Short Communication: Management of patients with extensive-stage small-cell lung cancer treated with radiotherapy: A survey of practice

Highlights • Increased use of thoracic radiotherapy in ES-SCLC following CREST trial.• Trial schedule of 30 Gy in 10 for thoracic radiotherapy has been widely adopted.• High consistency in the use of prophylactic cranial irradiation.


Introduction
Most patients with small-cell lung cancer present with extensivestage disease and have a 2-year survival of less than 5%. Standard treatment is four to six cycles of platinum-based chemotherapy, a regime unchanged over recent decades. In an EORTC trial, prophylactic cranial irradiation administered to those who have responded to chemotherapy, reduced the incidence of symptomatic brain metastases by over half and improved 1-year survival by 14% [1].
Persisting intrathoracic disease after completing chemotherapy is common, with approximately 90% of patients presenting with intrathoracic progression within a year of diagnosis [1]. Therefore the next logical step was to investigate the role of thoracic radiotherapy in this group of patients.
The results of the randomized phase 3 CREST trial evaluating the use of thoracic radiotherapy for extensive-stage small-cell lung cancer (ES-SCLC) were published in 2015 [2]. The CREST study enrolled 495 patients from 42 centres, mainly in the Netherlands and United Kingdom. The main eligibility criteria included Eastern Cooperative Oncology Group (ECOG) scale performance status 0-2, confirmed ES-SCLC defined as disease beyond the hemithorax, hilar, mediastinal and supraclavicular nodes, any response after 4-6 cycles of platinum-based chemotherapy without evidence of disease progression at any site; and no clinical evidence of brain, leptomeningeal or pleural metastases. Patients were randomly assigned (1:1) to either thoracic radiotherapy (30 Gy in 10 fractions over two weeks) plus prophylactic cranial irradiation or prophylactic cranial irradiation only. Before randomization, patients had a CT thorax and upper abdomen. Brain imaging with CT or https://doi.org/10.1016/j.ctarc.2018.08.004 Received 6 April 2018; Accepted 28 August 2018 MRI was also performed in any patient with symptoms suspicious for brain metastases. The primary endpoint (10% overall survival difference at 1-year) was not achieved, but there was significant improvement in 2-year overall survival (13% vs 3%; p = 0.004), suggesting thoracic radiotherapy should be considered for ES-SCLC patients who respond to chemotherapy. Furthermore severe treatment-related toxicity was uncommon with 10.5% and 7.2% of patients developing grade 3 toxicity in the thoracic radiotherapy and the control group respectively. These results have raised controversy regarding the implementation of thoracic radiotherapy [3][4][5][6][7][8][9], which led to the development of a survey in some European countries to determine the impact of the publication on clinical practice.

Materials and methods
In May 2015, an electronic questionnaire (see Appendix 1) comprising 34 items was developed using publicly available software.
Questions included in the survey: • Use of thoracic radiotherapy before and after the publication of the CREST study results in different clinical scenario (symptomatic residual disease, asymptomatic central residual disease, no central disease) • Practice of prophylactic cranial irradiation in ES-SCLC • Reasons for not implementing thoracic radiotherapy • Staging investigations performed • Future research questions One academic lead in radiation oncology per country circulated the survey by email to all centres within their country. It was requested, that when possible, one answer per centre was provided to reflect practice within the centre rather than an individual clinician opinion. The survey was distributed in 7 European countries.

Results
The survey received 95 responses (United Kingdom = 42, Belgium = 18, Netherlands = 14, France = 8, Germany = 7, Switzerland = 5, Poland = 1) from 93 centres and was re-sent to nonresponders. The overall response to the survey was 66% (95/143). In some centres it was not possible to provide a consensus, and therefore in two centres more than one dose and fractionation regime was provided.

Thoracic radiotherapy
Before the publication of CREST only 24 (25%) centres delivered thoracic radiotherapy routinely to patients who responded to chemotherapy, compared to the current practice of 81 (85%). Three clinical scenarios were provided to the surveyed centres with regards to response to initial chemotherapy, see Table 1. The largest increase in the use of thoracic radiotherapy was in patients with asymptomatic residual thoracic disease after chemotherapy.
An upper limit of performance status (ECOG2) is applied to select patients for thoracic radiotherapy in 54 (79%) centres.
Prior to the publication of the trial, thoracic radiotherapy dose fractionation varied widely, but now the dose delivered in the experimental arm of CREST (30 Gy in 10 fractions) is prescribed in 52 (69%) centres, see Fig. 1.
In the 18 (18%) centres who did not implement thoracic radiotherapy after the publication of the CREST trial, a variety of explanations were given, including the primary endpoint of the study not being met, or the difference in survival not being clinically meaningful, but no single reason stood out.
An upper age limit was applied in 30 (33%) centres for selection of patients for prophylactic cranial irradiation. Most commonly an upper age limit of 75 was applied in 18 (60%) centres.
An upper limit for performance status was applied in 81 (88%) centres, most commonly ECOG 2.

