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Clinical trials, ‘a lot more study’ needed to confirm statins’ effects on cancer outcomes
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For millions of Americans, taking a statin represents an integral part of everyday life.
Twenty-six percent of Americans regularly use a cholesterol-lowering drug, according to data from the CDC. Statins — used to decrease cholesterol levels and reduce the risk for cardiovascular disease, myocardial infarction and stroke — accounted for 93% of cholesterol-lowering drugs used in 2011 and 2012.
Published data indicate statins may have other benefits beyond cardiovascular health.
Several key observational studies have suggested that statin use may prevent certain cancers, and recent research shows statins may improve survival in patients already diagnosed with cancer.
Photo courtesy of Preet Paul Singh, MBBS.
“Significant preclinical data have shown anti-neoplastic and anti-inflammatory properties of statins, and multiple observational studies have shown a statistically significant protective effect from statin use in certain cancers — especially metabolic syndrome and inflammation-associated cancers,” Preet Paul Singh, MBBS, assistant professor of medicine at Washington University School of Medicine in St. Louis, told HemOnc Today. “Because these drugs have relatively minimum toxicity, they can be administered over the course of several years — similar to how they are administered to patients with coronary diseases — which is an important characteristic of any putative cancer prevention agent.”
However, discord exists among researchers as to the plausibility of statins as a legitimate cancer treatment. Clinicians also may discontinue statin use in their patients due to concerns about their interactions with other cancer therapies.
Further, questions about the reliability of the data on statin use in patients with cancer remain. Observational studies have yielded valuable epidemiological information but, so far, few clear-cut conclusions.
“There is heterogeneity among studies and conflicting results in various studies,” Singh said. “Secondary analyses of randomized trials of statins in coronary disease and stroke prevention have shown no cancer protective effect. ... The bottom line is that no practice-changing, randomized trial data currently exists.”
HemOnc Today spoke with clinicians regarding the potential of statins to prevent and treat cancer, the possibility for drug–drug interactions and other adverse effects, and the need for confirmatory prospective randomized trials.
Hormone-driven diseases
The majority of scientific literature related to the use of statins in the oncology community focuses on their potential to prevent cancer, and some of the data are striking.
A systematic review and meta-analysis by Singh and colleagues — published in 2013 in Gastroenterology — showed statin use significantly reduced risk for hepatocellular carcinoma (adjusted OR = 0.63; 95% CI, 0.52-0.76). A case-control study by Walker and colleagues, published in April in Cancer, showed statin ever-use was associated with a 34% reduction in risk for pancreatic cancer (OR = 0.66; 95% CI, 0.47-0.92), and that long-term use — defined as more than 10 years — conferred a greater protective effect (OR = 0.51).
The benefits appear to extend beyond solid tumors.
Pradelli and colleagues performed a meta-analysis — published in May in Cancer Medicine — that showed statin use reduced risk for hematologic malignancies (summary RR = 0.86; 95% CI, 0.77-0.96). Participants who reported long-term statin use — defined as more than 4 years — demonstrated a statistically significant reduction in risk (RR = 0.78; 95% CI, 0.71-0.87).
In recent years, however, research into the role of statins in cancer has shifted from prevention to treatment.
Because statins are thought to have a positive effect against hormone-driven diseases, prostate and breast cancers often are the focus of these studies.
“Some researchers have suggested that decreasing cholesterol — a precursor for estrogen and testosterone — levels in the blood, especially in cancers associated with sex hormones, may prevent cancer progression,” Jorge D. Ramos, DO, acting instructor of medicine at the University of Washington in Seattle, told HemOnc Today. “Some have also suggested that statins decrease angiogenesis — the formation of blood vessels — that feed the tumors.”
An observational study by Wang and colleagues — presented at the ASCO Annual Meeting this past spring — demonstrated statin use following a cancer diagnosis decreased risk for mortality from a variety of cancer types.
The researchers evaluated data from 146,326 women enrolled on the Women’s Health Initiative Observational Study, amongst whom 23,067 incident cancers occurred. Statin use significantly decreased the risk for cancer mortality overall compared with nonuse (HR = 0.78; 95% CI, 0.71-0.86). Researchers observed this association for women diagnosed with breast, ovarian, colorectal and bone cancers.
However, results showed that past statin users did not derive these same benefits, nor did statin use correspond with reduced cancer incidence (HR = 1.06; 95% CI, 0.85-1.33).
Additional studies have associated statin use with decreased breast cancer mortality. An observational study by Christopher R. Cardwell, PhD, and colleagues, published in Epidemiology, demonstrated a trend toward reduced breast cancer mortality with statin use (fully adjusted HR = 0.84; 95% CI, 0.68-1.04).
