두경부암의 치료발전과정과 새로운 치료전략
울산의대 서울아산병원 종양내과
김 성 배
1.재발성 또는 전이성 두경부 편평상피암 환자 를 대상으로 한 EXTREME trial(cetuximab+5- FU+CDDP vs 5-FU+ CDDP)에서 primary end point는?
1) Duration of response
2) Progression-free survival time 3) Overall survival
4) Time to treatment failure
5) Response rate
2. 다음 중 두경부암과 human papilloma virus (HPV)의 관계를 옳게 묘사한 것은?
1)
HPV는 두경부암 발생과 상관이 있고,
HPV+ HNSCC는 HPV-HNSCC에 비해 생존기간이 길다.
2) HPV는 두경부암 발생과 상관이 있고,
HPV+ HNSCC는 HPV-HNSCC에 비해 생존기간이 짧다.
3) HPV는 두경부암 발생과 상관이 있으나, HPV 감염과 두경부암 생존과는 무관하다.
4) HPV와 두경부암 발생과는 무관하다.
5) None of above
3. Human papilloma virus (HPV)와 관련된 두경부암이 호발하는 부위는 ?
1) Larynx
2) Oral cavity
3) Hypopharynx
4) Oropharynx
5) Maxillary sinus
Contents
• Epidemiology
• Advances in surgery, RT, and chemotherapy
• Re-exploration of induction treatment
• Anti-EGFR Therapy in SCCHN
• HPV and oropharyngeal cancer
• Palliative care for HNSCC
Epidemiology
around 500,000 new cases / year
World USA/EU Korea
8 16/18 6?
Annual
incidence rate per 100,000
inhabitants
Parkin DM, et al. Cancer Incidence in Five Continents. Vol. VIII. IARC. 2002.
Cancers of upper aerodigestive tract (UADT) in Korea (2001)
Primary site Male Female Total
Larynx 459(51.6%) 29(16.8%) 488(45.9%)
Oral cavity 112(12.6%) 63(36.4%) 175(16.5%)
Oropharynx 87 (9.8%) 19(11.0%) 106(10.0%)
Hypopharynx 99 (11.1%) 2 (1.2%) 101( 9.5%) Nasopharynx 53 ( 6.0%) 21(12.1%) 74 (7.0%) Paranasal
sinuses 33 ( 3.7%) 13 (7.5%) 46 (4.3%)
Nasal cavity 18 (2.0%) 10 (5.8%) 28 (2.6%) Unknown
Primary
18 (2.0%) 4 (2.3%) 22 (2.1%)
Lymphoma 8 (0.9%) 12 (6.9%) 20 (1.9%)
Trachea 2 (0.2%) 0 (0%) 2 (0.2%)
Esophagus 1 (0.1%) 0 (0%) 1 (0.1%)
Total 890(83.7%) 173(16.3%) 1,063(100%)
Kim KM et al. J Kor Med Sci 18:80, 2003
Advances in surgery
• Less extensive surgery
-Total laryngectomy supracricoid laryngecotomy -Hemimandibulectomy mandibular swing
• More reliable reconstructive surgery
-Myocutaneous flaps
(in particular major pectoralis flap)
-Free flap
Advances in radiation therapy
• Hyperfractionated RT
(to increase the total dose)
• Accelerated RT(to reduce overall
treatment time and cell repopulation)
• Radiosensitizer
• IMRT
Advances in chemotherapy
• HNSCC are chemosensitive tumors
- Platinum based chemotherapy - Taxane based chemotherapy
• Combining chemotherapy with radiation is better than alone in locally advanced HNSCC
- Induction chemotherapy followed by RT - Concurrent chemoradiotherapy
- Sequential induction CCRT - Adjuvant CCRT
• Molecular target therapy
- EGFR pathway is important
Contents
• Epidemiology
• Advances in surgery, RT, and chemotherapy
• Re-exploration of induction treatment
• Anti-EGFR Therapy in SCCHN
• HPV and oropharyngeal cancer
• Palliative care for HNSCC
STRATIFY Site
Stage
RA ND OM ZI E
Induction Chemotherapy
(2 cycles)
Responder (1 cycle)
Radiation Therapy
Complete Response Residual
Disease Non-
Responder Surgery
Radiation Therapy
Surgery
Radiation Therapy
Schema of VA Laryngeal Cancer Study
•332 patients, previously untreated stage Ⅲ or Ⅳ
VALCSG. N Eng J Med 324: 1685, 1991 Surgery
OS DFS
CT→ RT
S → RT
• Median follow-up : 33 months
• 2 yr Sur: 68% (p=0.9846)
CT→ RT
S → RT
Shorter DFS, but not significant (p=0.1195)
VALCSG. N Eng J Med 324: 1685, 1991
Patterns of Tumor Recurrence
S→RT CT→RT
SITE OF RECURRENCE (N=166) (N=166)
No. of patients (%)
Primary* 4(2) 20(12) =0.042
Regional 9(5) 14(8)
Distant 29(17) 18(11) =0.001
All 42(25) 52(31)
*Includes recurrences with either positive or negative nodes.
