Publications by authors named "Seppo Wang Langer"

3 Publications

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High-dose versus standard-dose twice-daily thoracic radiotherapy for patients with limited stage small-cell lung cancer: an open-label, randomised, phase 2 trial.

Lancet Oncol 2021 03;22(3):321-331

Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway; Department of Oncology, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.

Background: Concurrent chemoradiotherapy is standard treatment for limited stage small-cell lung cancer (SCLC). Twice-daily thoracic radiotherapy of 45 Gy in 30 fractions is considered to be the most effective schedule. The aim of this study was to investigate whether high-dose, twice-daily thoracic radiotherapy of 60 Gy in 40 fractions improves survival.

Methods: This open-label, randomised, phase 2 trial was done at 22 public hospitals in Norway, Denmark, and Sweden. Patients aged 18 years and older with treatment-naive confirmed limited stage SCLC, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, and measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1 were eligible. All participants received four courses of intravenous cisplatin 75 mg/m or carboplatin (area under the curve 5-6 mg/mL × min, Calvert's formula) on day 1 and intravenous etoposide 100 mg/m on days 1-3 every 3 weeks. Participants were randomly assigned (1:1) in permuted blocks (sized between 4 and 10) stratifying for ECOG performance status, disease stage, and presence of pleural effusion to receive thoracic radiotherapy of 45 Gy in 30 fractions or 60 Gy in 40 fractions to the primary lung tumour and PET-CT positive lymph node metastases starting 20-28 days after the first chemotherapy course. Patients in both groups received two fractions per day, ten fractions per week. Responders were offered prophylactic cranial irradiation of 25-30 Gy. The primary endpoint, 2-year overall survival, was assessed after all patients had been followed up for a minimum of 2 years. All randomly assigned patients were included in the efficacy analyses, patients commencing thoracic radiotherapy were included in the safety analyses. Follow-up is ongoing. This trial is registered at, NCT02041845.

Findings: Between July 8, 2014, and June 6, 2018, 176 patients were enrolled, 170 of whom were randomly assigned to 60 Gy (n=89) or 45 Gy (n=81). Median follow-up for the primary analysis was 49 months (IQR 38-56). At 2 years, 66 (74·2% [95% CI 63·8-82·9]) patients in the 60 Gy group were alive, compared with 39 (48·1% [36·9-59·5]) patients in the 45 Gy group (odds ratio 3·09 [95% CI 1·62-5·89]; p=0·0005). The most common grade 3-4 adverse events were neutropenia (72 [81%] of 89 patients in the 60 Gy group vs 62 [81%] of 77 patients in the 45 Gy group), neutropenic infections (24 [27%] vs 30 [39%]), thrombocytopenia (21 [24%] vs 19 [25%]), anaemia (14 [16%] vs 15 [20%]), and oesophagitis (19 [21%] vs 14 [18%]). There were 55 serious adverse events in 38 patients in the 60 Gy group and 56 serious adverse events in 44 patients in the 45 Gy group. There were three treatment-related deaths in each group (one neutropenic fever, one aortic dissection, and one pneumonitis in the 60 Gy group; one thrombocytic bleeding, one cerebral infarction, and one myocardial infarction in the 45 Gy group).

Interpretation: The higher radiotherapy dose of 60 Gy resulted in a substantial survival improvement compared with 45 Gy, without increased toxicity, suggesting that twice-daily thoracic radiotherapy of 60 Gy is an alternative to existing schedules.

Funding: The Norwegian Cancer Society, The Liaison Committee for Education, Research and Innovation in Central Norway, the Nordic Cancer Union, and the Norwegian University of Science and Technology.
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March 2021

Semi-automatic tumor delineation for evaluation of Cu-DOTATATE PET/CT in patients with neuroendocrine neoplasms: prognostication based on lowest lesion uptake and total tumor volume.

J Nucl Med 2021 Feb 26. Epub 2021 Feb 26.

Deptartment of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Copenhagen, Denmark; Cluster for Molecular Imaging, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; ENETS Neuroendocrine Tumor Center of Excellen.

