Post-ASCO 2011 - SKA Protokoller

Post-ASCO 2011
Hoved-hals
Hoved
hals tumorer
CNS tumorer
Mads Nordahl Svendsen
Ud l t abstracs
Udvalgte
b t
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#5500 A randomized phase III trial (RTOG 0522) of concurrent
plus cisplatin
p
with or without cetuximab for
accelerated radiation p
stage III-IV head and neck squamous cell carcinomas (HNC).
#5544 Exploring factors in diagnostic delays of head and neck
cancer at a public hospital.
#5505 Prediction of clinical outcome in patients with primary
laryngeal carcinoma using gene expression profiling.
#LBA5524 Ph
Phase III trial
i l off low-level
l
l l laser
l
therapy
h
to prevent
induced oral mucositis in head and neck cancer patients
submitted to concurrent chemoradiation.
chemoradiation
#5544 Exploring factors in diagnostic delays of head and neck
cancer at a public hospital.
Engelsk n=64
n 64
Non-engelsk n=30
P=0.05
Employed n=16
Non-employed n=55
P=0.06
Engelsk n=64
n 64
Non-engelsk n=30
P=0.05
Employed n=16
Non-employed n=55
P=0.06
#LBA5524 Phase III trial of low-level laser therapy to prevent
i d d orall mucositis
induced
i i in
i head
h d andd neckk cancer patients
i
submitted
b i d
to concurrent chemoradiation.
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N=94 ptt, +/- laser
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Prospektiv, dobbelt-blindet, randomiseret fase III studie
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Overkrydsning tilladt hvis mucositis grad 3
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Behandling: 70 Gy konkomittant m cisplatin
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Risiko for grad 3/4 mucositis reduceres
z
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laser: 6% mod 48%. HR 0.44 ((0.22 – 0.88)) p
p=0.003
Med mindre mucositis følger:
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Signifikant nedsat smerte og opioid forbrug (p=0
(p=0.006)
006)
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50% reduktion i behov for sonde-føde (p=0.005)
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Ø t selvrapporteret
Øget
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t t fysisk
f i k og psykisk
ki k ffunktion
kti
K kl i
Konklusion
Our results
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lt indicate
i di t th
thatt upfront
f t LLLT iin HNSCC pts
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submitted to CRT is an effective tool in reducing G 3/4
OM orall pain,
OM,
i use off narcotic
ti and
d gastrostomia.
t t i QoL
Q L
data supports the efficacy findings. Thereby LLLT
should be the new standard of care in this setting
setting.
Hvad ved vi om Low Level Laser Terapi?
z
Lokal antiinflammatorisk effekt
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Reduktion af inflammatoriske mediatorer
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Reduktion af ødem og reduktion af antal inflamm celler
Support
pp Care Cancer. 2011 Jun 10.
A systematic review with meta-analysis of the effect of low-level laser therapy (LLLT) in
cancer therapy-induced oral mucositis.
Bjordal JM, Bensadoun RJ, Tunèr J, Frigo L, Gjerde K, Lopes-Martins RA.
Udvalgte abstracts – CNS
ved overlæge Jørgen Johansen, OUH
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#2006 RTOG 0525: A randomized phase III trial comparing
standard adjuvant temozolomide (TMZ) with a dose-dense (dd)
schedule in newly diagnosed glioblastoma (GBM).
#2052 Randomized phase II study of neoadjuvant bevacizumab
and irinotecan versus bevacizumab and temozolomide followed
by
y concomitant chemoradiotherapyy in newlyy diagnosed
g
primaryy
glioblastoma multiforme.
#2008 Correlation of treatment effects on progression
progression-free
free
survival at 6 months (PFS-6) and overall survival (OS) in
patients with newlyy diagnosed
p
g
glioblastoma
g
(GBM).
