The evidence supporting this protocol is provided by the phase III CREST study, a European multicentre randomised trial involving 489 patients comparing CTRT plus PCI to PCI alone in patients with extensive stage SCLC who had a response after 4 to 6 cycles of platinum-based chemotherapy.r Between 2009 to 2012, 495 patients were randomised on a 1:1 ratio, with 247 patients receiving CTRT of 30 Gy in 10 daily fractions and 248 randomised to the control group. All patients received PCI.
The primary end point was overall survival (OS) at 1-year. The secondary end point was progression free survival (PFS). After a median follow up of 24 months, the difference in 1-year OS was not statistically significant at 33% (95% CI 37-39) for CTRT group versus 28% (95% CI 22-34) in the control group (HR 0.84, 95% CI 0.69–1.01; p=0.066). However, secondary analysis of 2-year OS demonstrated a significant OS benefit in those who received CTRT with 13% (95% CI 9–19) in the intervention group versus 3% (95% CI 2-8; p= 0.004) in the control group. Analysis of the secondary endpoint showed that CTRT patients were less likely to have progression than the control group (HR 0.73, 95% CI 0.61-0.67, p=0.001). PFS at 6 months was 24% (95% CI 19-30) versus 7% (95% CI 4-11; p=0.001). There were no severe toxic effects of thoracic radiation therapy observed. The most common grade 3 or higher toxicities were fatigue (11 vs 9) and dyspnoea (3 vs 4).
Secondary analysis of the CREST study cohort was conducted to clarify which group of patients would potentially benefit from more aggressive radiation therapy.r Slotman et al. selected 260 patients from the original study cohort, with the smaller study population generally equivalent in clinical characteristics to the original, except for having slightly worse WHO performance status. The analysis showed OS was significantly better in patients with 2 or fewer metastases (p=0.02). PFS was also significantly better in the same patients (p=0.04). A worse OS was associated with metastases in the liver (HR 1.34; 95% CI 1.03-1.73, p = 0.03) and/or bone (HR 1.34; 95% CI 1.02-1.73, p=0.04). In patients with 2 or fewer metastases, there was a significant PFS benefit with CTRT (HR 1.34; 95% CI 1.02-1.73). Conversely, there was no statistically significant benefit in patients with 3 or greater metastases.
Further analysis of the data considered stratification based on the presence or absence of residual thoracic disease post-chemotherapy.r This was assessed in 97% of the study cohort with a chest CT post-chemotherapy. Of the 495 patients, 434 patients had residual thoracic disease and 61 had no residual disease. Patients were allocated almost evenly across the treatment and control groups. Analysis showed that patients with residual thoracic disease benefited significantly from thoracic radiation therapy, with a longer OS (HR 0.81, 95% CI 0.66-1.00, p=0.044), longer PFS (HR 0.70, 95% CI 0.57-0.85, p=0.0002) and lower rates of intrathoracic progression (43.7% in the thoracic radiation therapy group versus 81.3% in the control group, p<0.0001). This benefit was not seen in the patients without residual thoracic disease.
Figure 1 – Kaplan-Meier curves for overall survival
© The Lancet 2015r
Figure 2. Overall survival at 1 year in subgroups
*CI is 99% for subgroups, 95% for total. CR=complete response. PR=partial response.
© The Lancet 2015r
Figure 3. Kaplan-Meier curves for progression-free survival
© The Lancet 2015r
Thoracic radiation therapy in the era of first line synchronous chemo-immunotherapy
There is an absence of randomised data for the utility and toxicity of thoracic radiation therapy in the era of first line synchronous chemo-immunotherapy. Recent trials such as IMpower133r and CASPIANr demonstrating a survival benefit with first-line immunotherapy with chemotherapy did not permit the use of CTRT. Specific data is lacking regarding the efficacy of combined CTRT and immunotherapy in the setting of extensive stage SCLC. However, promising data on the efficacy and safety of combined thoracic radiation therapy with immunotherapy in the setting of locally advanced NSCLC may indicate the utility of similar therapy in SCLC patients.r