Presentation on theme: "Dr Hannah Lord Ninewells Dundee 17th Sept 2010"— Presentation transcript:
1 Dr Hannah Lord Ninewells Dundee 17th Sept 2010 The rationale for concurrent chemotherapy and radiotherapy in small cell lung cancerDr Hannah LordNinewells Dundee17th Sept 2010
2 Small Cell 20% of all lung cancer Associated with smoking Rapid doubling timeFalling incidence in many parts of UK, not in ScotlandA 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 radiotherapyIn 1970s, advent of platinum based chemotherapy.Led to 4-5 fold improvement in response rates
4 Small CellWith 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 chemotherapyXRT has non over-lapping toxicities with chemotherapyXRT has different mode of action and may deal with potentially chemoresistant disease
6 Evidence For XRT13 randomised controlled trials have investigated the role of XRTPignon(1) 1992 meta-analysis (and Warde(2) 1993)2103 patients with LD433 had EDPignon JP et al, N Engl J Med 1992; 327: December 3, 1992Warde 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 deathNo 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 effectivenessMinimise 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 anotherii) ? to improve outcomes
10 How to determine timing of XRT? Randomised controlled trials8 looking at timing of XRT3 positive5 negative
11 Trial 1: NCIC study (3) 1993 Randomised controlled trial in Canada 308 ptsXRT commencing at cycle 2 (week 3) vs. cycle 6 (week 15)40Gy in 15 fractions given3. 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)21.216.00.0083 year survival30%22%5 year survival26%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 bdXRT weeks 1-4 (early) or weeks 6-9 (late)EarlyLateP valueMedian survival (months)34260.0275 year survival (%)30154. 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 bdXRT 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 (%)54.435.13 year survival (%)29.820.25 year survival (%)23.718.3P= not significant due to small sample size
16 Costs of XRT Increased haematolgical toxicity Similar oesophagitis ( 9% vs 4%)1% incraese in treatment related deathsWell tolerated overall
17 Negative trials 1: Perry (6) US Study 1987399 patients: chemo, vs. chemo + early XRT, vs. chemo + late XRTResults:XRT group as a whole did better that chemo alone groupBut no benefit from early vs delayed XRT6. 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 EPXRT with first course of EP (4th cycle of chemo) vs.XRT with last course (6th) of chemoFailed 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 3-5Work et al, James et al, Gregor et al, all negative.No advantage shown to early XRT
21 Meta-analysis 2004 (6)Looked at 7 studies (Spiro not published at that time )1524 patientsOutcomeIn favour ofearly XRT2 year survivalRelative risk(CI = )3 year survival1.13 (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 LRTSimilar 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.
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=0.02If 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 EuropeDose escalation – no proof that higher doses lead to better outcomes ( although common in N America - get paid / fraction)