Rationale for Combined chemo XRT in small cell lung cancer

Report
The rationale for concurrent
chemotherapy and
radiotherapy in small cell lung
cancer
Dr Hannah Lord
Ninewells Dundee
17th Sept 2010
Small Cell
20% of all lung cancer
Associated with smoking
Rapid doubling time
Falling incidence in many parts of UK,
not in Scotland
• A systemic disease, even when staged as
“localised.” As such, systemic treatment
is vital.
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The History
• In 1969, 5 year survival:
1% with surgery
4% with radiotherapy
• In 1970s, advent of platinum based
chemotherapy.
• Led to 4-5 fold improvement in response
rates
Small Cell
• With chemo, excellent responses, but
early and frequent relapse.
• Need to build on the improvement.
XRT
• XRT already well known as effective.
• XRT potentiates the effect of
chemotherapy
• XRT has non over-lapping toxicities with
chemotherapy
• XRT has different mode of action and
may deal with potentially
chemoresistant disease
Evidence For XRT
• 13 randomised controlled trials have investigated
the role of XRT
• Pignon(1) 1992 meta-analysis (and Warde(2) 1993)
• 2103 patients with LD
• 433 had ED
1.
2.
Pignon JP et al, N Engl J Med 1992; 327:1618-1624 December 3, 1992
Warde P et al “Does thoracic irradiation improve survival and local control in limited stage small cell
carcinoma of the lung?” JCO 1992;10:890-895
• 3 year survival improved
from 8.9% to 14.3%
(5% improvement)
• HR = 0.86 = 14% reduced
risk of death
• No difference if LD / ED or
timing of XRT
Role of XRT
• Value of XRT proven.
• Principles of radiotherapy are to give the
treatment in as short a time as possible
for maximum effectiveness
• Minimise re-growth of tumour, which is
known to have a rapid doubling time
XRT
• Concurrent treatment:
i) To reduce overall treatment time
(repopulation of tumour)
ii) To allow 2 modalities to potentiate
one another
ii) ? to improve outcomes
How to determine timing of XRT?
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Randomised controlled trials
8 looking at timing of XRT
3 positive
5 negative
Trial 1: NCIC study (3) 1993
• Randomised controlled trial in Canada
• 308 pts
• XRT commencing at cycle 2 (week 3) vs. cycle 6 (week
15)
• 40Gy in 15 fractions given
3. N Murray et al Importance of timing for thoracic irradiation in the combined
modality treatment of limited-stage small-cell lung cancer. JCO Vol 11 336-344, 1993
The National Cancer Institute of Canada Clinical Trials Group
NCIC Results
Early XRT
Late XRT
p Value
PFS
15.4
11.8
0.36
OS (
median)
21.2
16.0
0.008
3 year
survival
30%
22%
0.008
5 year
survival
26%
11%
0.008
Trial 2: Jeremic (4)
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Yugoslavian study 1997
107 patients
4 x Carbo Etop and 4 x Cis Etop (carbo with XRT)
54Gy in 1.5Gy / fraction given bd
XRT weeks 1-4 (early)
or
weeks 6-9 (late)
Early
Late
P value
Median
survival
(months)
34
26
0.027
5 year survival
(%)
30
15
0.027
4. Jeremic et al “Initial versus delayed accelerated hyperfractionated radiation therapy
and concurrent chemotherapy in limited small-cell lung cancer: a randomized study”
JCO Vol 15, 893-900, 1997
Trials 3: Takada (5)
• Japanese study 2006
• 231 patients
• 4 x EP with 45Gy in 1.5Gy fractions given bd
• XRT started d2 cycle 1
vs.
sequential rather than late)
after cycle 4 (
5. Takada M, Fukuoka M, Kawahara M, et al: Phase III study of concurrent versus sequential
thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung
cancer: Results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 20: 3054-3060,
2002
Results
Concurrent
Sequential
Median survival
(months)
27.2
19.7
2 year survival (%)
54.4
35.1
3 year survival (%)
29.8
20.2
5 year survival (%)
23.7
18.3
P= 0.097
not significant due to small sample size
Costs of XRT
• Increased haematolgical toxicity
• Similar oesophagitis ( 9% vs 4%)
• 1% incraese in treatment related deaths
• Well tolerated overall
Negative trials 1: Perry (6)
• US Study 1987
• 399 patients: chemo, vs. chemo + early XRT, vs.
chemo + late XRT
• Results:
• XRT group as a whole did better that chemo
alone group
• But no benefit from early vs delayed XRT
6. Perry MC et al Chemotherapy with or without radiation therapy in limited small cell lung carcinoma of the
lung NEJM 1987;316:912-918
Negative trials 2: Spiro
• A London based trial (7) published 2005, replicated
the NCIC study.
• 3 cycles of CAV followed by 3 cycles of EP
• XRT with first course of EP (4th cycle of chemo) vs.
XRT with last course (6th) of chemo
• Failed to demonstrate a survival advantage from
early XRT with chemo.
7. Spiro SG et al JCO Vol 24 No 24 2006: pp. 3823-3830 2006 Early Compared With Late Radiotherapy in
Combined Modality Treatment for Limited Disease Small-Cell Lung Cancer: A London Lung Cancer Group
Multicenter Randomized Clinical Trial and Meta-Analysis
Negative trials 3-5
• Work et al, James et al, Gregor et al, all
negative.
• No advantage shown to early XRT
What do we do?
A meta-analysis!
Meta-analysis 2004 (6)
• Looked at 7 studies (Spiro not published at
that time - 2006)
• 1524 patients
Outcome
In favour of
early XRT
2 year survival
1.17 (CI = 1.02-1.35)
Relative risk
3 year survival
1.13 (CI = 1.13-0.92)
Relative risk
(not significant)
6. B. Fried et al Systematic Review Evaluating the Timing of Thoracic Radiation Therapy in Combined Modality
Therapy for Limited-Stage Small-Cell Lung Cancer JCO Vol 22, No 23 , 2004: pp. 4837-4845 2004 American Society of
Clinical Oncology.DOI: 10.1200/JCO.2004.01.178
Meta-analysis Summary
• A small but significant improvement in
2-year OS for ERT versus LRT
• Similar to the benefit of adding RT to
chemotherapy, or to addition or
prophylactic cranial irradiation.
Cautions:
• Studies using platinum-based chemotherapy had
2 year OS RRs of 1.30 (95% CI, 1.10 to 1.53; P 0.002)
favouring early XRT.
3 year OS RRs of 1.35 (95% CI, 1.07 to 1.70; P 0.01)
BUT:
• Studies using once-daily fractionation showed no difference in 2and 3-year OS for early vs. late XRT.
• Studies using non-platinum-based chemotherapy regimens had
non-significant differences in OS.
• Next Step?
Cochrane Review
• OS at 2 and 5 years:
not significantly different for early vs late XRT.
• However, if removed 1 trail, which did not use platinum,
survival advantage at 5 years for early vs. late OR = 0.64
p=0.02
• If XRT was given within < 30 days:
5 year survival was even better OR=0.56 p = 0.02
So……
• Radiotherapy adds to chemotherapy
without doubt
• Early appears to be superior to late, but
this is more evident when given with
platinum based chemo, and if given in
hyperfractionated manner (i.e. bd)
• Short overall treatment time is best
Future
• Are you convinced? Or confused?
• bd fractionation ? Do we move to this?
CONVERT study ongoing to clarify this
question in UK and Europe
• Dose escalation – no proof that higher
doses lead to better outcomes ( although
common in N America - get paid / fraction)
Thank you and any
Questions

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