“Our study provides some evidence that breast cancer patients who used statins had reductions in death from cancer,” Cardwell, senior lecturer at Queen’s University Belfast School of medicine, Dentistry and Biomedical Sciences, told HemOnc Today. “However, the magnitude of the associations was relatively small and — as with all observational studies — there is the possibility of confounding. Statin users may differ from statin nonusers in other ways, for which we could not correct, that protect from death from cancer.”
Despite the small observed benefit and the potential for biased outcomes, the association between breast cancer mortality and statin use deserves further study, Cardwell said.
Several other studies — including an analysis by Harshman and colleagues, published in JAMA Oncology — suggest that prostate cancer also represents an area where statin use post-diagnosis can significantly improve treatment outcomes. In that study, men who took statins at the time of androgen deprivation therapy experienced longer mean time to progression than nonusers (27.5 months vs. 17.4 months; P < .001).
However, Ramos — who co-authored an editorial that accompanied the study — believes it is premature to conclude that statin use delays prostate cancer progression, particularly based on evidence from an observational study.
“Retrospective studies are fraught with inherent confounders and, therefore, produce mixed results,” Ramos said. “These findings should be validated through prospective, randomized control trials.”
The combination of statins and metformin appeared to reduce disease-specific mortality in patients with high-risk prostate cancer, according to study results presented at ASCO by Grace L. Lu-Yao, PhD, MPH, professor of medicine at Robert Wood Johnson Medical School and resident member of Rutgers Cancer Institute of New Jersey, and colleagues.
Results showed that men with high-risk prostate cancer who used statins and metformin together experienced a 43% decrease in prostate cancer-specific mortality (HR = 0.57; 95% CI, 0.38-0.88). Further, their findings suggested that the use of statins alone conferred considerable benefit among obese men or those with metabolic syndrome (HR = 0.09; 95% CI, 0.01-0.66).
Lu-Yao hopes to validate these findings in a prospective trial.
“I do not think it is wise to give statins to every single patient with prostate cancer, and there is a chance they may not work as well on low-risk patients compared with high-risk patients,” Lu-Yao said. “A lot more study needs to be done.”
Statins for other cancers
Although observational studies have demonstrated a possible link between statin use and improved outcomes in some gastrointestinal cancers, the data have been inconsistent for colorectal cancer.
“Existing data and meta-analyses support a modest effect of statins in the prevention of hepatocellular carcinoma, esophageal adenocarcinoma and gastric cancer,” Singh said. “Data in colorectal cancer is somewhat controversial, suggesting that if a protective effect truly exists, the effect size may be small at best.”
A population-based study by Cardwell and colleagues — published in Journal of Clinical Oncology — found an association between statins taken post-diagnosis and reduced disease-specific mortality among patients with newly diagnosed colorectal cancer (HR = 0.71; 95% CI, 0.61-0.84). Further, the likelihood of reduced mortality increased with the duration of statin intake.
However, letters to the editor written in response to the study identified potential confounding factors. Letter writers pointed out that the study did not include information regarding tumor or nodal stage, nor did it provide information related to diet or other lifestyle factors.
“At least nine studies have shown that cancer is associated with low cholesterol, measured 10 to [more than] 30 years before diagnosis,” Uffe Ravnskov, MD, PhD, a researcher based in Sweden, wrote in one letter. “Because most patients receiving statin treatment have lived most of their lives with high cholesterol, risk for cancer mortality might have been lower even without statin treatment compared with the untreated cohort with normal or low cholesterol. ... To claim that statin treatment protects against cancer is therefore impossible with the method used by Cardwell et al. ... In fact, evidence that statin treatment may cause cancer is much stronger.”
However, Cardwell disagrees.
“We found no evidence that colorectal cancer patients who took statins had increased mortality,” Cardwell told HemOnc Today. “Rather, we observed that taking statins appears to reduce mortality.”
A population-based cohort study conducted by Hoffmeister and colleagues and published in Journal of the National Cancer Institute showed no association between statin use and decreased mortality following colorectal cancer diagnosis.
In a cohort of 2,697 patients, 412 (15%) patients used statins and 769 deaths occurred. Statin use did not significantly affect OS (HR = 1.1; 95% CI, 0.85-1.41), disease-specific survival (HR = 1.11; 95% CI, 0.82-1.5) or RFS (HR = 0.9; 95% CI, 0.63-1.27). However, researchers did observe a significant association between statins and improved RFS among patients with stage I or II disease (HR = 0.5; 95% CI, 0.26-0.95).
“The results ... do not support suggestions of beneficial effects of statins for colorectal cancer prognosis derived from registry-based studies and suggest that such effects reported in previous studies might partly reflect the lack of or incomplete control for stage at diagnosis and other factors associated with the use of statins, such as better medical surveillance,” Hoffmeister and colleagues wrote. “Our finding of better RFS associated with use of statins among early-stage patients may be because of chance.”
Statins also have been evaluated in genitourinary and lung cancers.
