The South West Area Mesothelioma and Pemetrexed trial: a multicentre prospective observational study evaluating novel markers of chemotherapy response and prognostication

Our plain-English summary of The South West Area Mesothelioma and Pemetrexed trial: a multicentre prospective observational study evaluating novel markers of chemotherapy response and prognostication, by C.E. Hooper, I.D. Lyburn, J. Searle, et al (British Journal of Cancer, 2015).

The study

• Authors: C.E. Hooper, I.D. Lyburn, J. Searle, M. Darby, T. Hall, D. Hall, A. Morley, P. White, N.M. Rahman, E. De Winton, A. Clive, V. Masani, D.T. Arnold, A. Dangoor, S. Guglani, P. Jankowska, S.A. Lowndes, J.E. Harvey, J.P. Braybrooke, N.A. Maskell
• Journal: British Journal of Cancer
• Published: 2015;112(7):1175-82
• Cited by: 46 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Robust markers that predict prognosis and detect early treatment response in malignant pleural mesothelioma (MPM) would enhance patient care.

Methods: Consecutive patients with MPM who were considered fit for first-line chemotherapy were prospectively recruited. Patients of similar performance status opting for best supportive care were included as a comparator group. Baseline and interval CT, PET-CT and serum markers (mesothelin, fibulin-3 and neutrophil-lymphocyte ratio (NLR)) were obtained, and patients followed up for a minimum 12 months.

Findings: Seventy-three patients were recruited (58 chemotherapy/15 comparator arm). Baseline TGV (total glycolytic volume on PET-CT) was an independent predictor of worse overall survival (OS) (P=0.001). Change in interval TGV(baseline/after two cycles of chemotherapy) did not predict OS or chemotherapy response on CT. Baseline NLR<4 was an independent predictor of better OS (median survival 453 (IQR 272-576) days vs NLR⩾4, 257 (IQR 147-490), P=0.002). Although baseline serum mesothelin did not predict OS, a falling level at 8 weeks significantly predicted longer time to progression (TTP) (P<0.001).

Interpretation: Neutrophil-lymphocyte ratio and baseline TGV predict prognosis in malignant pleural mesothelioma (MPM), but PET-CT is unhelpful in monitoring chemotherapy response. Serum mesothelin is a useful early treatment response marker when measured serially during chemotherapy and may have a role in evaluating patients' treatment response.