(
)
#2052 Randomized phase II study of neoadjuvant bevacizumab
andd irinotecan
ii t
versus bevacizumab
b
i
b andd temozolomide
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l id followed
f ll
d by
b
concomitant chemoradiotherapy in newly diagnosed primary
glioblastoma multiforme.
multiforme
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#2052: Randomized phase II study of neoadjuvant bevacizumab and irinotecan versus bevacizumab and temozolomide followed by
concomitant
it t chemoradiotherapy
h
di th
in
i newly
l diagnosed
di
d primary
i
glioblastoma
li bl t
multiforme
ltif
ASCO annuall meeting,
ti
June
J
2011
Kenneth F. Hofland1, Steinbjørn Hansen2, Morten P. Sørensen1, Henrik P. Schultz3, Aida Muhic1, Silke Engelholm1, Anders Ask1, Charlotte Kristiansen2, Carsten Thomsen1,
Hans Skovgaard Poulsen1,Ulrik Lassen1 1)Rigshospitalet, Copenhagen University Hospital, 2) Odense Universitets Hospital, 3) Århus Universitets Hospital, Denmark
Background
Methods
on the text to edit)
Abstract (Clickand
Endpoints: The primary endpoint was response at 8 weeks. Secondary endpoints were: 6-months and 12-months PFS, overall survival, safety
and feasibility. Response was assessed every 8 weeks. Toxicity was assessed every 2 weeks.
Methods: Patients with newly diagnosed GBM (previously untreated except for primary surgery/biopsy), were randomized to bevacizumab and
irinotecan on days 1 and 14 (BI regimen) or to bevacizumab on days 1 and 14 and temozolomide on days 1-5 in a 28-day cycle (BT regimen) for
8 weeks, followed by radiotherapy (60 Gy/30 fractions) and concomitant BI or BT. Post-radiotherapy, chemotherapy was continued for 8 weeks.
See table “treatment outline”
Protocol procedure: We employed a ”two-stage” design and a true response rate of 30% was considered worthy of further study, while a
response rate of 10% would not be. In the first stage, if for each group ≤1 response was observed among the first 10 patients, the regimen was
thought to be ineffective and inclusion to that specific experimental arm should be terminated. However, if 2 or more responses were observed,
then inclusion would continue. A pre-planned safety and feasibility analysis was made already after of the first 12 patients, 6 patients on each
experimental arm, confirmed efficacy with 2 responders in each group and inclusion was therefore continued.
Inclusion criteria: 1) Signed informed consent, 2) Primary glioblastoma multiforme, 3) No prior therapy except primary surgical resection or
biopsy, 4) PS 0-2; 5) Age > 18 years, 6) Expected survival > 3 months, 7) Adequate liver, renal and bone-marrow function. 8) No sign of cerebral
bleeding on cerebral MR-scanning at baseline
Chemotherapy:
Bevacizumab was dosed 10 mg/kg every 14. days, intravenously.
Irinotecan was dosed every 14. days. The dose was dependent on use of enzyme-inducing anti-epileptic drugs (EIAID) so the patients not on
EIAED were dosed with irinotecan 125 mg/m2 and patients on EIAED were dosed with 340 mg/m2.
Temozolomide was administered differentially during the study: During the neo-adjuvant and the adjuvant part, temozolomide 200 mg/m2 was
given daily for 5 days followed by 23 days off (The dose in the first cycle was 150 mg/m2 though). During radiotherapy, temozolomide 75 mg/m2
was given daily.
Radiotherapy: Target was determined from fusion of CTC and baseline MRC. If PD after neo-adjuvant part, the largest target (baseline or 8week MRC was used for radiotherapy planning. Planning is with Eclipse-system (Varian Medical Systems). Volumes of interest were defined in
agreement with ICRU, Report 50 and 62:
GTV : The enhancing tumor volume on the post-contrast T1 image and/or the none-enhancing area on the T2 image on the baseline MR-scan.
CTV : GTV + 2 cm margin,
i exceptt for
f bony
b
structures.
t t
Meningeal
M i
l structures
t t
were considered
id d anatomic
t i barriers
b i to
t tumor
t
spreadd when
h
appropriate. If present, operation cavity were included in the tumor volume.
