Transcript Innovations in treatment of head and neck cancer

Innovations in treatment of head
and neck cancer
Dr Katie Wood
St Luke’s cancer Centre
Guildford
Introduction
 Head and neck cancer
 Radiotherapy dose escalation
 New drugs – TKIs, antibodies, viruses
 HPV
 Thyroid cancer
 Use of radioiodine
 Use of tyrosine kinase inhibitors
Targeted agents - EGFR
 Surgery, radiation, chemotherapy non-selective
 Epidermal growth factor receptors (EGFR)
overexpressed in 40-80% head and neck SCCs
 EGFR activation leads to cell growth and proliferation
 Inactivated
 by antibodies (cetuximab)
 tyrosine kinase inhibitors (TKIs)
Drugs in development
 Evaluation in combination with chemoRT or adjuvantly
 Antibodies
 Cetuximab - only licenced molecularly targeted HNSCC therapy
 panitumumab - ?benefit in HPV –ve with mets
 TKIs
 Lapatinib, sunitinib, sorafenib
 Erlotinib (TKI) being evaluated as a preventative agent in patients
with pre-cancerous lesions of the oral cavity
De-escalate
 Cetuximab + RT vs chemo-RT
 Hypothesis – cetuximab targeted therapy, ?less toxic,
therefore quicker return to normal function
 RT + cetuximab vs RT improved locoregional control and
survival
Tyrosine kinase inhibitors in
thyroid cancer
 Decision trial
 Non-iodine avid metastatic thyroid cancer
 Sorafenib vs placebo
 Progression-free survival 10.8 vs 5.8 mo (p<0.0001)
 Side-effects
 Hand-foot skin reaction, diarrhoea, alopecia, rash/desquamation, fatigue, weight loss,
hypertension
 Worse in first 4-6 months
 UK – NICE approved, available through CDF
Side-effects
 Epidermal growth factor receptor inhibitors
 Cetuximab (acne like rash)
 Erlotinib (DVT, arrhythmia, CVAs, myocardial ischaemia, pulmonary
toxicity)
 Tyrosine kinase inhibitors
 Lapatinib (diarrhoea, rash)
 Sorafenib (cardiac ischaemia, hypertension, thromboembolism)
 Sunitinib (pulmonary haemorrhage)
Nimorazole
 Radiation sensitiser
 Fixes DNA damage and prevents repair
 Long history – similar agents caused significant nausea and vomiting, peripheral
neuropathy
 Nimorazole- transient nausea and vomiting
 Oral, given daily prior to radiotherapy
 Improved loco-regional control
 NIMRAD study – over 70s, no concomitant chemo.
Viral therapy
 Oncolytic viruses
 naturally occurring or genetically engineered
 specifically replicate in and kill malignant cells
 Infection, destruction and release of tumour antigens
generates immune response against infected cancer
cells
 Tumour cell specific
 Viral therapy dates back over 100 years
1896 – Patient with ‘myelogenous leukaemia’
went in to remission after a presumed
influenza infection
Chickenpox lead to the regression of
lymphatic leukaemia in a 4 year old boy
1949 - two patients with Hodgkin’s disease
went in to remission after contracting viral
hepatitis
Formal evaluation of viral therapy at this time
43 Hodgkin’s disease patients were
innoculated with ‘the hepatitis virus’
7 showed an improvement lasting at least 1
month
 1970s-80s – interest waned due to regulatory barriers of nonattenuated pathogens
 1990s - Advances in virology, cell signalling, gene transfer etc have
lead to renewed interest and several viruses investigated for their
oncolytic potential since early 1990s
 Possible to attenuate and manipulate viruses so that they are more
specific for cancer cells, and less pathogenic to the host
 Known as oncolytic viruses.......
Why are viruses cancer
specific?
