No Survival Benefit When Pravastatin Is Added to Standard Chemotherapy in Small Cell Lung Cancer


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In a UK phase III study (LUNGSTAR) reported in the Journal of Clinical -Oncology, Michael J. Seckl, MD, PhD, of Imperial College London, and colleagues found that adding pravastatin to first-line standard chemotherapy did not improve overall survival in patients with small cell lung cancer (SCLC).1

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; as well as in all tumors combined, with meta-analyses also showing benefits in all cancers combined, prostate cancer, and colorectal cancers. 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 a benefit to statin therapy in cancer patients. 

Study Details

In the current double-blind trial, 846 patients with limited- or extensive-disease SCLC from 91 sites in the United Kingdom 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 at and AUC of 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, baseline characteristics were similar. 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). 


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.
— Michael J. Seckl, MD, PhD

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 those 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 a 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.”

ROLE OF PRAVASTATIN IN SCLC

  • The addition of pravastatin to standard chemotherapy did not prolong overall survival in patients with small cell lung cancer.
  • No progression-free survival benefit was observed.

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: 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.” 

Disclosure: The study was supported by Cancer Research UK. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference

1. Seckl MJ, Ottensmeier CH, Cullen M, et al: Multicenter, phase III, randomized, double-blind, placebo-controlled trial of pravastatin added to first-line standard chemotherapy in small-cell lung cancer (LUNGSTAR). J Clin Oncol 35:1506-1514, 2017.


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