Can Statins Increase Lung Cancer Survival?

There is growing evidence that statin drugs used to reduce cholesterol and prevent heart attacks can decrease the risk of death and improve survival times in people with lung cancer. The drugs may also help overcome drug resistance to certain chemotherapy medications, prolonging life in people with advanced disease.

Even so, statins are not considered a traditional part of lung cancer treatment, and their effectiveness can vary based on the type and stage of cancer you have.

If used inappropriately, statins can cause serious harm, including liver toxicity, muscle damage, and type 2 diabetes. There is also evidence, albeit weak, that statins may increase the risk of breast cancer.

How They Work

Statins are a category of medications known as HMG-CoA reductase inhibitors, whose primary function is to lower the risk of heart attacks. In addition to reducing cholesterol, they can stabilize and reduce the size of plaques in arteries as well as prevent the formation of blood clots. The drugs can even help decrease the risk of a heart attack in people with normal cholesterol levels.

In the past decade or so, a great deal of research has been devoted to the impact of statin use on mortality and survival rates in people with lung cancer, breast cancer, kidney cancer, and colon cancer with studies suggesting that the drugs can prolong survival in people with advanced disease.

The mechanism for this response in people with lung cancer remains unknown. Studies suggest that statins may improve the function of a gene known as epidermal growth factor receptor (EGFR) that is involved in the repair of damaged DNA. In people with EGFR mutations associated with lung cancer, statins are thought to improve outcomes by slowing the overall progression of the disease, including the speed at which tumor cells grow and spread (metastasize).

A 2019 review in Pharmacological Research supports the contention that statins can increase lung cancer survival but accedes that the benefits can vary significantly based on the cancer stage and when the statins are used.

The effectiveness also appears to be influenced by whether the lung cancer cells have specific EGFR gene mutations, something that only one in three people with non-small cell lung cancer (NSCLC) has.

Other studies have reported that statins can overcome resistance to a class of drugs known as EGFR tyrosine kinase inhibitors (EGFR TKIs), thereby extending the efficacy of the drugs as well as survival times in people with stage 4 lung cancer. These include medications like Tarceva (erlotinib) and Iressa (gefitinib).

Several animal and lab studies have also suggested that statins have anti-cancer properties that may help prevent lung cancer, although the current body of research does not support this.

Indications

There are no guidelines for the appropriate use of statins in people with lung cancer. With that said, studies suggest that certain people with lung cancer may be candidates for treatment if the benefits outweigh the risks.

Factors that should be considered include:

• Cancer type: People with NSCLC are more likely to benefit from statin use. Those with small cell lung cancer (SCLC), a less common form of the disease, are unlikely to benefit.
• Cancer stage: People with stage 4 NSCLC are also more likely to benefit compared to people with stage 1 to stage 3 NSCLC in whom the response is generally nominal to insignificant.
• Genetic profile: People with EGFR lung cancer mutations generally respond better to statin therapy. People with certain KRAS mutations can also benefit because that the mutation is linked to EGFR TKI resistance. Both mutations can be confirmed with genetic testing.
• Timing of treatment: People with advanced disease who start statins after their lung cancer diagnosis tend to respond better than people who were already on statins prior to the diagnosis.

Types and Dosage

Studies suggest that lipophilic (fat-soluble) statins like Lipitor (atorvastatin) and Zocor (simvastatin) are associated with longer survival times in people with lung cancer compared to hydrophilic (water-soluble) statins such as Pravachol (pravastatin), Crestor (rosuvastatin), and Lescol (fluvastatin). It is not entirely clear why this is.

By and large, statin doses used in medical research align closely with those used for the prevention of cardiovascular disease. Of the two commonly used in lung cancer research, they are typically dosed as follows:

• Lipitor: 10 milligram (mg) to 80 mg daily
• Zocor: 10 mg to 40 mg daily

These dosages should in no way suggest that they are beneficial in the treatment of lung cancer. Statins should only be used under the supervision of a healthcare provider and may not be effective or appropriate for everyone.

Effectiveness

A 2019 analysis of observational studies concluded that statin use in people with advanced lung cancer improved survival by 21% compared to a matched set of people not on statins.

Moreover, those who used statin drugs after their diagnosis of lung cancer had greater increases in survival times than those who used them prior to their diagnosis (32% versus 14% improvement, respectively).

In terms of actual survival times, a 2016 study in the journal Lung Cancer reported that the use of statins in people with metastatic lung cancer increased survival from three to seven months (a significant increase given that stage 4 NSCLC has a median survival time of four months).

When used in people on EGFR TKI therapy, statins also appear to extend progression-free survival from 6.1 months to as much as 8.9 months, a 45% increase.

Despite the positive findings, not all studies concur with these results. A comprehensive analysis published in the January 2019 edition of Drug Design, Development, and Therapy concluded that statins showed improvements in observational studies (which measure "real-world" results) but not in any of the randomized controlled studies (which measure results in a controlled environment).

(Randomized control studies are considered the gold standard for clinical research given that they can exclude or contextualize any factors that might otherwise influence the results.)

Side Effects

Statin drugs are among the most commonly prescribed chronic medications in the United States, but they are not without their risks. The common side effects of Lipitor and Zocor, the two drugs most commonly studied in the treatment of lung cancer, are (by order of frequency):

These side effects occur in at least 2% of Lipitor or Zocor users.

On rare occasions, severe side effects can develop with ongoing statin use, some of which may require medical intervention. These include:

• Rhabdomyolysis, the breakdown of muscle tissue that can lead to kidney damage
• Acute kidney injury, primarily associated with rhabdomyolysis but also due to drug-induced proteinuria (high blood protein)
• Drug-induced liver injury, due to increased liver enzymes
• Interstitial lung disease, the inflammation and scarring of the lining of the lungs

These side effects are exceptionally rare, occurring in as few as three of every 20,000 cases.

Contraindications and Interactions

Statins are contraindicated for use in people with a known hypersensitivity to the active drug or any of the other inactive ingredients. Drug hypersensitivity is extremely rare but can occur.

Statins are also contraindicated during pregnancy due to their effect on cholesterol levels. Cholesterol is vital to the growth and development of a fetus. Some studies have suggested that use of the drug can cause miscarriage. There is little evidence that statins cause birth defects.

Statins should be stopped the moment pregnancy is recognized and should not be used in breastfeeding mothers.

Statins are contraindicated for use in people with active (symptomatic) liver disease and should be used with extreme caution in people with a history of liver disease or alcoholism. Should statins be used, liver function tests should be routinely performed in high-risk individuals to identify and treat hepatotoxicity (liver toxicity).

Drug Interactions

Statins utilize cytochrome P450 (CYP450) for metabolization and can interact with other drugs that also rely this liver enzyme for this purpose. When statins are taken with these drugs, they can compete for the available enzyme, causing drug levels to either rise or drop precipitously.

Other drugs that specifically inhibit CYP450 can also reduce the effectiveness of statins. Among the interactions of concern are:

• Antibiotics like clarithromycin and erythromycin
• Anti-epileptic drugs like Dilantin (phenytoin) and Tegretol (carbamazepine)
• Antifungals like Sporanox (itraconazole) and Nizoral (ketoconazole)
• Fibrate drugs like Lopid (gemfibrozil) and Atromid-S (clofibrate)
• Grapefruit juice
• HIV protease inhibitors Kaletra (lopinavir plus ritonavir) and Prezista (darunavir)