A retrospective cohort study by Kaffenberger and colleagues — published in Urologic Oncology — showed statin use at the time of surgery improved 3-year OS (83.1% vs. 77.3%) and significantly improved disease-specific survival (90% vs. 83.5%; P = .015) in patients with renal cell carcinoma. Adjusted analysis indicated statin use at the time of surgery was independently associated with longer OS (HR = 0.62; 95% CI, 0.43-0.9) and disease-specific survival (HR = 0.48; 95% CI, 0.28-0.83).
Another population-based study conducted by Cardwell and colleagues and published in Cancer Epidemiology, Biomarkers & Prevention showed a potential link between statin use — particularly with simvastatin — and positive lung cancer outcomes. Patients who took statins prior to diagnosis demonstrated reduced risk for lung cancer mortality (adjusted HR = 0.88; 95% CI, 0.83-0.93).
The reason for differing outcomes across these observational studies may be caused by the fact that cancer is not monolithic, experts said.
“Cancer is not a homogenous disease,” Evan J. Walker, MD, resident physician at University of California, San Francisco, told HemOnc Today. “Each tumor type is a unique entity. Different exposures are related to the risk and different patterns are related to the progression. Different response to different treatments will result in each cancer.
“Prospective research is needed to verify the observed associations between statin use and individual tumor types,” Walker added. “[Prospective research] can also elucidate the various mechanisms within each tumor and confirm whether these associations are, in fact, valid.”
Adverse interactions
Despite the considerable interest surrounding the use of statins in patients with various cancers, questions about the potential adverse events remain. The possibility for multidrug interactions with other cancer therapies represents one of the most commonly reported areas of concern.
“Many of the reported drug-to-drug interactions [with statins] are actually cases where the statin level is increased,” Jonathan M. Gerber, MD, director of the leukemia program at Levine Cancer Institute at Carolinas HealthCare System and a HemOnc Today Editorial Board member, said during an interview. “Rather than the statin affecting the level of the other drugs we use, many of the interactions reported involve the blocking of the metabolism of the statin, resulting in muscle breakdown.”
Statin use may pose a particular risk to patients treated for hematologic malignancies, Gerber said.
“Many of our patients with leukemia tend to be on antibiotics or antifungals, and many of the basal antifungals are big offenders with many of the common statins,” he said. “Some of the newer statins are less likely to interfere with that, but they certainly can be involved. [Interactions with] some of our common antibiotics have even been reported.”
It also is possible that the activity of statins is influenced by the use of other drugs.
“The data on aspirin — particularly related to colorectal cancer — appears much stronger than statins,” Singh said. “As indications for aspirin and statins overlap — such as coronary heart disease, diabetes, stroke, increased cardiac risk factors, hyperlipidemia — the protective effect of statins may be partly attributable to aspirin, as not all studies adjust for concomitant aspirin use.”
A retrospective study by Pastore and colleagues — published in BMC Cancer — sought to evaluate the influence daily aspirin with or without statins had on the risk for tumor recurrence in 574 patients with nonmuscle-invasive bladder cancer who underwent transurethral bladder resection. Results showed patients treated with statins alone experienced more recurrences (mean, 1.46) than patients treated with aspirin and statins (mean, 1.14) and untreated patients (mean, 0.64).
Until a direct link between cancer outcomes and statin use can be determined, it is best not to risk their use, Gerber said.
“Statins can injure the liver, and many of our chemotherapy drugs can also be injurious to the liver,” Gerber said. “If you need to give a patient a life-saving chemotherapy drug — and they are taking a statin but have not experienced [myocardial infarction] or a stroke — I find it an easy decision to stop the statin to give the patient as much liver function as possible and to allow the chemotherapy to do its job.”
Prospective data needed
The need for prospective, randomized clinical trials on statins in cancer to confirm these observational study data remains a regular refrain among clinicians.
“Based on the quality of data we have, I would not recommend using a statin post-cancer diagnosis, outside of a clinical trial setting,” Singh said. “Although it is tempting to look at the observational data and conclude that statins reduce risk for cancer or improve cancer outcomes, one has to remember that observational studies cannot prove causality. They only show an association.”
However, conducting prospective, randomized trials present their own challenges.
“One factor is related to economics,” Walker said. “Observational studies are intrinsically easier to perform — they cost less than randomized, controlled trials and they take less time to complete.”
Researchers initiated a phase 3 randomized controlled trial of statin use in early-stage colorectal cancer in 2010, but the trial closed prematurely.
“The NSABP P5 trial enrolled patients with resected stage I or II colorectal cancer — a high-risk population — and randomly assigned them to receive rosuvastatin (Crestor, AstraZeneca) at 10 mg daily or placebo for 5 years following surgical resection,” Singh said. “Anticipated enrollment was 1,740, but the study was recently terminated after an enrollment of 406 patients in nearly 5 years. ... There are no study results available and it is unclear why the study was terminated, but this illustrates how challenging it could be to conduct such a trial.”
