The rationale for concurrent chemotherapy and radiotherapy in small cell lung cancer
Dr Hannah Lord
Ninewells Dundee17th 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.
The History
• In 1969, 5 year survival:
1% with surgery4% 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. Pignon JP et al, N Engl J Med 1992; 327:1618-1624 December 3, 19922. 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?
• 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)
• 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. after cycle 4 ( sequential rather than late)
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
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
Outcome In favour of early XRT
2 year survival
Relative risk
1.17 (CI = 1.02-1.35)
3 year survival
Relative risk
1.13 (CI = 1.13-0.92)
(not significant)
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 2- and 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