Transcript SYSTEMIC THERAPY IN HEAD & NECK CANCER Radiation Oncology Grand Rounds Tuesday, December 3, 2013 Michelle T.

SYSTEMIC THERAPY
IN HEAD & NECK
CANCER
Radiation Oncology Grand Rounds
Tuesday, December 3, 2013
Michelle T. Ashworth, MD
Clinical Fellow, Hematology-Oncology
Epidemiology: World
560,000
cases
per year
M:F
2-4:1
300,000
deaths
per year
#5
cancer
Epidemiology: US
53,000
cases
per year
M:F
2-4:1
11,500
deaths
per year
Epidemiology: US
3% of all
cancers
in US
$3.6B
per year
Anatomic structures
Nasal cavity & paranasal sinuses
Oral cavity
Salivary glands
Pharynx
Larynx
Lymph nodes
Presenting symptoms
Voice
change
Dysphagia
Cough
Pain
Ulcer
Mass
Weight
loss
Anatomic divisions per NCCN guidelines
Lip
Glottic
larynx
Oral
cavity
Supraglottic
larynx
Oropharynx
Ethmoid
sinus
Hypopharynx
Maxillary
sinus
Nasopharynx
Occult
primary
Incidence by primary site [SEER, 2009]
2%
7%
Larynx
5%
Oral cavity
28%
10%
Tongue
Oropharynx
Lip
11%
Hypopharynx
17%
20%
Nasopharynx
Other
Tissues of origin
Squamous
mucosal
epithelium
90%
SCCHN
Blood
vessels
Glands
Muscle
Bone
Lymph
nodes
Cartilage
Nerves
Risk factors
#1:
tobacco
& alcohol
HPV (16):
>60%
oropharyngeal
cancer
Betel
nut
Occ
Exp
Diet
EBV:
Nasopharyngeal
cancer
RT
Agent
Orange
HIV:
2-3x RR
Genetics
HPV as prognostic biomarker in oropharyngeal
SCCHN
SCCHN – Pathogenesis
Field
cancerization
Premalignant
lesions
Stepwise
progression
May be
reversible
EGFR
90%
p53
50-80%
HER2
50%
PTEN
10%
PI3KCA
6-8%
HRAS
5%
Pretreatment & staging evaluation
All patients: H&P,
biopsy, preanesthesia studies
Fiber-optic
exam, EUA,
video-strobe
Dental, nutrition,
speech & swallow,
audiogram
CT/MRI
primary
& neck
Chest
imaging
F PRN
D
PRN
PRN
Oral cavity
F, EUA PRN
D
N, SS PRN
√c
√
√
Oropharynx
F, EUA PRN
D
N, SS, A PRN
√c
√
√
Hypopharynx
F,VS PRN
EUA,
D
N, SS, A PRN
√c
√
√
Nasopharynx
F
D, N, SS, A PRN
*c
PRN
√*
F,VS PRN
EUA
D, N, SS, A PRN
√c•
√
√
Ethmoid sinus
F PRN
D PRN
^
√
Maxillary sinus
F PRN
D PRN
√c
√
F PRN, EUA
PRN
^
√
Lip
Glottic &
supraglottic larynx
Occult primary~
Consider
PET/CT for
stage III-IV
PRN
HPV,
EBV
HPV
EBV
PRN
Role of systemic therapy (ST)
 Adjuvant (after surgery) [early stage, adverse features discovered at
time of surgery]
 Concurrently with RT, as a radiosensitizer
 Definitive-intent [later stage, adverse features apparent prior to
surgery]
 Concurrently with RT, as a radiosensitizer, or
 Induction followed by concurrent chemo/RT
 Controversial: careful patient selection and expert management of toxicities required
 Possibly followed by surgery for residual or recurrent disease
 Palliative-intent (unresectable/metastatic)
 Concurrently with RT or alone; combination regimens or monotherapy
 Intended to control symptoms, prolong life
Treatment paradigms for early stage SCCHN
 Lip, oral cavity & oropharynx:
 Surgery → ST/RT → VAHNC
 Hypopharynx:
 RT or ST or ST/RT → assess for response → surgery or ST/RT
 Nasopharynx:
 RT or ST/RT +/- adjuvant ST or ST → ST/RT or ST
 Glottic & supraglottic larynx:
 RT or surgery +/- adjuvant ST or ST/RT or ST → assess for response →
surgery or ST/RT
 Ethmoid sinus:
 Surgery → RT or ST/RT → observation or RT or ST/RT
Very advanced SCCHN
 “Very advanced” SCCHN
of lip, oral cavity,
oropharynx, hypopharynx,
glottic larynx, supraglottic
larynx
 T4b, Nany, M0 or
unresectable nodal disease
or, if patient is not a surgical
candidate
 Clinical trial preferred
 For PS 1: ST/RT or ST →
RT or ST/RT
 For PS 2: RT +/- ST
 For PS 3: RT or singleagent ST or best
supportive care (BSC)
 If primary controlled +
residual disease, follow
with salvage surgery /
neck dissection if
possible
Systemic therapy agents
 Bleomycin
Cytotoxic
chemotherapy
 Cisplatin or carboplatin
 5-FU
 Docetaxel or paclitaxel
 Hydroxyurea
 Epirubicin
 Methotrexate
 Ifosfamide
 Gemcitabine (NPC)
 Vinorelbine
 Capecitabine
 Targeted therapy
 EGFR/HER1 inhibitor
cetuximab
 Clinical trial agents
 Anti-PD1 or anti-PDL1
antibody, e.g. MK-3475
 Injectable oncolytic virus, e.g.