In plain English

The SWAMP trial was a prospective observational study at seven hospitals in South West England. It followed 73 patients with malignant pleural mesothelioma recruited from 2008 to 2011. Fifty-eight received first-line pemetrexed with cisplatin or carboplatin. Fifteen who chose supportive care without chemotherapy formed a comparator group. The article did not report asbestos exposure. The authors tested whether PET-CT scans and blood markers (mesothelin, fibulin-3, neutrophil–lymphocyte ratio or NLR) predicted survival or treatment response. Of 41 chemotherapy patients in the main analysis, 33 (80%) had a fall of 30% or more in PET-CT total glycolytic volume, but this did not significantly predict time to progression or survival. In chemotherapy patients, a baseline volume of 1800 or more was linked with shorter median survival (266 vs 456 days). In the same group, an NLR of 4 or more was linked with shorter median survival (257 vs 453 days for NLR below 4). A falling mesothelin after two cycles was associated with longer time to progression. The authors concluded that baseline PET-CT and NLR predict prognosis, that PET-CT does not help monitor response, and that mesothelin change warrants further study. They noted small numbers.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Multicentre prospective observational parallel cohort study, with a self-selected (not randomised) comparator group of patients who declined chemotherapy
• Who was studied: 73 patients with histologically proven malignant pleural mesothelioma, enrolled from oncology clinics of seven hospitals in South West England between September 2008 and December 2011. 58 were in the chemotherapy arm and 15 in the comparator arm. 63 (86%) were male and 50 (68%) had epithelioid histology.
• Exposure: First-line chemotherapy with pemetrexed and cisplatin or carboplatin, up to six cycles at 21-day intervals, compared with best supportive care. The markers studied were PET-CT total glycolytic volume (TGV), serum mesothelin, plasma fibulin-3 and the neutrophil–lymphocyte ratio. Asbestos exposure was not reported.
• Main results:
  • Median survival from consent to death was 368 days (IQR 195–526) in the chemotherapy group and 325 days (IQR 176–458) in the comparator group (P = 0.401).
  • Primary end point: of 41 chemotherapy patients analysed, 33 (80%) were metabolic responders on interval PET-CT (a 30% or greater fall in TGV). There was no significant difference in time to progression on CT between responders and non-responders at 2 months (P = 0.429) or 4 months (P = 0.703).
  • TGV fell, by any amount, between baseline and the 6-week PET-CT in 38 of 41 (93%) chemotherapy patients and 2 of 13 (15%) comparator patients with interval scans.
  • Median overall survival was not significantly higher in metabolic responders (456 days, IQR 254–657) than in non-responders (401 days, IQR 166–635) (P = 0.362).
  • In the chemotherapy group, a baseline TGV of 1800 or more was associated with shorter median survival: 266 days (IQR 180–479) vs 456 days (IQR 266–653) with TGV below 1800 (HR 3.00; 95% CI 1.53–5.88; P = 0.001). TGV remained independently predictive of survival in a model including histological subtype (P less than 0.001).
  • In the chemotherapy group, a baseline NLR below 4.0 was associated with longer median survival: 453 days (IQR 272–576) vs 257 days (IQR 147–490) with NLR of 4 or more (HR 0.38; 95% CI 0.20–0.71; P = 0.002). NLR was an independent predictor of overall survival in a model including histological subtype and TGV (P = 0.01).
  • In the chemotherapy group, baseline serum mesothelin was not significantly associated with survival (P = 0.196).
  • A falling mesothelin level between baseline and 6–8 weeks was associated with longer time to progression (P less than 0.001). After three cycles, progression occurred in 5/20 (25%) chemotherapy patients with falling or stable mesothelin vs 15/25 (60%) with rising mesothelin.
  • A falling mesothelin between baseline and completion of chemotherapy was associated with longer survival: 481 days (IQR 192–525) vs 293 days (IQR 204–493) with a rising level (HR 0.46; 95% CI 0.22–0.93; P = 0.031).
  • Interval change in plasma fibulin-3 was not associated with survival (P = 0.972) or time to progression. The authors found fibulin-3 did not help predict treatment response.
  • Across all patients, epithelioid histology was associated with median survival of 456 days (IQR 303–609) vs 197 days (IQR 155–239) for non-epithelioid histology (HR 0.17; 95% CI 0.08–0.35).
• The authors' conclusion: The authors concluded that baseline PET-CT and NLR predict prognosis, but that the data do not support using PET-CT to predict treatment response. They also concluded that change in serum mesothelin could indicate treatment response and warrants further study.
• Limitations the authors state:
  • Because of time and financial constraints, the study did not recruit the number of patients identified in the original power calculation.
  • Often because of patient deterioration, only 41 of 58 chemotherapy patients were included in the primary end point analysis.
  • Small patient numbers raise the possibility of type II errors (missed real effects) in the secondary outcomes.
  • The study was not randomised; the comparator group was self-selected.
  • Because of study size, patients were not split into rising, falling and stable mesothelin groups.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pemetrexed (Alimta), Chemotherapy, Prognosis, Pleural Mesothelioma, Performance Status, PET-CT, Mesothelin.

Related studies

• The effect of chemotherapy on health-related quality of life in mesothelioma: results from the SWAMP trial — D.T. Arnold, C.E. Hooper, et al. (2015)
• Folylpoly-glutamate synthetase expression is associated with tumor response and outcome from pemetrexed-based chemotherapy in malignant pleural mesothelioma — D.C. Christoph, B.R. Asuncion, et al. (2012)
• Tumour Treating Fields in combination with pemetrexed and cisplatin or carboplatin as first-line treatment for unresectable malignant pleural mesothelioma (STELLAR): a multicentre, single-arm phase 2 trial — G.L. Ceresoli, J.G. Aerts, et al. (2019)
• Continued pemetrexed and platin-based chemotherapy in patients with malignant pleural mesothelioma (MPM): value of 18F-FDG-PET/CT — N.G. Schaefer, P. Veit-Haibach, et al. (2012)
• A pathological complete response in malignant pleural mesothelioma after combination chemotherapy with Carboplatin and pemetrexed — S.C. Kao, B. McCaughan, et al. (2010)
• Soluble mesothelin, megakaryocyte potentiating factor, and osteopontin as markers of patient response and outcome in mesothelioma — K. Hollevoet, K. Nackaerts, et al. (2011)

Browse more research in British Journal of Cancer, or return to medical research.