Sequential vs. concurrent chemoradiotherapy for locally advanced non-small cell carcinoma

1. Sequential vs. concurrent chemoradiotherapy for locally advanced non-small cell carcinoma

2. Background • Lung cancer remains leading cause of cancer death in UK • 5 year survival 8% (all stages) • Non-small cell lung cancer accounts for 80% of cases • 40% of patients present with locally advanced unresectable disease (Stage 3A and 3B)

3. Radical treatment of locally advanced disease • Until mid-1990’s patients of good performance status whose disease could be encompassed in a radical radiotherapy treatment volume were offered conventionally fractionated radical radiotherapy alone. • Poor survival rates (10% or less at 5 years) reflected low local control rates and high risk of micrometastatic disease leading to systemic relapse

4. In mid-1990’s meta-analysis showed that the sequential addition of chemotherapy to radical radiotherapy improved survival for these patients - absolute survival advantage of 4% at 2 years (BMJ 1995; 311:899). • In 2004 an individual patient meta-analysis comparing concurrent chemoradiotherapy to radiotherapy alone based on 9 trials and 1764 patients showed that concurrent chemoradiotherapy improved survival– absolute survival advantage of 4% at 2 years (Ann Oncol 2006; 17:473)

5. Theoretical advantages of concurrent chemoradiotherapy over sequential treatment • Risk of disease progression during chemotherapy – 1/3 patients in one RCT did not go on to receive RT • Tumour biology suggests that tumours which shrink with chemotherapy may then undergo accelerated repopulation • Sequential treatment increases overall treatment time - not good in tumours shown to undergo accelerated repopulation during treatment • Radiosensitising effect of chemotherapy if given concurrently with radiation

6. Evidence to support concurrent chemoradiotherapy over sequential treatment • Cochrane review 2004 • Only 3 trials fulfilled selection criteria for review • All published in abstract only • Significant reduction in risk of death at 2 years with concurrent vs. sequential therapy but caution advised in adopting concurrent treatment as standard of care because of uncertainty about true magnitude of benefit, short follow up in selected trials and concerns that any benefit may be at expense of unquantified increased toxicity.

7. Now, the NSCLC Collaborative Group has performed a meta-analysis of six randomised trials (involving 1205 patients) that compared outcomes associated with sequential versus concurrent chemoradiation (JCO 2010 28:2181) • The chemotherapy regimens varied among the trials, but all regimens incorporated a platinum agent.

8. At median follow-up of 6 years, the results were as follows: • Concurrent therapy conferred a significant survival benefit compared with sequential therapy (hazard ratio, 0.84; 95% confidence interval, 0.74–0.95; P=0.004). • The survival benefit corresponded to a 5.7% improvement at 3 years (23.8% with concurrent therapy vs. 18.1% with sequential therapy) and a 4.5% improvement at 5 years (15.1% with concurrent therapy vs. 10.6% with sequential therapy).

9. Progression-free survival was only numerically better with concurrent therapy (HR, 0.90; 95% CI, 0.79–1.01; P=0.07). • Local control was better with concurrent therapy (HR, 0.77; 95% CI, 0.62–0.95; P=0.01), • Distant progression rates were the same with both treatments. • Grade 3–4 oesophageal toxicity was more common with concurrent therapy (relative risk, 4.9; 95% CI, 3.1–7.8; P<0.001).

10. Grade 3–4 oesophageal toxicity was more common with concurrent therapy - 4% vs 18% (relative risk, 4.9; 95% CI, 3.1–7.8; P<0.001) • No difference in acute pulmonary toxicity rates • Not possible to pool data on haematological toxicity • No data on late toxicity

11. Conclusion • Concomitant chemoradiotherapy as compared with sequential chemoradiotherapy improves survival of patients with locally advanced NSCLC primarily because of better locoregional control but at the cost of manageable increased acute oesophageal toxicity.

12. Unanswered questions • Can concurrent chemotherapy be safely combined with 55Gy/20 fractions/4 weeks? • Could similar survival advantage be obtained without concurrent chemotherapy by using altered radiotherapy fractionation schedules e.g CHART?

13. What do we do here? • Offer concurrent chemoradiotherapy to highly selected patients with: • Locally advanced non-resectable non-small cell lung cancer • Disease (as staged on CT, PET and pathologically) encompassible in radical radiotherapy volume • PS0-1 • Adequate lung function • Fit for cisplatin-based chemotherapy • Cisplatin/vinorelbine chemotherapy x4 with radiotherapy (60Gy in 30 fractions over 6 weeks) running concurrently with cycles 2 and 3.

14. What do we do here? Offer sequential chemoradiotherapy to highly selected patients with: • Locally advanced non-resectable non-small cell lung cancer • PS0-1 • Adequate lung function AND • Whose disease (as staged on CT, PET and pathologically) not currently encompassible in radical radiotherapy volume but may become so with successful downstaging chemotherapy OR • In whom cisplatin chemotherapy is contraindicated. Gemcitabine/carboplatin chemotherapy x4 followed by radiotherapy (55Gy in 20 fractions over 4 weeks).

15. This move to concurrent chemoradiotherapy in selected patients represents a change in practice in this department and we need to collect data (ideally prospectively) on toxicity and tumour control rates to ascertain safety and whether we are making a meaningful difference to patient outcome.