VALCSG. N Eng J Med 324: 1685, 1991
Investiga tors
N of patients
Induction
chemotherapy
Local therapy
Comments
VA 1991
332 PF×3 S/XRT
vs. XRT
64% larynx preservation with chemotherapy; fewer distant metastases
EORTC 1996
194 PF×3 S/XRT
vs. XRT
42% larynx preservation with chemotherapy
Pacca -gnella (Studio) 1994
237 PF×4 S/XRT
vs. XRT
Survival advantage for
chemotherapy in subgroup analysis
Domenge (GEETEC) 2000
174 PF×3 S/XRT
vs XRT
Survival advantage for chemotherapy
Abbreviations: S = surgery; XRT = radiation therapy
Selected studies of PF induction
chemotherapy
Debates on Induction Chemotherapy
• Pros
• Hight RR→Survival
• Feasible in multiple trials
• Not enhance RT toxicity
• Organ preservation
• Systemic control
• Testing of new agents
• Evaluation of targeted therapies
• Cons
• No improvement in local- regional control or overall
survival in randomized study
• Delay of definitive local therapy
• Accelerated repopulation
• Loss of curative option if PD
• Added toxicities (regimen specific)
• Additional small decrease in distant mets= survival
benefit
Meta-Analysis of Locoregional Treatment With and Without Chemotherapy: Effect on Survival
Trial
Category
Hazard
Ratio(95% CI)
Chemo therapy Effect(p)
Hetero geneity (p)
Absolute benefit
2Yr 5Yr
Adjuvant 0.98
(0.85-1.19)
0.74 0.35 1% 1%
Neoadjuvant 0.95
(0.88-1.01)
0.10 0.38 2% 2%
Concomitant 0.81
(0.76-0.88)
<0.0001 <0.0001 7% 8%
Total 0.90
(0.85-0.94)
<0.0001 <0.0001 4% 4%
Pignon et al, Lancet 355: 949, 2000
MACH-NC: Effect of Chemotherapy on 5-Yr Survival
Trial Category No of Trials
No of Patients
Difference (%)
P value
All trials 65 10850 +4 <0.0001
Adjuvant 8 1854 +1 0.74
Induction 31 5269 +2 0.10
PF 15 2487 +5 0.01
Other chemoTx 16 2782 0 0.91
Concomitant 26 3727 +8 <0.0001
Monnerat, et al. Annals of Oncology, 13995-1006,2002
CCRT for Organ Preservation in
Advanced Laryngeal Cancer (RTOG 91-11)
