studies reporting locoregional control as an outcome 6: Only studies with comparable mortality to Bonner et al. in RT arm

7: As for Locoregional Control 2, with adjusted hazard ratio used in place of unadjusted for Huguenin et al.

0.92 (0.72–1.21)1 1.02 (0.74–1.40)2 0.93 (0.68–1.28)3 0.97 (0.62–1.52)4

1.15 (0.80–1.64)5

0.99 (0.56–1.77)7 1.02 (0.66–1.58)6

0.0 0.5 1.0 1.5 2.0

HR (95%CI) for Erbitux + RT relative to CRT

Favors Erbitux + RT Favors CRT

Overall Survival

Locoregional Control

Survival benefit of adding Erbitux to RT is

within the same range as CRT.

(45)

PET CT scan 31th Jan, 2013

MRI scan 31th Jan, 2013

Erbitux based CCRTx

PET CT scan 13th May , 2013

(46)

Q3 이 환자에게 시행할 가장 적합한 치료 방법은 ?

1) Operation

2) definitive CCRTx

3) Induction chemo  CCRTx 4) Induction chemo  op

5) definitive Erbitux based RTx (ERT)

(47)

Optimizing quality of survival for patients with locally advanced SCCHN

 Adding Erbitux to RT significantly:

Extends survival

Prolongs disease control

Increases response rate

 …while maintaining the quality of that survival

 Erbitux + RT is appropriate for patients eligible f or CT

 Maximizing QoS is the principle of treatment of L ASCCHN

(48)

I. Introduction

II. Treatment in Locally advanced SCCHN

- Upfront surgery + postop RT/CRT - RT-based treatment

Concurrent chemoradiotherapy (CRT)

Induction CTx  CRT - CRT + cetuximab

III. Summary

Contents

(49)

HPV in oropharyngeal ca

Risk group based on HPV, tobacco use & T/N status

- Possible role for dose de-escalation in patient subgroup-

Ang KK et al New Engl J Med 2010;363:24-35

(50)

OS by HPV status in prospective trials

(51)

De-intensification candidate in HPV+ OPC

3yr Distant control rate (%) RT alone vs. CRT

No significant differences Low risk group: T1-3N0-2a

Good risk HPV+ tumors may do well with RT alone

O’Sullivan B et al J Clin Oncol 2013;31:543-50

HPV+ OPC

(52)

Q4. LA-HNSCC 에 관련한 설명 중 틀린 것을 고르시오 .

1) HPV + oropharynx cancer 환자는 HPV – 환자보다 예후가 좋다.

2) Erbitux based concurrent chemoradiotherapy (CCRTx)는 cisplatin based CCRTx보다 생존율을 증가시킨다.

3) Erbitux based CCRTx는 cisplatin based CCRTx에 비하여 삶의질 측면에서 우월하다.

4) Induction chemotherapy 은 LA-HNSCC 환자의 생존율 을 증가 시키지 못하였다.

5) Unresectable 두경부 암 환자에 대하여 induction

chemotherapy를 시행하여 수술하는 것은 standard care 가 아 니다.

(53)

Q4. LA-HNSCC 에 관련한 설명 중 틀린 것을 고르시오 .

1) HPV + oropharynx cancer 환자는 HPV – 환자보다 예후가 좋다.

2) Erbitux based concurrent chemoradiotherapy (CCRTx)는 cisplatin based CCRTx보다 생존율을 증가시킨다.

3) Erbitux based CCRTx는 cisplatin based CCRTx에 비하여 삶의질 측면에서 우월하다.

4) Induction chemotherapy 은 LA-HNSCC 환자의 생존율 을 증가 시키지 못하였다.

5) Unresectable 두경부 암 환자에 대하여 induction

chemotherapy를 시행하여 수술하는 것은 standard care 가 아 니다.

(54)

Summary

Adjuvant concurrent chemoradiation in high-risk disease is standard of care.

Chemoradiation in LA-HNSCC is standard of care and improve tumor control and OS in HNSCC, compared with RT alone.

Adding induction chemotherapy to CRT in LA-HNSCC did not improve survival.

Consider in subset group: Good PS; Large or low neck node (+); Oropharynx, hypopharynx, larynx primary.

Erbitux based CRT is comparable in survival outcome and better in QoL compare with CRT.

(55)

This small recurrent disease will eventually…… kill our patient

Scar from previous

surgery

Dermatitis from

previous RT

(56)

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