ITV : ITV=CTV. No variations in size, shape or position of CTV in relation to anatomical reference structures were considered.
PTV : CTV + 0.5 cm margin for patient setup inconsistencies.
Tolerance doses for organs at risk (including normal brain, optic chiasm, bilateral optic nerves, bilateral lenses, and brainstem) were as given in
Emami et al, IJROBP 1991, 21; 109-122. Radiotherapy was performed using a linear accelerator, and the dose prescribed was 60 Gy in 30
fractions to PTV, 5 fractions per week. The PTV was encompassed by the 95% isodose line.
Response evaluation: Response evaluation was according to the MacDonald criteria, modified as described below.
Complete response (CR): A complete disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks
with no new lesions. Patient should be off corticosteroids and with stable or improved clinical status. Partial response (PR) required a ≥50%
decrease in the sum of pproducts of pperpendicular
p
diameters of all measurable enhancingg lesions compared
p
with baseline with no new lesions, on
stable or reduced corticosteroid dose and with stable or improved clinical status. A minor response (mPR) required a decrease of 25% or more
of the product of perpendicular diameters of all measurable enhancing lesions compared to baseline but less than 50%, thus not qualifying for a
formal PR. As with CR and PR, there could be no new lesions and corticosteroids and neurological status should be stable. Progressive
disease (PD) was defined as an increase of ≥25% in the sum of the products of perpendicular diameters of enhancing lesions, the appearance
of new enhancing lesions or signs of clinical deterioration.
Methods
Results
MRI-baseline
MRI
Cycle 1
Cycle 2
MRI
cycle 3
Cycle 4
MRI
Cycle 5
Cycle 6
Day 1
Day 15
Day 29
Day 43
Day 57
Day 71
Day 85
Day 99
Day 113
Day 127
Day 151
Day 165
Bevacizumab
Irinotecan
Bevacizumab
Irinotecan
Bevacizumab
Irinotecan
Bevacizumab
Irinotecan
Bevacizumab
Irinotecan
Bevacizumab
Irinotecan
Bevacizumab
Irinotecan
Bevacizumab
Irinotecan
Bevacizumab
Irinotecan
Bevacizumab
Irinotecan
Bevacizumab
Irinotecan
Bevacizumab
Irinotecan
Bevacizumab
Bevacizumab Bevacizumab
Temozolomide
(5/28 days)
Radiotherapy 2 Gy x 30
Neo-adjuvant phase
Bevacizumab Bevacizumab
Temozolomide
(5/28 days)
Concomitant phase
Bevacizumab Bevacizumab
Temozolomide
(5/28 days)
Adjuvant phase
Bevacizumab Bevacizumab Bevacizumab
Daily temozolomide during radiotherapy
Bevacizumab Bevacizumab
Temozolomide
(5/28 days)
Response evaluation (Continued)
Stable disease (SD) was declared if the patient did not qualify for complete response, partial response or progressive disease
and was stable clinically. Because of the neo-adjuvant study design, it was not mandatory that PR or mPR could be confirmed at
subsequent evaluations. Contrast enhancing (CE) lesions <10 mm in diameter at baseline were not measurable but were
evaluable. When such lesions increased in size to ≥10 mm they were included as measurable. CE lesions that were ≥10 mm in
diameter at baseline were measurable and were followed as measurable, even if they decreased in diameter to <10 mm during
therapy. Immediately following the chemo-radiotherapy, an aggravation of neurological symptoms necessitating dose-escalation
of corticosteroids may be seen; however, this should not in itself be considered evidence of PD. In case of radiological
progression on MRI within 2 months following the chemo-radiotherapy, PD was declared if this was confirmed on subsequent MRI
or if the clinical condition deteriorated. If PD on MRI could not be confirmed, the increase in size of the lesion following chemoradiotherapy
py was defined as p
pseudoprogression
p g
(PsPD),
(
) and the status of the ppatient was SD.