547 III/IV resectable laryngeal cancer Study enrollment: 1992.8.-2000.5.
Major end point: organ preservation Median FU: 3.8 yr
Forastiere et al, N Eng J Med 349:2091, 2003
Tx Arm Larynx
Preservation Rate at 2 Yr
Rate of LRC
Rate Of DM
2yr Sur
Induction
FP x 3 RT 70Gy
75% 61% 9% 76%
Concurrent
CDDP (D1, 22, 43) + RT 70Gy
88% 78% 8% 74%
RT alone, 2Gy/Fx 70Gy/ 7wk
70% 56% 16% 75%
Induction ChemoTx plus RT does not improve organ preservation vs RT alone in patients with locally advanced laryngeal cancer (RTOG91-11, Med FU 6.9 yr)
Tx Arm Larynx
Preservation Rate at 5 Yr
Rate of LRC at 5yr
Rate of DM at 5yr
5 yr Sur G3,4/5 toxicity
Induction FP x 3 RT 70Gy
70% 45% 14% 59% 49.6/0.6
CCRT
CDDP (D1, 22, 43) + RT 70Gy
84% 47% 13% 55% 76.4/3.5
RT alone, 2Gy/Fx 70Gy/ 7wk
66% 34% 22% 54% 46.7/1.8
Forastiere et al, PASCO abst #5517, 2006
Phase Ⅲ Trials: Taxane Induction Therapy
Study Induction Therapy
Local Therapy
n ORR
(%)
CR (%)
Med PFS (Mo)
Med OS (Mo) Hitt CDDP, FU
Paclitaxel CDDP, FU
70 Gy + CDDP 70 Gy +
CDDP
193 189
69 80
14 33
12 20
37 43 Vermor
-ken CDDP, FU Docetaxel, CDDP, FU
66-70Gy 66-70Gy
181 177
54 68
7 9
8.4 12.7
14.2 18.6
Hitt et al. J Clin Oncol 23: 8636, 2005
Vermorken et al. J Clin Oncol 24(18S): 5516, 2006
TAX324 Phase Ⅲ Study
Statification Stage Ⅲ, IV Unresectable
Organ preservation RA ND OM ZI AT OI N
T P
EUA
P F
F
Carboplatin weekly
Radiotherapy
3 Cycles of chemotherapy
3-yr OS : 62% for TPF & 48% for PF ( HR: 0.70; P = .0058) 3-yr PFS: 49% for TPF & 37% for PF (HR: 0.71; P = .004)
PASCO 2006
.
TPF vs PF
1, 2 cycle TPF vs PF 3 cycle
Concomitant Chemo/RT
종양평가 종양평가
R A N D OM I Z A T I O N
Follow up
종양평가
Study Schema
Primary end point: clinical response rate
Seconday end point: pathologic response rate, overall survival,
progression survival
.
Inclusion Criteria
• 조직학적 또는 세포학적으로 입증된, 국소적으로 진행된 두경부암 (적합한 원발종양부위: 구강, 구강인두, 하인두, 후두, 부비강, 비인두)
• 최소 한 개 이상의 양측 또는 단측 계측 가능한 병변
• 원격전이의 증거가 없는 Stage III 또는 Stage IV
• 수술불가능한 종양
1) 기술적 절제불능: 종양 고정 (Tumor Fixation), 두개저부 또는 경추침범, 비인두침범, 림프절 고정
2) 연구자 판단 – 수술후 기대되는 치료효과 저하 – 다음에 해당하는 환자 -모든 T3-4
-모든 N2-3 단계 (T1N2 제외) -장기 보존을 위한 환자
KCSG –HN (7개 기관)
ORR 1yDFR 2yDFS 1yOS 2yOS
TPF (n=43)
84.9% 75.9% 70.0% 88.5% 79.2%
PF (N=43)
81.0% 65.7% 55.1% 75.3% 67.8%
A Randomized Phase II Study of CCRT +/- Neoadjuvant Docetaxel, Cisplatin in Advanced Nasopharyngeal Ca
C T
C
T P P P P P P P P
RT
Week 1 2 3 4 5 6 7 8 9 10 11 12 13 14
C = cisplatin 75 mg/m2 T = taxotere 75 mg/m2 P = cisplatin 40 mg/m2
Chan AT, PASCO abst #5544, 2005
Response Rate by Treatment Arm
(NP: nasopharygeal tumor, LN: neck lymph nodes)
Response Rate Neoadjuvant arm
(n=28)
Control arm (n=25) (a) after neoadjuvant TC NP LN*
CR 6(22%) 10(50%) PR 18(64%) 6(30%)
SD 4(14%) 4(20%) PD 0(0%) 0(0%)
(b) after cisplatin-RT NP LN* NP LN*
CR 27(96%) 16(80%) 21(84%) 15(65%) PR 1(4%) 3(15%) 4(16%) 8(35%)
SD 0(0%) 1(5%) 0(0%) 0(0%) PD 0(0%) 0(0%) 0(0%) 0(0%)
* Pts with LN(-) at baseline were excluded for calculation of LN response
Gr 3/4 toxicities during cisplatin-RT
Toxicity during cisp-RT
Neoadjuvant arm (n=28)
G3 G4
Control arm (n=25)
G3 G4