Staging investigations
The practice that differed most between centres was which routine staging investigations were performed before chemotherapy. A computed tomography (CT) thorax and abdomen was performed in 61 (64%) centres, CT thorax, abdomen and pelvis in 27 (28%) centres, Positron Emission Tomography (PET) scan in 33 (35%) centres, imaging of the brain (CT or MRI) in 55 (57%) centres and an Isotope bone scan in 13 (14%) centres. Interestingly, in the United Kingdom CT/MRI imaging of the brain was only performed in 8 (14%) centres compared to 51 (86%) of centres outside the United Kingdom.

Future research
When asked which research question was most important to study next in this group of patients, responses varied widely from adding targeted agents/immunotherapy to thoracic radiotherapy, both increasing the dose of thoracic radiotherapy and using radiotherapy and/ or SABR to treat metastatic sites and determining which patient groups would benefit from thoracic radiotherapy.

Discussion
Our results show an increase in the use of thoracic radiotherapy in patients with ES-SCLC, suggesting the CREST trial has changed practice. The largest increase was in patients with asymptomatic residual thoracic disease after chemotherapy. The dose and fractionation schedule used in the trial has been widely adopted across Europe. The survey also shows high consistency in European practice in the use of prophylactic cranial irradiation. The staging procedures were very heterogeneous with limited use of PET-CT and brain imaging, which can impact on the outcome of these patients after thoracic radiotherapy.
A question raised in correspondence to the Lancet [7,9] following the publication of CREST and from a number of the responders to our questionnaire was which subgroups of patients will benefit most from thoracic radiotherapy in ES-SCLC. This has been initially addressed by further analysis of patients in the CREST trial. In the trial, patients were stratified by the presence or absence of intrathoracic disease after chemotherapy and further analysis demonstrated a statistically significant overall survival benefit in patients with residual intrathoracic disease who received thoracic radiotherapy (hazard ratio 0.81, 95% CI  [8]. Additional data on sites and number of metastases has been collected from 260 patients across the top 9 recruiting centres in the CREST trial (53% of the 495 study patients were included) [10]. The overall survival (p = 0.02) and progression free survival (PFS) (p = 0.04) were significantly better in patients with 2 or fewer metastases, with significantly worse overall survival if liver (p = 0.03) and/or bone metastases (p = 0.04) were present. The additional analysis suggests that future studies evaluating more intensive thoracic and extra-thoracic radiotherapy in ES-SCLC should focus on patients with fewer than 3 distant metastases.

Funding
The CREST trial was funded by the Dutch Cancer Society (CKTO), Dutch Lung Cancer Research Group, Cancer Research UK, Manchester Academic Health Science Centre Trials Coordination Unit, and the UK National Cancer Research Network.

Conflicts of interest
The authors declare no conflicts of interest.  Other, please specify 32. If thoracic radiotherapy is not going to be implemented in your centre following the publication of the (C)REST study, please tick if any of the explanations apply below or we would be grateful if you could expand using the free text? a) Not applicable, my centre has implemented thoracic RT b) Difference in survival not clinically meaningful c) Primary endpoint of the study not met d) Concerns regarding toxicity of thoracic radiotherapy e) Confirmatory trial needed before a change in practice is implemented f) Other, please specify 33. Following the publication of the (C)REST study which research question do you think is most important in this group of patients? a) Increasing the dose of thoracic radiotherapy b) Using radiotherapy and/or SABR to treat metastatic sites c) Both increasing the dose of thoracic radiotherapy and using radiotherapy and/or SABR to treat metastatic sites d) Delivery of thoracic radiotherapy concurrently with chemotherapy e) Addition of targeted agents/immunotherapy to thoracic radiotherapy f) Other, please specify 34. Please make any general comments on the use of thoracic radiotherapy in patients who have responded to chemotherapy in ES-SCLC, and/or any difficulties in answering the survey.