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
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
From: Cancer Management: A Multidisciplinary Approach
Oral cavity: 44%
Larynx: 31%
Pharynx: 25%
Anatomy
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
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
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)
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
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
Q2. 수술 후 보조 항암 방사선 요법을 시행 시 병합 요법으로 가장 적절 한 항암제를 고르시오
1) Cisplatin 2) Cetuximab 3) Taxane
4) Taxol+ carboplatin
5) Cetuximab + Cisplatin
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%
5-yr PFS 47% vs. 36% 5-yr OS 53% vs. 40%
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
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
23-weekly or 30~40
mg/m
2weekly)
Q1 이 환자에게 시행해야 하는 보조 치료 ? 1) Adjuvant chemotherapy
2) Adjuvant radiotherapy
3) Adjuvant chemotherapy sequential RTx 4) Adjuvant chemoradiotherapy (CCRTx)
5) Observation
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
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
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.
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
CRT is Better than XRT alone for Oropharynx Cancer: 5-year results
Denis, F et al. JCO. 2004
Organ Preservation Protocol Achieve Similar Locoregional & Overall Control
Rate Compared to Surgery
Soo KC et al. Br J Cancer 2005
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
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
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
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
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%)
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
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
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
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
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)
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
Results of recent induction study
PRADIGM
DeCIDE
Overall Conclusion
DeCIDE/PARADIGM/TTCC
Adding TPF to CRT in LA-HNSCC
Did not improve survival
Improved cumulative incidence of
distant failure
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
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
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
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
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)
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
Multiple molecular target in HNSCC
EGFR pathway
VEGF pathway
Hypoxia
C-MET
IGF-1R pathway
Downstream target of RTK (PI3K)
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
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
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.
PET CT scan 31th Jan, 2013
MRI scan 31th Jan, 2013
Erbitux based CCRTx
PET CT scan 13th May , 2013
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)
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
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
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
OS by HPV status in prospective trials
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
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.
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.
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.
This small recurrent disease will eventually…… kill our patient
Scar from previous
surgery
Dermatitis from
previous RT