Sherif Y. El Sharouni

Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial

BACKGROUND Most patients with extensive stage small-cell lung cancer (ES-SCLC) who undergo chemotherapy, and prophylactic cranial irradiation, have persistent intrathoracic disease. We assessed thoracic radiotherapy for treatment of this patient group. METHODS We did this phase 3 randomised controlled trial at 42 hospitals: 16 in Netherlands, 22 in the UK, three in Norway, and one in Belgium. We enrolled patients with WHO performance score 0-2 and confirmed ES-SCLC who responded to chemotherapy. They were randomly assigned (1:1) to receive either thoracic radiotherapy (30 Gy in ten fractions) or no thoracic radiotherapy. All underwent prophylactic cranial irradiation. The primary endpoint was overall survival at 1 year in the intention-to-treat population. Secondary endpoints included progression-free survival. This study is registered with the Nederlands Trial Register, number NTR1527. FINDINGS We randomly assigned 498 patients between Feb 18, 2009, and Dec 21, 2012. Three withdrew informed consent, leaving 247 patients in the thoracic radiotherapy group and 248 in the control group. Mean interval between diagnosis and randomisation was 17 weeks. Median follow-up was 24 months. Overall survival at 1 year was not significantly different between groups: 33% (95% CI 27-39) for the thoracic radiotherapy group versus 28% (95% CI 22-34) for the control group (hazard ratio [HR] 0.84, 95% CI 0.69-1.01; p=0.066). However, in a secondary analysis, 2-year overall survival was 13% (95% CI 9-19) versus 3% (95% CI 2-8; p=0.004). Progression was less likely in the thoracic radiotherapy group than in the control group (HR 0.73, 95% CI 0.61-0.87; p=0.001). At 6 months, progression-free survival was 24% (95% CI 19-30) versus 7% (95% CI 4-11; p=0.001). We recorded no severe toxic effects. The most common grade 3 or higher toxic effects were fatigue (11 vs 9) and dyspnoea (three vs four). INTERPRETATION Thoracic radiotherapy in addition to prophylactic cranial irradiation should be considered for all patients with ES-SCLC who respond to chemotherapy. FUNDING 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.

Sequencing chemotherapy, radiotherapy and surgery in combined modality treatment of stage III nonsmall cell lung cancer.

Purpose of review Combined modality treatment is nowadays the standard of care in stage III nonsmall cell lung cancer, but the overall survival is still poor. Therefore, the challenge for clinicians is to optimize the combination of the treatment modalities. The review will focus on bimodality and trimodality approaches in stage III nonsmall cell lung cancer. Although the role of surgical resection in combined modality treatment is unclear, surgery will be discussed as a potential part of the treatment approach. Recent findings Concurrent chemoradiotherapy has proven to be more effective than chemotherapy followed by radiotherapy. Full-dose consolidation chemotherapy after concurrent chemoradiation showed an improvement of survival in some studies. Consolidation chemotherapy is, however, difficult to administer owing to its toxicity in these complex regimens. Both the Eastern Cooperative Oncology Group and the Radiation Therapy Oncology Group showed similar survival after surgery compared to sequential or concurrent chemoradiotherapy; however, pneumonectomies and residual malignant mediastinal disease after induction treatment had a negative impact on survival. Summary Concurrent chemoradiotherapy in combination with full-dose chemotherapy should be the standard of care for nonsmall cell lung cancer stage IIIA/B. Surgery is still experimental, but seems to be promising for certain subgroups of patients. More research has to be done in optimizing radiotherapy schedules and chemotherapy schemes in order to minimize toxicity. Novel therapeutics have to be introduced in the combined modality approach of stage III nonsmall cell lung cancer.

Prophylactic Cranial Irradiation Versus Observation in Radically Treated Stage III Non–Small-Cell Lung Cancer: A Randomized Phase III NVALT-11/DLCRG-02 Study

Purpose The purpose of the current study was to investigate whether prophylactic cranial irradiation (PCI) reduces the incidence of symptomatic brain metastases in patients with stage III non-small-cell lung cancer (NSCLC) treated with curative intention. Patients and Methods Patients with stage III NSCLC-staged with a contrast-enhanced brain computed tomography or magnetic resonance imaging-were randomly assigned to either observation or PCI after concurrent/sequential chemoradiotherapy with or without surgery. The primary end point-development of symptomatic brain metastases at 24 months-was defined as one or a combination of key symptoms that suggest brain metastases-signs of increased intracranial pressure, headache, nausea and vomiting, cognitive or affective disturbances, seizures, and focal neurologic symptoms-and magnetic resonance imaging or computed tomography demonstrating the existence of brain metastasis. Adverse effects, survival, quality of life, quality-adjusted survival, and health care costs were secondary end points. Results Between 2009 and 2015, 175 patients were randomly assigned: 87 received PCI and 88 underwent observation only. Median follow-up was 48.5 months (95% CI, 39 to 54 months). Six (7.0%) of 86 patients in the PCI group and 24 (27.2%) of 88 patients in the control group had symptomatic brain metastases ( P = .001). PCI significantly increased the time to develop symptomatic brain metastases (hazard ratio, 0.23; [95% CI, 0.09 to 0.56]; P = .0012). Median time to develop brain metastases was not reached in either arm. Overall survival was not significantly different between both arms. Grade 1 and 2 memory impairment (26 of 86 v seven of 88 patients) and cognitive disturbance (16 of 86 v three of 88 patients) were significantly increased in the PCI arm. Quality of life was only decreased 3 months post-PCI and was similar to the observation arm thereafter. Conclusion PCI significantly decreased the proportion of patients who developed symptomatic brain metastases with an increase of low-grade toxicity.

Differences in Longitudinal Health Utility between Stereotactic Body Radiation Therapy and Surgery in Stage I Non–Small Cell Lung Cancer

Introduction: There is an ongoing debate on the optimal treatment for stage I NSCLC, with increasing evidence for comparable health outcomes after surgery and stereotactic body radiation therapy (SBRT). For clinical decision making, the experienced quality of life, summarized as health utility, is of importance to choosing between treatments. In this study, we evaluated differences in longitudinal health utility in stage I NSCLC in the first year after surgical resection versus after SBRT before any recurrence of disease. We also assessed the impact of potential prognostic variables on health utility. Methods: Prospectively collected databases containing data on patients with stage I NSCLC treated with either SBRT or surgery were pooled from two large hospitals in the Netherlands. Quality of life data were measured by the Quality of Life Questionnaire–Core 30 questionnaire at baseline and 3, 6, and 12 months after treatment. Health utility (measured using the European Quality of Life Five‐Dimension questionnaire) was calculated from the Quality of Life Questionnaire–Core 30 questionnaire by using a mapping algorithm. Propensity score matching was used to adjust for selection bias. Treatment effects were estimated for the matched patients by using a longitudinal mixed model approach. Results: After correction for Eastern Cooperative Oncology Group score, sex, and age, the difference in 1‐year averaged health utility between the SBRT and surgery groups was 0.026 (95% confidence interval: 0.028–0.080). Differences in health utility decreased over time. Conclusions: A small but not statistically significant difference in health utility was found between patients with stage I NSCLC treated with surgery and those treated with SBRT. Current analysis strengthens existing evidence that SBRT is an equivalent treatment option for early‐stage NSCLC. Comparative cost‐effectiveness remains to be determined.