Mechanisms that stop viral replication are defective in cancer
cells
Immune system is less effective, so virus less likely to be
erradicated
 Currently 7 viral species in clinical testing at the moment ;
reovirus,adenovirus, coxsackie, herpes simplex, measles,
seneca valley virus, vaccinia
 Against head and neck, gynae, brain, melanoma, breast,
prostate, myeloma, pancreas, NSCLC, SCLC,
neuroendocrine
 Intravenous, intraperitoneal, intratumoural
Reovirus
 Naturally occurring oncolytic virus
 Exposure is common in human population
 Up to 100% adults are seropositive
 No known clinical syndrome in humans
 Generally regarded as benign
 Infrequent upper respiratory or mild GI symptoms
 Reovirus infection causes normal cells to activate a series
of processes that defend against infection
 In tumour cells, this process is not activated allowing viral
replication to continue unchecked and cell lysis occurs
 Tumour antigens exposed by viral oncolysis may cause an
immune response against the exposed cells
Reovirus
 Studies of local and systemic administration with
radiotherapy or chemotherapy
 Clinical activity in head and neck, downstaging hepatic
metastases from colorectal cancer, GBM
 Chemotherapy causes immunosuppression - ?may
enhance anti-cancer effects of reovirus
 Addition of reovirus doesn’t enhance toxicity of chemo
REO 18
 Randomized double-blind phase 3 study of carboplatin
and paclitaxel +/- REOLYSIN (reovirus)
 Metastatic or recurrent head and neck SCC progressed
on or within 190 days of platinum chemotherapy
 Primary endpoint : overall survival
 Secondary endpoints : progression-free survival,
response (CR + PR), safety and tolerability
Regimen
 Day 1: carboplatin and paclitaxel i.v. followed by
reolysin/placebo i.v. 1h
 Day 2-5 : reolysin/placebo i.v. 1h
 3 weekly
Problems with viral therapy
 Studies have shown early responses to reovirus only for
tumour to resume growth after several weeks
 Correlates with the development of an antibody response
 Future potential in combined therapy rather than as a
single agent as immunosuppression may prolong response
 General reluctance to administer i.t. therapy repeatedly,
doesn’t fit in to treatment frameworks already in place, ?if
sufficient evidence, may change practise
Human papilloma virus HPV
 Incidence of oropharyngeal cancer increasing in UK, unlike most other
head and neck SCC
 281(1997) vs 703(2007) tonsillar cancers in England
 Similar trends in USA, Sweden, Greece
 Associated with HPV
 37-60% oropharyngeal carcinoma
 Already known risk factor for development of cervical (99.7%) and other
anogenital malignancies (vulva, vagina, anus, penis)
Epidemiology
 Different population to previously typical
 HPV + oropharyngeal ca younger by 5-10 years
 Male/Female 1:1
 More likely non-smokers, non-drinkers
 Present with more advanced stage with cystic LN
metastases
 Poorly differentiated, basaloid histology
 Sexually acquired
 Temporal relationship between acquisition of virus
and development of malignancy unknown
Risk factors
 Early age at first intercourse
 Infrequent use of condoms
 History of HPV-associated carcinoma in situ or
cervical cancer
 Partners of women with CIS or cervical cancer
 Oral HPV infection
 Seropositivity for HPV16 L1 capsid protein reflects
lifetime exposure to HPV16
Why oropharynx?
 HPV found in epithelial crypts in tonsils
 HPV binds DNA and codes ‘oncoproteins’ E6 and E7 that inhibit
cell death
 Allows mutations to collect and lead to cancer
 Oropharyngeal cells allow persistence of infection and failure to
eradicate HPV
Prognosis of HPV+ oropharyngeal
carcinoma
 50-80% reduction in risk of cancer-related death
 RTOG 0129
-317 patients stage III/IV OPC
-59% reduction in risk of death
-2-year overall survival 87.5% vs 67.2%
-progression-free survival 71.9% vs 51.2%
 HPV+ p16+ improved prognosis vs HPV+ p16- p16 expression represents relevant active HPV
infection
 Better prognosis
Response to treatment
 Better response to induction chemotherapy,
chemoradiation and radiotherapy
 CR in up to 94% having RT alone
Cancer 2001;92:805-813. Anticancer Res 2005;25:4375-4383.
 HPV+ OPC treated with surgery +/- adjuvant RT
improved outcome
J ClinOncol 2006;24:56305636
HPV+ in smokers
 RTOG 0129
-HPV+ OS in non-smokers 95% vs smokers 80% at 2 years
-HPV- non-smokers 71% OS at 2 years vs 63% in smokers
 HPV + smokers 7x risk of tumour recurrence vs HPV+ non-smoker
2009;27:15s
J Clin Oncol
 DAHANCA 5 (nimorazole)
-P16+ 58% vs 28% 5y locoregional control and lower mortality
-Locoregional control 42% at 5 years vs 28% in p16- vs p16+
(p=0.02)
-no significant benefit for p16
-hypoxic modification beneficial for p16-
Change of prognostic
classification?
