UK Trial Shows No Survival Benefit in Adding Pravastatin to Standard Chemotherapy in Small Cell Lung Cancer
In the UK phase III LUNGSTAR study reported in the Journal of Clinical Oncology, Seckl et al found that adding pravastatin to first-line standard chemotherapy did not improve overall survival in patients with small cell lung cancer (SCLC).
Numerous large prospective cohort and registry studies have shown the use of statin therapy to be associated with reductions in total cancer mortality; prostate cancer mortality; all-cause mortality in pancreatic cancer; recurrence and death in breast cancer; and recurrence or mortality in esophageal, colorectal, and lung cancers and in all tumors combined, with meta-analyses also showing benefits in all cancers combined, prostate cancer, and colorectal cancer. Preclinical studies in lung cancer cell lines have shown reduced proliferation, reduced migration, increased apoptosis, and reduced tumor growth with statin treatment. However, four randomized, placebo-controlled trials, smaller than the LUNGSTAR trial, found no evidence of benefit of statin therapy in patients with cancer.
Study Details
In the current double-blind trial, 846 patients with limited or extensive SCLC from 91 sites in the UK were randomized between February 2007 and January 2012 to receive up to 6 cycles of etoposide plus cisplatin or carboplatin every 3 weeks until disease progression or intolerable toxicity plus pravastatin at 40 mg (n = 422) or placebo daily (n = 424) for 2 years. Chemotherapy was administered as etoposide at 120 mg/m2 on day 1, then either the same on days 2 and 3 or 100 mg twice per day orally on days 2 and 3 with either cisplatin at 60 mg/m2 on day 1 or carboplatin AUC = 5 or 6 on day 1. Radiotherapy was administered according to local practice.
Patients were ineligible if they had used statins within the previous 12 months or fibrates within the previous 4 weeks. Overall, 22% of screened patients were ineligible for the study due to being recent or current statin users. The primary endpoint was overall survival in the intent-to-treat population.
For the pravastatin and placebo groups: median age was 63 and 64 years, 52% and 51% were male; Eastern Cooperative Oncology Group performance status was 0 or 1 in 76% and 75% and 2 or 3 in 24% and 25%; disease extent was limited in 43% in both and extensive in 57% in both; 25% and 26% had ipsilateral pleural effusion; 23% and 25% had positive ipsilateral supraclavicular fossa lymph nodes; 87% and 91% received carboplatin and 13% and 9% received cisplatin; and the most common metastatic sites were the liver (30% and 28%) and adrenal glands (12% and 13%). Most patients were smokers.
Overall Survival
Median follow-up was 39.6 months. Median time on study drug was 8.6 months for pravastatin and 7.8 months for placebo. Thoracic radiotherapy was administered to 47.9% of pravastatin patients and 49.5% of placebo patients (median total dose = 39 Gy and 40 Gy). Prophylactic cranial brain irradiation was administered to 48.1% and 48.8% (median total dose = 25 Gy and 25 Gy).
Median overall survival was 10.6 months vs 10.7 months (hazard ratio [HR] = 1.01, P = .90), and 2-year overall survival was 14.1% vs 13.2%. Median overall survival was 14.6 months vs 14.6 months in patients with limited-stage disease and 9.1 months vs 8.8 months in patients with extensive-stage disease (P = .53 for interaction). No treatment effects were observed for subgroups according to performance status, age, sex, type of platinum therapy, pleural effusion, or presence of affected lymph nodes.
Median progression-free survival was 7.7 months vs 7.3 months (HR = 0.98, P = .81), with 1-year and 2-year rates of 25.3% vs 24.2% and 7.5% vs 7.2%. Response rates were 69.0% vs 69.1%.
Adverse Events
Adverse events were similar in the pravastatin and placebo groups. Grade ≥ 3 adverse events occurred in 81.2% vs 81.4%, with the most common being neutropenia (44.9% vs 43.0%), leukopenia (15.1% vs 12.7%), and fatigue (14.9% vs 13.0%). Myalgia or myositis of any grade occurred in 18.0% vs 18.8%.
The authors noted that the absence of benefit of statin treatment might have been related to the type and dose of statin tested or to a ‘too simplistic’ understanding of the potential mechanism of reported statin effects in cancer patients. Pravastatin is a hydrophilic agent, unlike lipophilic statins such as simvastatin and others. The 40-mg dose was the highest approved at the time the trial was designed, but 80 mg/d has now been approved. Further, blood lipid levels were not measured during the study, prohibiting analysis of outcomes according to lipid-lowering effects. They stated, however, that “… there is insufficient evidence to reliably conclude whether any one type of statin is better than another, and biologic plausibility for a difference is lacking.”
The investigators concluded: “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.”
They noted: “There are several ongoing trials of statins in various cancers (eg, ClinicalTrials.gov [identifiers] NCT02360618, NCT01980823, NCT01038154, NCT02161822, NCT02483871, NCT02569645, and NCT02029573). Given the findings from our trial and the other published, double-blind, randomized controlled trials, independent data monitoring committees of studies that are still recruiting or in follow-up should examine interim analyses of clinical end points and stop early if there is sufficient evidence for futility, thus saving resources.”
The study was supported by Cancer Research UK.
Michael J. Seckl, MD, of Charing Cross Hospital Campus of Imperial College London, is the corresponding author of the Journal of Clinical Oncology article.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