P-value Hematological
Anemia 3(10%) 0 5(20%) 0 0.3133 Thrombocytopenia 1(4%) 1(4%) 0 1(4%) 0.1090 Neutropenia 6(21%) 22(79%) 3(12%) 1(4%) <0.0001 Febrile neutropenia 0 0 1(4%) 0 0.2853 Non-hematological
Anorexia/nausea/vomiting 3(10%) 0 3(12%) 0 0.3556 Dehydration/renal 5(18%) 0 7(28%) 0 0.5820 Fatigue 2(7%) 0 2(8%) 0 0.9061 Electrolytes 4(14%) 0 0 0 0.0699 Mucositis/odynophagia 10(36%) 1(4%) 11(44%) 1(4%) 0.2387 Transfusion 4(14%) 0 4(16%) 0 0.8618
Renewed interest in a re-exploration of induction treatment
• There is the recognition that more effective induction regimens may well exist.
• A reversal in the pattern of failure previously seen in this disease.
• Chemotherapy responsiveness may be a kind of biomarker, which might prove useful in
identifying those patients who might be best
treated nonoperatively.
Paradigm Shift in the Treatment of Head and Neck Cancer
Induction Chemotherapy
(Surgery) Chemoradiotherapy RT Chemotherapy Surgery
Posner M, et al, Oncol Spectrumns, 2001
Locally Advanced SCCHN
R A N D O M I Z E
Chemotherapy
Radiation plus chemotherapy
Radiation plus chemotherapy
Future Randomized Trials of Induction Chemotherapy
What chemoradiotherapy combination to use?
In which population is this strategy most likely beneficial?
Contents
• Epidemiology
• Advances in surgery, RT, and chemotherapy
• Re-exploration of induction treatment
• Anti-EGFR Therapy in SCCHN
• HPV and oropharyngeal cancer
• Palliative care for HNSCC
Type of tumor
Tumors with EGFR expression Head and neck 90–100%
Colon 75–89%
Pancreas Up to 95%
Breast Up to 91%
Renal Up to 90%
NSCLC Up to 80%
Ovary Up to 77%
Bladder Up to 72%
Glioma Up to 63%
EGFR Expression in Human Tumors
Lung (NSCLC)
Colorectal Head and neck
Ang K, et al. Cancer Res 2002;62:7350–7356
Tumor EGFR expression as a prognostic factor
High EGFR expression in SCCHN is linked to lower survival and increased risk of locoregional relapse
EGFR-targeted monoclonal antibody
therapy has
demonstrated additive or synergistic
antitumor activity in a variety of animal models in vitro and in
vivo when administered in combination with
chemotherapy or radiation therapy
Courtesy of José Baselga (modified)
Cetuximab:
Mechanisms of action
Comparison of EGFR Mabs & TKIs
MAb TKI
examples Cetuximab,
Panitumumab
Gefitinib,Erlotinib, Lapatinib
Mechanism of action
Bind to
extracellular ligand binding domain
Bind to
intracellular TK domain
Route of
administration
Intravenous Oral
Schedule Every 1-3 weeks Daily
Common AE Rash,
hypersensitivity reactions
Rash, diarrhea, nausea
Cost per month 13000 USD (cetuximab)
2500 USD (erlotinib) Availability Cetuximab is FDA
approved (CRC, SCCHN)
Erlotinib is FDA approved (NSCLC), gefitinib in Japan (NSCLC)
Ph III RT ± Cetuximab in LA HNSCC:
Study Design
RT
+ cetuximab
RT
Locally advanced HNSCC
Stratification
KPS
90-100 vs 60-80 Tumor stage
T1-3 vs T4 N0 vs N1
RT fractionation Once daily Twice daily
Concomitant boost
*Absence of locoregional disease progression at scheduled follow-up visits (assessed by an independent review committee)
n=211
n=213
Bonner JA, et al. N Engl J Med. 2006;354:567-578.