TVEC
 Other targeted agents, e.g.
dasatinib
Systemic therapy agents
Cisplatin
or
Carboplatin
Hydroxyurea
Cetuximab
Docetaxel
or
paclitaxel
5-FU
Epirubicin
MTX
Ifos
Bleo
Gem
Cape
Vin
Commonly used SCCHN treatment regimens
Concurrent systemic therapy as radiosensitizer
 Cisplatin 100 mg/m2 IV every 3 weeks, or 40 mg/m2 IV weekly
 Carboplatin AUC 5-6 IV every 3 weeks
 Cetuximab 400 mg/m2 IV week 1, then 250 mg/m2 weekly thereafter
Induction
 “PF,” Cisplatin 100 mg/m2 IV d1 + 5-FU 1000 mg/m2 daily IV d1-5
 “TPF,” taxane, platinum, 5-FU: docetaxel 75 mg/m2 + cisplatin 80
mg/m2 + 5-FU 800 mg/m2/day x96h CIVI every 3 weeks x3
Palliative-intent
 Single-agent or combination regimens
Outcomes:
Concurrent ST/RT in SCCHN
 Metaanalysis of chemotherapy trials in SCCHN: MACH-NC
 87 trials
 16,665 patients
 Median follow-up of 5.5 years
 Concurrent treatment, platinum-based
MACH-NC
MACH-NC
Weekly vs every 3 weeks concurrent
cisplatin/RT in SCCHN
 Series of patients treated with cisplatin/RT: younger
patients with ECOG PS 0-1 were treated with cisplatin
every 3 weeks and older patients with ECOG 2 were
treated with cisplatin weekly
 CR 50% vs 40%, p>0.05
 ORR 92% vs 90%, p>0.05
 G3-4 AEs 53% vs 40%, p>0.05
Concurrent cetuximab/RT in SCCHN
 Phase III study in advanced/
inoperable SCCHN with XRT
+/- cetuximab 400 mg/m2 then
250 mg/m2 weekly showed
median locoregional control
24.4 mo vs 14.9 mo and OS 49
mo vs 29.3 mo, with acneiform
rash and infusion reactions in
cetuximab-treated group but
otherwise no difference in
grade ≥3 AEs (Bonner, Ang et al N
Engl J Med 2006 Feb 9;354(6):56778)
Concurrent
cetuximab/RT in SCCHN
 Phase III study in
recurrent/metastatic
SCCHN of PF+XRT +/cetuximab 400 mg/m2
then 250 mg/m2 weekly
maintenance showed
response rate 36% vs 20%,
median PFS 5.6 vs 3.3 mo,
and OS 10.1 mo vs 7.4 mo
(Vermorken, Hitt et al N Engl J Med
2008 Sep 11;359(11):1116-27)
Subgroup
Analysis
Cetuximab-related rash as predictive
biomarker in SCCHN
Recurrent/metastatic SCCHN
Overall survival 6-9 mo
 Factors correlating with good prognosis: ECOG 0-1, poorly
differentiated histology, h/o response to chemotherapy
 Factors correlating with poor prognosis: ECOG ≥2, weight loss,
recurrence after RT, current smoking, significant medical
comorbidity
Combination therapy regimens increase PFS but
have not been shown to increase OS
Treatment varies by PS, prior treatment, goals of
care, and medical comorbidities
Treatment outcomes –
Combination therapy in metastatic SCCHN
