The predictive role of serum VEGF in an advanced malignant mesothelioma patient cohort treated with thalidomide alone or combined with cisplatin/gemcitabine

Our plain-English summary of The predictive role of serum VEGF in an advanced malignant mesothelioma patient cohort treated with thalidomide alone or combined with cisplatin/gemcitabine, by S.C. Kao, R. Harvie, F. Paturi, et al (Lung Cancer, 2012).

The study

• Authors: S.C. Kao, R. Harvie, F. Paturi, R. Taylor, R. Davey, R. Abraham, S. Clarke, G. Marx, M. Cullen, Z. Kerestes, N. Pavlakis
• Journal: Lung Cancer
• Published: 2012;75(2):248-54
• Cited by: 23 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

There is a need for new treatment strategies and prognostic markers for the management of malignant mesothelioma (MM). The activity of thalidomide/cisplatin/gemcitabine (arm A) or thalidomide alone (arm B) was investigated in two parallel phase II studies in patients with advanced MM, using 6 month progression free survival (PFS) as the principal end-point. The predictive role of pre-treatment and 8 week follow-up serum C-reactive protein (CRP), interlukin-6 (IL-6), interlukin-6 soluble receptor (sIL-6R), mesothelin (SMRP) and vascular endothelial growth factor (VEGF) was also assessed. The proportion of patients with stable disease for >6 months was similar in both studies (arm A 35%, arm B 29%) and toxicity was mainly grade I/II. In univariate analyses only pre-treatment VEGF and CRP were correlated with survival. At 8 weeks post treatment, increased survival was found with low (<median) VEGF and CRP compared with high (>median) VEGF and CRP (P<0.05). Change in VEGF over the first 8 weeks of treatment was also predictive for survival (P<0.05). When pre-treatment VEGF was >median, decreasing VEGF was associated with increased survival (P<0.05). In conclusion, thalidomide alone, or in combination with cisplatin/gemcitabine, controlled disease for >6 months in ∼30% of patients. Patients with decreasing VEGF during treatment had longest survival. Pre-treatment VEGF or CRP and early change in VEGF on treatment may predict treatment benefit and should be examined in future studies.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

In plain English

This report described two parallel, non-randomized phase II studies at two Australian hospitals. Between April 2001 and August 2003, 63 patients with inoperable pleural malignant mesothelioma enrolled. In arm A, 34 patients not previously given chemotherapy received thalidomide with cisplatin and gemcitabine. In arm B, 29 received thalidomide alone. The article did not report the patients' asbestos exposure. Stable disease lasting at least 6 months occurred in 8 of 23 evaluable arm A patients (35%) and 5 of 17 evaluable arm B patients (29%). Side effects were mainly grade 1 or 2. Five blood markers were measured. Patients with high pre-treatment VEGF had a median survival of 31 weeks, against 70 weeks with low VEGF. For CRP the figures were 31 and 62 weeks (P less than 0.05 for both). Among 45 patients with 8-week samples, mean survival was 79 weeks when VEGF fell and 39 weeks when it rose. The authors judged the combination unlikely to be more active than cisplatin and gemcitabine alone. They concluded that VEGF and CRP appeared to predict survival and warranted prospective study. They noted the small cohort and missing samples.