Primary:
locoregional control*
Secondary:
OS, PFS, ORR,
QOL, Safety
Efficacy results for phase III study
RT (n = 213) Cetuximab + RT (n = 211)
Hazard ratio [CI]/ p value
Median survival 29.3 months 49.0 months
0.74 [0.57–
0.97]
p = 0.03
3-year rate 45% 55% p = 0.05
Median
locoregional control
14.9 months 24.4 months
0.68 [0.52–
0.89]
p = 0.005
3-year rate 34% 47% p < 0.01
Median
progression-free survival
12.4 months 17.1 months
0.70 [0.54–
0.90]
p = 0.006
3-year rate 31% 42% p = 0.04
Adverse event RT (n=212)
Cetuximab + RT (n=208)
p valuea
Mucositis/stomatitis 52% 56% 0.44
Dysphagia 30% 26% 0.45
Radiation dermatitis 18% 23% 0.27
Xerostomia 3% 5% 0.32
Fatigue/malaise 5% 4% 0.64
Acne-like rash 1% 17% <0.001
Infusion-related reactionsb 0% 3% 0.01
aFisher’s exact test
bListed for its relationship to Erbitux
Cetuximab + RT:
Relevant grade 3–5 adverse events
Bonner J, et al. N Engl J Med 2006;354:567–578
51/M, Tonsil ca, Before
After RT+weekly Erbitux
Survival advantage with Cetuximab + RT compared to CRT vs RT
1 Bonner JA, et al. N Engl J Med 2006; 2Huguenin P, et al. J Clin Oncol 2004; 3Calais G, et al. J Natl Cancer Inst 1999;
4Semrau R, et al. Int J Radiat Oncol Biol Phys 2006; 5Budach V, et al. J Clin Oncol 2005
7 7
14
18
20
0 5 10 15 20
Median survival advantage (months) Carboplatin + 5-FU
+ conventional RT3 Cisplatin + hyperfractionated RT2
Cetuximab + RT1
Carboplatin + 5-FU + hyperfractionated RT (CB)4
Mitomycin C + 5-FU + hyperfractionated RT5
CB, concomitant boost
p=0.15 (not significant)
p=0.02
p=0.02
p=0.02 p=0.03
RTOG 0522: Phase III CRT ± Cetuximab in Locally Advanced HNSCC (Ongoing)
RT
+ cisplatin + cetuximab
RT
+ cisplatin
Locally advanced HNSCC
Stratification
Primary site
Larynx vs non-larynx Zubrod status
0 vs 1 Nodal status
N0 vs N1, N2a, N2b vs N2c, N3
Use of IMRT No vs Yes
Pretreatment PET/CT No vs Yes
Required enrollment: 720 patients
Primary:
DFS
Secondary:
OS,
locoregional
control, safety
Recurrent/Metastatic SCCHN
• 1
stline setting
(Cisplatin/Carbo+ 5-FU/or Taxane) -30% RR
-3~4 Mo PFS -6~8 Mo OS
• 2
ndline setting
- 3~4 Mo OS
Year Patients Regimen OS OR G3-4 toxicity 1992 Forastiere AA,
et al.1
277 cisplatin + 5-FU carboplatin + 5-FU
methotrexate
NS 32%
21%
10%
neutropenia mucositis
1992 Jacobs C, et al.2
249 cisplatin + 5-FU 5-FU
cisplatin
NS 32%
13%
17%
vomiting mucositis
1994 Clavel M, et al.3
382 CABO
cisplatin + 5-FU cisplatin
NS 34%
31%
15%
vomiting
2005 Gibson MK, et al.4
218 cisplatin + 5-FU cisplatin + paclitaxel
NS 27%
26%
reduced for ci splatin + pacli
taxel
Recurrent and/or metastatic SCCHN:
phase III chemotherapy results in first line
No improvement in overall survival in recent decades
CABO=cisplatin, methotrexate, bleomycin and vincristine; NS=not significant; OR=overall response 1. Forastiere AA, et al. J Clin Oncol 1992;10:1245–1251; 2. Jacobs C, et al. J Clin Oncol 1992;10:257–263;
3. Clavel M, et al. Ann Oncol 1994;5:521–526; 4. Gibson MK, et al. J Clin Oncol 2005;23:3562–3567
EXTREME: Phase III Platinum/5-FU
± Cetuximab in 1 st Line RM HNSCC
Platinum/5FU† + cetuximab‡
Platinum/5FU†
Treatment-naïve refractory and/or metastatic HNSCC*
Stratification
Prior chemotherapy KPS <80 vs ≥80
†EITHER carboplatin (AUC 5, d1) OR cisplatin (100
mg/m2 IV, d1) + 5-FU (1000 mg/m2 IV, d1-4) q3w for a maximum of 6 cycles
‡Cetuximab 400 mg/m2 initial dose then 250 mg/m2 weekly until progression or unacceptable toxicity
n=222
n=220
Vermorken JB, et al. Presented at: American Society of Clinical Oncology Annual Meeting 2007. June 1-5, 2007. Abstract 6013.