 Cisplatin 100 mg/m2 or carboplatin AUC 5 + 5-FU 1000 mg/m2/d d1-4 +/-
cetuximab every 3 weeks, up to 6 cycles, + maintenance cetuximab
 Limited to patients not previously treated for advanced cancer, KPS ≥ 70, largely
≤ age 65
 Median PFS 5.6 mo vs 3.3 mo; median OS 10.1 mo vs 7.4 mo
Treatment outcomes –
Combination chemotherapy in recurrent/
metastatic SCCHN
 A Cisplatin 100 mg/m2 IV
d1 + 5-FU 1000 mg/m2 IV/d
d1-4 every 21d vs. B
carboplatin 300 mg/m2 IV
d1 + 5-FU 1000 mg/m2 IV
d1-4 every 28d vs. C MTX
40 mg/m2 IV weekly
 ORR 32% vs. 21% vs. 10%;
however, similar median OS
across all 3 groups
Treatment outcomes –
Cetuximab in metastatic SCCHN
 Platinum-refractory patients
 ORR 13%; disease control rate 46%
 Median PFS 70 days; median OS 178 days
Future directions in SCCHN
RTOG 1016
RT/cisplatin vs RT/cetuximab in HPV+
oropharyngeal cancer
Stratification by stage, PS, smoking hx
Future directions – targeted therapy in
SCCHN
Afatinib: TKI of HER2, EGFR
 PII study in R/M SCCHN comparing afatanib 50 mg PO
daily vs cetuximab 400 mg/m2 then 250 mg/m2 weekly
showed 6/34 (18%) vs 3/40 (8%) PR, 18/34 (53%) vs
20/40 (50%) SD, 10/34 (30%) vs 17/40 (43%) with PD,
and comparable safety profile (Siewert, Cohen et al J Clin
Oncol 28:15s, 2010 suppl; abstr 5501)
 Recent FDA approval in NSCLC; multiple clinical trials in
SCCHN now open
Future directions – targeted therapy in
SCCHN
 Panitumumab: humanized mAb  Nimotuzumab: humanized
EGFR inhibitor
 PIII study in R/M SCCHN comparing
panitumumab + CT to CT reported
efficacy of panitumamab in pts with
HPV+ vs HPV- tumors
(retrospectively) and showed median
OS in HPV+ PCT 11 mo vs CT 12.6
mo, and HPV- PCT 11.7 mo vs CT
8.6 mo*, i.e. improvement in OS with
P only in HPV- (Vermorken et al Lancet
Oncol 2013 Jul; 14(8):697-710)
 Open clinical trials in SCCHN
mAb EGFR inhibitor
 PIII study in A/I SCCHN
comparing nimotuzumab 200
mg weekly x 6-7 wks with or
without cisplatin + XRT
showed 24/25 (96%) vs. 18/25
(72%) objective response rate
at 6 mo, without increased
toxicity (Bhatnagur, Kumbaj et al J Clin Oncol
30, 2012 suppl; abstr e16012)
 Open clinical trials in SCCHN
Future directions – targeted therapy in
SCCHN
 Combination
therapy?
Future directions – immunotherapy in SCCHN
 Ipilimumab: mAb CTLA-4
inhibitor
 Experience in NSCLC: PII
trial in stage IIIB/IV NSCLC
comparing paclitaxel 175
mg/m2 + carboplatin AUC 6
with ipilimumab 3 mg/m2 q3
wks x4 then q12 wks showed
median irPFS of 5.7, 5.5, and
4.6 mo; in phased arm, HR 0.55
in SCC vs 0.82 in NSCC.