All MRI were reviewed by an expert neuroradiologist, blinded to treatment.
Results
Patient flow diagram according to CONCORT guidance
Patients randomised (n=65)
Enrollment
Allocation
BI arm (n=33)
Erroneously randomised (n=2)
ITT population
Allocated to and recieved
intervention (n= 31)
Did not receive allocated
intervention (n=0)
ITT population (n=31)
ITT population: Patient characteristics
Median age (range)
ECOG performance status
BT arm (n=32)
Erroneously randomised (n=0)
Allocated to, and recieved,
intervention (n=32)
Did not receive allocated
intervention (n= 0)
ITT population (n=32)
6-months progression free survival
Bevacizumab Bevacizumab Temozolomide
Irinotecan
12
14
4
2
54%
Response
espo se aafter
te 8 weeks
ee s o
of neoadjuvant
eoadju a t ttherapy
e apy
Treatment outline
RANDOMISATION
Background: Concomitant Temozolomide (T) and radiotherapy (RT) is standard of care in patients with newly diagnosed Glioblastoma
multiforme (GBM) and good performance status (PS). Bevacizumab (B) and irinotecan (I) has shown activity in patients with recurrent disease
with a significant number of responders. The response rate of temozolomide is in the range of 10%, and increased response rates may be an
indicator of survival benefit. We tested the use of Bevacizumab in combination with Temozolomide or Irinotecan with concomitant radiotherapy
as first-line therapy in patients with newly diagnosed GBM.
BT (n=32)
62 (30 - 73)
BI (n=31)
59 (36 - 77)
0
13
20
1
17
10
2
2
1
Male / Female
21 / 11
18 / 13
Surgical resection / biopsy only
30 / 2
28 / 3
Median McDonald (baseline)
1
0
25% - 75% range of scores
0-2
0 -3
Median dose prednisolone
25 mg
25 mg
25% - 75% range of doses
10 - 50 mg
12 - 50 mg*
Data on prednisolone dose were missing from 5 patients on the BIarm. Data on the McDonald score was missing for 6 patients on the
BI-arm and 1 patient on the BT-arm, respectively.
Two patients were erroneously randomized to the BI arm prior to their baseline MR scan: One patient was claustrophobic
and refused the MRI pprocedure. The second ppatient had a bleedingg on the baseline MRI. Both were excluded from the studyy and
were not included in the ITT population.
According to protocol, patients that went off-study prior to the chemo-radiation and proceeded to radiotherapy immediately and
crossed over therapy, were replaced by new patients, in order to also obtain the secondary endpoints. Three patients that had
early clinical progression prior to the chemo-radiation (2 on BI-arm and 1 on the BT-arm) were therefore replaced during the
study. However, these 3 patients were mistakenly replaced by 2 patients on the BT arm and 1 on the BI arm.
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Complete response
Partial response
Minor response*
Stable disease
Progressive disease
Not evaluable
Bevacizumab - Bevacizumab Temozolomide Irinotecan
0
0
10
6
11
7
6
7
4
6
***1
**5
Status at 6 months
Progressed
Non-progressed
Not determined
Censored
6-months PFS
MRI were reviewed by an expert neuroradiologist, blinded to
treatment. (*) 50-75% of baseline. (**) three patients had
p
quality
q
y MR at
non-enhancingg tumors at baseline,, 2 had poor
8 wks. All were clinical non-PD and received planned
chemoRT. (***) One patient had a non-enhancing tumor at
baseline.
Non-hematological toxicity from neoadjuvant therapy
BevacizumabBevacizumabTemozolomide
Irinotecan
Toxicity graded
according to
CTCAE criteria
I II III IV
version 3.0
I II III IV
Nausea
8 4
11 2
Emesis
7 1
2 1
Diarrhoea
6
5 3
3
Constipation
8 1
Thrombosis
0
1
6 1
Alopecia
0
Hypertension
7 5 3
7 3
19 4
Fatique
19 3 2
The most severe toxicity for each patient during the first 2
cycles of neoadjuvant therapy is shown. The more common
chemotherapy-induced toxicities are shown, as well as the
types of toxicity that resulted in grade III or worse toxicity,
h
hhere. Th
There were no wound-healing
d h li
are shown
complications.