Primary:
OS
Secondary:
ORR, duration of response,
TTP, QOL,
Safety
Patients at risk PFS time (months)
CT only CT + Cetuximab
220 103 29 8 3 1
222 138 72 29 12 7
HR [95%CI]: 0.538 [0.431–0.672]
Strat. log-rank test: <.0001
EXTREME: Progression-free Survival (PFS)
CT only
CT + Cetuximab
Progression free (%)
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
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5.6 months 3.3 months
Vermorken JB, et al. ECCO 2007 (Abstract No. O#5501; updated information presented)
10.1 months 7.4 months
Patients at risk Survival time (months)
CT only CT + Erbitux
220 173 127 83 65 47 19 8 1
222 184 153 118 82 57 30 15 3
HR [95%CI]: 0.797 [0.644–0.986]
Strat. log-rank test: 0.0362
EXTREME: Overall Survival
CT only
CT + Cetuximab
Survival probability
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
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Vermorken JB, et al. ECCO 2007 (Abstract No. O#5501; updated information presented)
EGFR-inhibitor are associated with related skin reactions
• Mechanism-based toxicity
-EGFR is expressed in skin
• Sterile, acneiform follicular or perifollicular dermatitis
-affects face, trunk, neck
• Typically develops within first 3 weeks of therapy
• Similar rash rate
-cetuximab ≥80%
-panitunimab 90-95%
-erlotinib 61.7%
-gefitinib 45-67%(dose-related)
EGFR signaling
Contents
• Epidemiology
• Advances in surgery, RT, and chemotherapy
• Re-exploration of induction treatment
• Anti-EGFR Therapy in SCCHN
• HPV and oropharyngeal cancer
• Palliative care for HNSCC
Improved Survival of Patients With Human
Papillomavirus--Positive Head and Neck Squamous Cell Carcinoma in a Prospective Clinical Trial
• Nonsmoker, nondrinker
• Younger age
• Similar sex ratio
• Low level of p53 and pRB protein
• P16 upregulated
• Favorable prognosis -absence of field
cancerization,
-immune surveillance to viral- specific tumor antigens
- an intact apoptotic response to radiation
OS DFS
J Natl Cancer Inst. 2008;100(4):261-269
Symptom Treatment Notes
Mucositis Allopurinol mouthwash
GM-CSF gargle
Human placental extract
Weak supporting evidence
Dysphagia Hydration and nutrition Speech & language pathologist
Transient or permanent or severe
Dependent on types of treatment
Xerostomia Frequent intake of water, icechips
Artificial saliva Pilocarpine
Evidence is weak
Change in speech Adaptive
devices(amplifiers)
May not return to baseline level Decreased QOL Supportive treatments,
psychotherapy
Return to baseline level over the long term
Depression Emotional support
antidepressant
Transient or prolonged
Anxiety Emotional support
anxiolytics
Anxiolytics can induce fatigue or delirium
Goldstein NE et al, JAMA 299:1818-1825, 2008
Follow up
• Local and/or regional and/or distant failure
• Second primary cancer
• Treatment side effects
• Comorbid illness
• Pain and/or denutrition
• Need for functional rehabilitation and/or social reinsertion