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

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 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 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? 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% 5 year survival 26% 11%

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, 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 Outcome In favour of early XRT 2 year survival Relative risk 1.17 (CI = 1.02-1.35) 3 year survival 1.13 (CI = 1.13-0.92) (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 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