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: Two parallel, non-randomized, single-arm phase II treatment studies with an exploratory analysis of blood biomarkers
• Who was studied: 63 patients with histologically confirmed inoperable pleural malignant mesothelioma, enrolled April 2001 to August 2003 at Royal North Shore Hospital, Sydney and the Prince Charles Hospital, Brisbane. Arm A had 34 patients and arm B had 29. Both studies closed before reaching target accrual when pemetrexed became available in Australia.
• Exposure: Treatment, not asbestos exposure, was studied. Arm A (chemotherapy-naive patients) received thalidomide with cisplatin 25 mg/m2 and gemcitabine 800 mg/m2 on days 1, 8 and 15 of 28-day cycles. Arm B (patients previously given chemotherapy or considered unsuitable for it) received thalidomide alone, started at 100 mg nightly and escalated weekly up to 500 mg. Serum VEGF, CRP, IL-6, sIL-6R and SMRP were measured. Patients' asbestos exposure was not reported.
• Main results:
  • Stable disease for 6 months or more occurred in 8 of 23 evaluable arm A patients (35%) and 5 of 17 evaluable arm B patients (29%).
  • One-year survival was 39% in arm A and 31% in arm B.
  • Toxicity was mainly grade 1 or 2. There were 12 grade 3 events in arm A and 6 in arm B.
  • In the whole cohort (n = 63), patients with epithelial histology had a median survival of 57.7 weeks, against 34.9 weeks for those with non-epithelial histology (P = 0.02).
  • Patients with high (above median) pre-treatment VEGF had a median survival of 31 weeks, against 70 weeks for those with low VEGF (P less than 0.05).
  • Patients with high pre-treatment CRP had a median survival of 31 weeks, against 62 weeks for those with low CRP (P less than 0.05).
  • In multivariate analysis, only low baseline VEGF remained associated with survival.
  • Among the 45 patients with 8-week samples, those whose VEGF increased had a mean survival of 39 weeks, against 79 weeks for those whose VEGF decreased (P less than 0.05).
  • Among patients with high pre-treatment VEGF, a decrease in VEGF was linked to a mean survival of 56 weeks, against 26 weeks with an increase (P less than 0.05). In patients with low pre-treatment VEGF, the change was not significantly correlated with survival.
  • Patients with epithelial histology had higher SMRP levels than those with non-epithelial histology (10.0 versus 3.5 nM, P = 0.01).
  • The EORTC prognostic index showed no significant difference in median survival between good and poor prognosis groups (10.1 versus 8.7 months, P = 0.97).
  • The authors judged the thalidomide, cisplatin and gemcitabine schedule unlikely to be more active than cisplatin and gemcitabine alone.
• The authors' conclusion: The authors concluded that a subset of patients appeared to obtain prolonged disease control with thalidomide. They found that baseline VEGF and CRP, and the change in VEGF with treatment, appeared to be predictors of survival. They called for further prospective evaluation of VEGF and CRP.
• Limitations the authors state:
  • The patient cohort was relatively small.
  • Because of missing values, only 45 patients had complete 8-week follow-up data.
  • The median was used as the cut-off because of the small cohort. Other cut-offs might be more appropriate in a larger cohort.
  • The design did not allow comparison of treatment effects, and the response rate was too low to link VEGF levels with response.
  • Prolonged disease control could reflect selection bias rather than a true effect of thalidomide.

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Cisplatin, Gemcitabine, Mesothelin, Soluble Mesothelin-Related Peptides (SMRP).

Related studies

• Recombinant human endostatin (endostar) decreased recurrent ascites, pleural fluid and ascitic VEGF in a case of advanced mesothelioma — X. Chen, Y. Liu, et al. (2012)
• Sunitinib combined with pemetrexed and cisplatin: results of a phase I dose-escalation and pharmacokinetic study in patients with advanced solid malignancies, with an expanded cohort in non-small cell lung cancer and mesothelioma — D.R. Camidge, N. Blais, et al. (2013)
• A phase II trial of low-dose gemcitabine in a prolonged infusion and cisplatin for malignant pleural mesothelioma — V. Kovac, M. Zwitter, et al. (2012)
• Triplet chemotherapy with cisplatin, gemcitabine and vinorelbine for malignant pleural mesothelioma — R. Maruyama, F. Shoji, et al. (2005)
• Comparison of cisplatin plus pemetrexed and cisplatin plus gemcitabine for the treatment of malignant pleural mesothelioma in Japanese patients — T. Shukuya, T. Takahashi, et al. (2014)
• A phase II trial of prolonged, continuous infusion of low-dose gemcitabine plus cisplatin in patients with advanced malignant pleural mesothelioma — O. Arrieta, D. López-Macías, et al. (2014)

Browse more research in Lung Cancer, or return to medical research.