1. Dr Hannah Lord Ninewells Dundee 17th Sept 2010
The rationale for concurrent chemotherapy and radiotherapy in small cell lung cancer
Dr Hannah Lord
Ninewells Dundee
17th Sept 2010

2. 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.

3. 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

4. Small Cell
With chemo, excellent responses, but early and frequent relapse.
Need to build on the improvement.

5. 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

6. 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
Pignon JP et al, N Engl J Med 1992; 327: 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:

7. 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

8. 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

9. 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

10. How to determine timing of XRT?
Randomised controlled trials
8 looking at timing of XRT
3 positive
5 negative

11. 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 , 1993 The National Cancer Institute of Canada Clinical Trials Group

12. 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%
5 year survival
26%
11%

13. 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
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, , 1997

14. Trials 3: Takada (5) Japanese study 2006 231 patients
4 x EP with 45Gy in 1.5Gy fractions given bd
XRT started d2 cycle 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 J Clin Oncol 20: , 2002

15. 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= not significant due to small sample size

16. Costs of XRT Increased haematolgical toxicity
Similar oesophagitis ( 9% vs 4%)
1% incraese in treatment related deaths
Well tolerated overall

17. 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:

18. 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 : pp 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

19. Negative trials 3-5
Work et al, James et al, Gregor et al, all negative.
No advantage shown to early XRT

20. What do we do?
A meta-analysis!

21. Meta-analysis 2004 (6)
Looked at 7 studies (Spiro not published at that time )
1524 patients
Outcome
In favour of
early XRT
2 year survival
Relative risk
(CI = )
3 year survival
1.13 (CI = )
(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 American Society of Clinical Oncology.DOI: /JCO

22. 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.

23. 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.

24. Next Step?

25. 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

26. 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

27. 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)

28. Thank you and any Questions