Patients with neuroendocrine neoplasms (NEN) have heterogeneous somatostatin receptor expression with highly differentiated lesions having higher expression. Receptor expression of the total tumor burden may be visualized by somatostatin receptor imaging, e.g. Cu-DOTATATE PET/CT. Assessment of maximal lesion uptake is associated with progression-free survival (PFS), but not overall survival (OS). We hypothesized that the lesion with lowest, rather than highest, Cu-DOTATATE uptake would be more prognostic and developed a semi-automatic method for evaluating this. Patients with NEN underwent Cu-DOTATATE PET/CT. A standardized semi-automatic tumor delineation method was developed and used to identify the lesion with the lowest uptake, i.e. lowest of lesion mean standardized uptake values (SUV)mean. Additionally, we assessed total tumor volume derived from the semi-automatic tumor delineation. Kaplan-Meier and Cox regression analyses were used to determine association with OS and PFS. In 116 patients with NEN, median PFS (95% confidence interval) was 23 (20-31) months and median OS was 85 (68-113) months. Minimum SUVmean and total tumor volume were significantly associated with PFS and OS in univariate Cox regression analyses, while SUV was only significant for PFS. In multivariate Cox analyses, both minimum SUVmean and total tumor volume remained statistically significant. Minimum SUVmean and total tumor volume were then dichotomized by their median, and patients were categorized into 4 groups: High/low total tumor volume and high/low minimum SUVmean. Patients with low total tumor volume and high minimum SUVmean had a hazard ratio (95% confidence interval) of 0.32 (0.20-0.51) for PFS and 0.24 (0.13-0.43) for OS, both P<0.001 (reference: high total tumor volume and low minimum SUVmean). We propose a standardized semi-automatic tumor delineation method to identify the lesion with lowest Cu-DOTATATE uptake and total tumor volume. Assessment of lowest, rather than highest lesion uptake greatly increases prognostication by Cu-DOTATATE PET/CT. Combing lesion uptake and total tumor volume, we derived a novel prognostic classification of patients with NEN.
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February 2021

Phase II study of a 3-day schedule with topotecan and cisplatin in patients with previously untreated small cell lung cancer and extensive disease.

J Thorac Oncol 2008 Aug;3(8):902-6

Department of Oncology, the Finsen Centre, Rigshospitalet, Copenhagen, Denmark.

Introduction: Treatment with a topoisomerase I inhibitor in combination with a platinum results in superior or equal survival compared with etoposide-based treatment in extensive disease small cell lung cancer (SCLC). Five-day topotecan is inconvenient and therefore shorter schedules of topotecan and cisplatin are needed. The aim of this phase II study was to establish the response rate and response duration in chemo-naive patients with SCLC receiving a 3-day topotecan and cisplatin schedule.

Methods: Simons optimal two-stage design was used. Patients with previously untreated extensive disease SCLC, adequate organ functions and performance status less than 3 were eligible. Topotecan (2.0 mg/m, intravenously) was administered on days 1 to 3 with cisplatin (50 mg/m, intravenously) on day 3 every 3 weeks for a total of six cycles.

Results: Forty-three patients received 219 cycles of chemotherapy. Median age was 59 (range 44-74), 79% had performance status 0 or 1. Thirty-one patients completed all six cycles. Grade 3/4 anemia, neutrocytopenia, and thrombocytopenia were recorded in 9.5%, 66.7%, and 21.4% of patients, respectively. Fourteen percent of patients experienced neutropenic fever. No episodes of fatal sepsis occurred. Non-hematologic toxicity was mild and manageable. Overall and complete response rates were 72.1% and 9.3%, respectively. The median overall survival and response duration were 10.3 months (95% confidence interval: 8.6-12.0) and 7.0 months (95% confidence interval: 6.3-7.7), respectively.

Conclusion: Three-day topotecan with cisplatin on day 3 is active and safe in extensive disease SCLC. An ongoing phase III randomized trial compares this combination to standard treatment.
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August 2008