title: Multicenter, Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Pravastatin Added to First-Line Standard Chemotherapy in Small-Cell Lung Cancer (LUNGSTAR).
abstract: Purpose Treating small-cell lung cancer (SCLC) remains a therapeutic challenge. Experimental studies show that statins exert additive effects with agents, such as cisplatin, to impair tumor growth, and observational studies suggest that statins combined with anticancer therapies delay relapse and prolong life in several cancer types. To our knowledge, we report the first large, randomized, placebo-controlled, double-blind trial of a statin with standard-of-care for patients with cancer, specifically SCLC. Patients and Methods Patients with confirmed SCLC (limited or extensive disease) and performance status 0 to 3 were randomly assigned to receive daily pravastatin 40 mg or placebo, combined with up to six cycles of etoposide plus cisplatin or carboplatin every 3 weeks, until disease progression or intolerable toxicity. Primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), response rate, and toxicity. Results Eight hundred forty-six patients from 91 United Kingdom hospitals were recruited. The median age of recruited patients was 64 years of age, 43% had limited disease, and 57% had extensive disease. There were 758 deaths and 787 PFS events. No benefit was found for pravastatin, either in all patients or in several subgroups. For pravastatin versus placebo, the 2-year OS rate was 13.2% (95% CI, 10.0 to 16.7) versus 14.1% (95% CI, 10.9 to 17.7), respectively, with a hazard ratio of 1.01 (95% CI, 0.88 to 1.16; P = .90. The median OS was 10.7 months v 10.6 months, respectively. The median PFS was 7.7 months v 7.3 months, respectively. The median OS (pravastatin v placebo) was 14.6 months in both groups for limited disease and 9.1 months versus 8.8 months, respectively, for extensive disease. Adverse events were similar between groups. Conclusion Pravastatin 40 mg combined with standard SCLC therapy, although safe, does not benefit patients. Our conclusions are the same as those found in all four much smaller, randomized, placebo-controlled trials specifically designed to evaluate statin therapy in patients with cancer.
authors.affiliation: Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Seckl
authors.affiliation: Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.
authors.forename: Christian H
authors.initials: CH
authors.lastname: Ottensmeier
authors.affiliation: Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Cullen
authors.affiliation: Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Schmid
authors.affiliation: Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.
authors.forename: Yenting
authors.initials: Y
authors.lastname: Ngai
authors.affiliation: Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.
authors.forename: Dakshinamoorthy
authors.initials: D
authors.lastname: Muthukumar
authors.affiliation: Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.
authors.forename: Joyce
authors.initials: J
authors.lastname: Thompson
authors.affiliation: Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.
authors.forename: Susan
authors.initials: S
authors.lastname: Harden
authors.affiliation: Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.
authors.forename: Gary
authors.initials: G
authors.lastname: Middleton
authors.affiliation: Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.
authors.forename: Kate M
authors.initials: KM
authors.lastname: Fife
authors.affiliation: Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.
authors.forename: Barbara
authors.initials: B
authors.lastname: Crosse
authors.affiliation: Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Taylor
authors.affiliation: Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Nash
authors.affiliation: Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.
authors.forename: Allan
authors.initials: A
authors.lastname: Hackshaw
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D017035:Pravastatin / Q000008:administration & dosage; D066066:Response Evaluation Criteria in Solid Tumors; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy*; D015996:Survival Rate
chemical_list: D005047:Etoposide; D016190:Carboplatin; D017035:Pravastatin; D002945:Cisplatin