Phase III trial open in
squamous NSCLC (Lynch, Reck et al J
Clin Oncol 2012 Jun 10;30(17):2046-54)
Future directions – immunotherapy in SCCHN
Various mAb PD-1 or PDL-1 inhibitors
 Evidence for PD-1:PDL-1 pathway in HPV+ SCCHN, with
membranous expression of PDL-1 in tonsillar crypts (site of
primary HPV infection), on tumor cells, and on tumor-associated
macrophages, and high PD-1 expression on CD8+ TILs (Lyford-Pike, Pai
et al Cancer Res 2013 Mar 15;73(6):1733-41)
 In-vitro blockade of tumor growth in oral SCC cell line with anti-
PD-1 mAb (Tsushima, Azuma et al Oral Oncol 2006 Mar;42(3):268-74)
 Clinical trial now open
 T-VEC: talimogene laherparepvec, injectable oncolytic
herpesvirus
Salivary gland tumors
 Adenoid cystic carcinoma, adenocarcinoma, mucoepidermoid carcinoma
 High grade (more likely to invade) vs low grade (more likely to be cured with local






treatment)
Epidemiology: not related to tobacco + ETOH, but prior RT may increase risk
Standard of care is surgery +/- RT
Systemic therapy as radiosensitizer or with palliative intent in advanced disease is
often used; however, due to rarity of disease and mixed histology in trials, there is
not clear evidence to support or contradict this
KIT mutation noted in 80% of ACC; however, ORR of 0% in one trial of imatinib
given to KIT-mutation-unknown patients with ACC
Clinical trial recommended: targeted therapy, e.g. EGFR or VEGF
Salivary duct carcinoma may express androgen receptors or overexpress HER2 or
EGFR; responses reported to anti-androgen therapy, trial of trastuzumab ongoing
Nasopharyngeal
carcinoma
 Nasopharynx:
 RT or ST/RT +/- adjuvant ST or ST →
ST/RT or ST
 Concurrent cisplatin 100 mg/m2 IV every
3 weeks +RT, then cisplatin 80 mg/m2 +
5-FU 1000 mg/m2/d d1-4 every 4 weeks
 5-year PFS 62 vs 53%, 5-year OS 68 vs 64%
 Single-arm study of concurrent
carboplatin AUC 6 every 3 weeks then
carboplatin AUC 5 + 5-FU 1000 mg/m2/d
d1-4 every 4 weeks
Nasopharyngeal
carcinoma
 Concurrent cisplatin 40 mg/m2 IV
weekly + RT
Advanced nasopharyngeal carcinoma
 Induction with TPF: docetaxel
70 mg/m2 d1 + cisplatin 75
mg/m2 d1 + 5-FU 1000
mg/m2/d IV d1-4 x3 cycles, then
RT + cisplatin 100 mg/m2 every
3 weeks
 3-year PFS 75.6%, 3-year OS 86.1%
Mucosal melanoma
 4% of all sinonasal malignancies
 Melanocytes are found in the mucosa in the sinonasal cavity
in 21% of individuals
 Mean age of presentation 64.3 years
 RT improves local control; 50% will have local (vs. distant)
recurrence
 Historically, studies have shown no difference in OS in
treated with surgery vs surgery + RT or ST or all 3
 5-year OS 25-42%
Mucosal melanoma
Mucosal melanoma
 Up to stage T4aN1: Surgery → RT
 Stage IVB onwards: Clinical trial preferred or RT or ST
 Systemic therapy in advanced disease:
 KIT mutation present in 30-40% of mucosal melanoma; responses
reported to KIT inhibitors e.g. imatinib, and targeted therapy is
available off-label or on clinical trials
 Imatinib: ORR 21%, median OS 46.3 weeks
 Ipilimumab: CR in 1/30 patients, PR 1/30, median OS 6.4 mo
 Anti-PD1 antibody on clinical trial: early reports of observed
response
 Palliative-intent chemotherapy
Conclusion
 Systemic therapy is generally used as a radiosensitizer or as
palliative-intent treatment in head & neck cancer
 Advanced head & neck cancer has a generally poor
prognosis despite systemic therapy
 New directions:
 Immunotherapy
 Targeted therapy
 Don’t forget:
 Prevention
 Early detection (screening algorithms)
Thank You
Dr. Alain
Algazi
Indications for adjuvant ST/RT after surgery –
adverse pathologic findings
 Lip: For ECE and/or pos margin;
consider for multiple positive LNs,
perineural/lymphatic/vascular
invasion
 Oral cavity: For ECE and/or pos
margin; consider for pT3 or pT4
primary, N2 or N3 inv, levels IV or
V, PNI, vascular embolism
 Oropharynx: For ECE +/- pos
margin; consider for pos margin,
pT3 or pT4, N2 or N3, levels IV
or V, PNI, vascular embolism
 Hypopharynx: For ECE and/or pos




margin; consider for pT3 or pT4, N2
or N3, PNI, vascular embolism
Nasopharynx: n/a
Glottic larynx: For ECE +/- pos
margin; consider for pos margin, pT3
or pT4, N2 or N3, PNI, vascular
embolism
Supraglottic larynx: For ECE and/or
pos margin; consider for pT4
primary, N2 or N3, PNI, vascular
embolism
Ethmoid sinus: Consider for pos
margins, intracranial extension