13
15
3
0
54%
Response: A total of 21 patients on the BT-arm had significant tumour
shrinkage (PR + minor response) after the first 8 weeks of therapy, while 4
patients had stable disease. Only 4 patients had progression of their disease
prior to the initiation of the chemoradiotherapy. In contrast, there were only 13
patients with PR + minor response on the BI-arm, while 7 patients had stable
disease. There were 6 patients with progression. A number of patients were
non-evaluable at 8 weeks (1 on the BT-arm and 5 on the BI-arm), but none of
these were clinically progressing, and all continued planned protocol therapy.
Thus, the response rate after 8 weeks seemed to favor the BT-arm.
6-months PFS: In some cases, the blinded MRI review diagnosed
radiological progression in patients where the evaluation clinically as well as
the day-to-day radiological service did not find progression. In other cases, the
Conclusions
MRI review could not confirm radiological progression where this had been
determined duringg the study.
y This is thus the reason for the censoringg of the 2
patients in the 6 months PFS data. The MRI review could not be completely
finalised for this meeting, wherefore some 6-months PFS data are still
pending.
We found a completely similar 6-months PFS of 54% from both treatment
arms; however, 7 patients are missing from this preliminary analysis. The 12months-PFS and the survival data are not yet available.
The caveat with evaluation of GBM with MRI are well known, and it may be
difficult to ever reach agreement among reviewers. Therefore, it may be very
difficult to directly compare our response-rates and PFS data with those of
others. However, we recommend this procedure for the sake of uniformity in
evaluating response from various different treatments
treatments. The survival data
therefore are eagerly awaited, since these will not be subject to this type of
bias.
References
Conclusion
The response rate at 8 weeks seemed to favour the combination of bevacizumab and temozolomide compared to bevacizumab and
irinotecan, although the difference in true response rate was not statistically significant. When including the “minor responses”, this
difference was borderline statistically significantly different. However, it should be remembered that no formal statistical comparison of
efficacy data were planned, due to the relatively small sample sizes. As it is, the preliminary 6-months PFS data were similar for the BI and
the BT arm. We await final analysis of both the 6-months and 12-months PFS as well as overall survival, but at present two cycles of neoadjuvant chemotherapy and bevacizumab do not seem to compromise outcome. Our response data give strong support to the strategy of
combining bevacizumab with Stupp’s regimen in 1. line therapy of GBM. If the opposite had been the case, BI seemed superior to BT, a
phase III study comparing this regimen with the Stupp regimen should be proposed.
The use of blinded critical review of all MRI perhaps deflated both the response rate as well as the 6-months PFS. The discussion of the
validity of radiological evaluation of response/relapse in GBM is ongoing, however, in this study, it ensured unbiased and similar evaluations
Printed by
of all patients.
Baggrund
gg
z
z
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Både bevacizumab og irinotecan har vist effekt
hos pt med recidiv
Temodal
e oda virker
e i 1. linie
e med
ed st
strålebehandling
å ebe a d g
Virker bevacizumab bedre med irinotecan end
med
d ttemodal?
d l?
Endpoints
z
Respons efter 8 uger + 6. og 12. mdr. PFS +
OS + Safety
S f t
Inklussion
z
65 patienter med primær glioblastom
” Thus
Thus, the response rate after 8 weeks seemed to
favor the BT-arm. ”
K kl i
Konklusion
” As it is, the preliminary 6-months PFS data were similar for
the BI and the BT arm. ”
” at p
present two cycles
y
of neoadjuvant
j
chemotherapy
py and
bevacizumab do not seem to compromise outcome. ”
” Our response data give strong support to the strategy of
combining bevacizumab with Stupp’s regimen in 1. line
therapy of GBM.
GBM ”