 Low, intermediate, high risk
 3 year survival 93%, 70.8%, 46.2%
 Depends on 4 factors
 HPV status
 pack-years of tobacco smoking
 tumour stage
 nodal stage
J Natl Compr Canc Netw 2011;9:665
Possible reasons for improved
outcome in HPV+
 Better mechanism for getting rid of damaged cells
 Presence of immune surveillance to viral antigens
 Absence of field change leading to second primaries
Gardasil vaccination programme
•
Vaccination in women


UK vaccination programme against 12-13 year old girls since
2008 to reduce chance of cervical cancer
May result in reduction in OPC in women
 mean age of HPV+ OPC presentation is 50-55y, may
take 30-40 years to realise
 Vaccination in men Gardasil licenced for use in <26 years
 Not for oropharyngeal HPV prophylaxis
 prevention of HPV-related anal and penile cancers
 Routinely used in Australia and US
 Cost-effectiveness and efficacy being evaluated for use as part of
vaccination programme in UK
Innovations in thyroid cancer
 Reduction in use and dose of radioiodine
 Use of recombinant TSH (thyrogen)
 New drugs to prolong sensitivity and uptake of
radioiodine in metastatic patients
 Tyrosine kinase inhibitors in metastatic thyroid
cancer, non-iodine avid
Reduction in dose of iodine and
thyrogen
 Hi-Lo study
 Multicentre RCT
 High dose (3.7 GBq) vs low dose (1.1GBq)
 rhTSH or thyroid hormone withdrawal
 Remnant ablation following total thyroidectomy
 End points
 Successful ablation
 QoL
 Toxicity
 Closed 2010, 438 patients
438 patients with differentiated thyroid cancer
and have had total thyroidectomy
Thyrogen (patients remain
on thyroid hormone therapy)
N=219
Discontinue or do not start
thyroid hormone therapy
N=219
Pre-ablation scan using Technetium 99m
RAI ablation
1.1 GBq
N=110
RAI ablation
3.7 GBq
N=109
RAI ablation
1.1 GBq
N=110
RAI ablation
3.7 GBq
N=109
Assessments post-ablation:
• 7 days: Whole body 131I scan
• 3 months: QoL
• 6-9 months: Success/failure of ablation using
131I Iodide diagnostic scan (140-185 MBq) and Thyroglobulin
Ablation success using diagnostic scan alone
(no uptake or <0.1% uptake)
% ablation
success
Difference
95% CI
P-value
1.1 GBq 3.7 GBq
N=123
N=109
Thyrogen
N=119
Hormone
withdrawal
N=113
92.7
94.1
93.8
95.4
-2.7
-8.8 to +3.3
P=0.38
+0.3
-5.8 to +6.4
P=0.92
All comparisons are within ± 10%, so
(i)1.1 considered equivalent to 3.7 GBq
(ii)Thyrogen considered equivalent to hormone withdrawal
Quality of Life during 4 weeks immediately prior to radioiodine ablation
% of patients whose
following symptoms
were moderate/a lot
Thyrogen
N=219
Hormone
withdrawal
N=219
P-value
Fatigue
28.8
48.0
<0.001
Difficult to concentrate
16.9
36.5
<0.001
Difficult to perform usual
activities at home
12.8
18.7
0.09
Difficult to take care of
children at home
(% with dependent
children)
8.2
14.9
0.19
(39%)
(34%)
(0.27)
Difficult to perform usual
activities at work
(median no. days off
work)
9.9
22.1
0.007
(1)
(5)
(0.21)
HiLo - Conclusions
 Successful ablation on 6 month scan in 90+%
 No significant difference in main endpoint between any arm
 1.1GBq has less acute side effects & less time spent in hospital
isolation (less overall costs)
 Patients given Thyrogen experienced fewer adverse quality
of life symptoms before ablation, and were able to perform
better at home and work
Further reduction in use of
radioiodine!
 Sawka et al, 2008. Meta-analysis of ablation for low risk – no consistent
effect on thyroid cancer mortality or recurrence in early stage disease
 IoN
Is ablative radioiodine Necessary for low risk DTC patients?
 Low risk randomised to 1.1GBq ablation v no ablation
 Primary endpoint – 5 year disease free survival
 Secondary endpoints – locoregional control, metastases, QoL, cause
specific survival
selumetinib
 Hypothesis – increases expression of NaI symporter therefore
increasing uptake of iodine
 Pre-clinical mouse models have shown that iodine refractory
thyroid cancer regains the ability to concentrate iodine
 Ho et al, NEJM 2013




20 patients with iodine refractory DTC
Selumetinib 75mg bd for 4 weeks
12/20 increased iodine uptake on I124 PET
8 received I131 – all had a fall in Tg, 5/8 had a partial radiological response
Sel-I-Pet
 National UK study proposed
 5 Centres in UK – Guildford included
 60 patients
 Change in radioiodine uptake with selumetinib
Intensity Modulated Radiotherapy
(IMRT)
IMRT
 Creates 3-D volumes of irradiation
 Reduces dose to normal structures
 Parotids, spinal cord, orbit, optic nerves etc
 Allows dose escalation;
 ART-DECO
 In house study (Dr Joanna Lynch, RSCH)
Evaluation of 18F-FDG-PET/CT for
adaptive and dose escalated radiotherapy
in Oropharyngeal squamous cell cancer
 Can a PET scan done early radiotherapy identify
radioresistant areas of tumour to dose escalate in the
second part of treatment?
 Recruiting patients with Stage III/IV Oropharyngeal
cancer undergoing chemo-RT with Cisplatin.
 Pre-treatment PET scan immobilised in RT shell.
 Interim PET scan and planning CT scan between
fractions 8 – 10.
Patient 1 – T2N2b, p16+ve, never smoked
Pre-treatment
After 8 fractions
Patient 2 – T2N2b, p16 +ve, ex-smoker
Pre treatment
After 8 fractions
IMRT
 Improve long term function post-radiotherapy




Xerostomia
Osteoradionecrosis
PEG dependency rates
Hearing loss
Summary
 Use of biological agents increasing in head and neck and
thyroid
 Treatment of HPV+ sub-population may be different – deescalate treatment
 Use of viral treatments investigational
 Radioiodine use diminishing
 IMRT continues
 ?reduce or increase dose
 Reduce volume
 Increasing choice of concomitant agents, may depend on HPV
status, age, etc