The conflicting data generated by observational studies may contribute to a reluctance to initiate clinical trials to evaluate statins.
“The mixed results of the retrospective studies out there may have dampened enthusiasm for pharmaceutical companies to invest in costly prospective trials,” Ramos said. “There are a few trials currently underway, and perhaps positive findings from these trials could increase enthusiasm.”
Ahern and colleagues wrote a personal viewpoint — published in The Lancet Oncology — that states the available evidence justifies the initiation of a clinical trial to study statins as a form of adjuvant therapy for patients with breast cancer.
“Such a trial is not only overdue, but is one of the few remaining options to substantially improve the human evidence concerning this treatment question,” Ahern and colleagues wrote. “While new observational evidence would be welcome ... postponing a trial to await such evidence is unlikely to be a rewarding strategy.”
Other factors — including the identification of an appropriate patient population and concerns regarding dosage — must be addressed prior to prospective trials.
“If we can show that patients with certain characteristics are more likely to benefit, then that would make it easier for us to carry out a more targeted clinical trial,” Lu-Yao said. “It is so important to identify a potential target population who will benefit the most before initiating a clinical trial.”
However, clinical trials would elucidate the effectiveness of statins across disease variants, Lu-Yao suggested.
“Statins may not work as well for patients with low-risk prostate cancer [as] those with high-risk prostate cancer,” Lu-Yao said. “We do not have the appropriate data yet, and this is one of the reasons why we need further studies.”
Despite the prospect of clinical trials, some clinicians remain unconvinced of even the basic effects of statins on cancer outcomes.
“Whatever effects statins may have are probably subtle,” Gerber said. “These drugs are being touted as cure-alls [in certain cancers], but without the strongest data. I think if the effect were a home run, we would already know it by now.” – by Cameron Kelsall
- References:
- Ahern TP, et al. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70119-6.
- Cardwell CR, et al. Cancer Epidemiol Biomarkers Prev. 2015;doi:10.1158/1055-9965.EPI-15-0052.
- Cardwell CR, et al. Epidemiology. 2015;doi:10.1097/EDE.0000000000000189.
- Cardwell CR, et al. J Clin Oncol. 2014;doi:10.1200/JCO.2013.54.4569.
- Harshman LC, et al. JAMA Oncol. 2015;doi:10.1001/jamaoncol.2015.0829.
- Hoffmeister M, et al. J Natl Cancer Inst. 2015;doi:10.1093/jnci/djv045.
- Kaffenberger SD, et al. Urol Oncol. 2015;doi:10.1016/j.urolonc.2014.10.007.
- Lu-Yao GL, et al. Abstract 5018. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.
- Pastore AL, et al. BMC Cancer. 2015;doi:10.1186/s12885-015-1152-x.
- Pradelli D, et al. Cancer Med. 2015;doi:10.1002/cam4.411.
- Ramos JD, Yu EY. JAMA Oncol. 2015;doi:10.1001/jamaoncol.2015.0833.
- Ravnskov U, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2014.58.9564.
- Singh S, et al. Gastroenterology. 2013;doi:10.1053/j.gastro.2012.10.005.
- Walker EJ, et al. Cancer. 2015;doi:10.1002/cncr.29256.
- Wang A, et al. Abstract 1506. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.
- For more information:
- Christopher R. Cardwell, PhD, can be reached at Queen’s University Belfast School of Medicine, Dentistry and Biomedical Sciences, Health Sciences Building, 97 Lisbum Road, Belfast, U.K. BT9 7BL; email: c.cardwell@qub.ac.uk.
- Jonathan M. Gerber, MD, can be reached at Levine Cancer Institute, 1021 Morehead Medical Drive, Charlotte, NC 28204; email: jonathan.gerber@carolinashealthcare.org.
- Jorge D. Ramos, DO, can be reached at 1100 Fairview Ave. North, D5-100, Seattle, WA 98109; email: jorgedr@u.washington.edu.
- Preet Paul Singh, MBBS, can be reached at Washington University School of Medicine, Division of Oncology, Campus Box 8056, 660 S. Euclid Ave., St. Louis, MO 63110; email: psingh@dom.wustl.edu.
- Evan Walker, MD, can be reached at University of California, San Francisco, School of Medicine, 505 Parnassus Ave., Room 987, San Francisco, CA 94143; email: evan.walker@ucsf.edu.
- Grace L. Lu-Yao, PhD, MPH, can be reached at Rutgers Cancer Institute of New Jersey, 195 Little Albany St., New Brunswick, NJ 08901; email: luyaogr@cinj.rutgers.edu.
Disclosure: Lu-Yao reports employment and leadership roles with Sun Pharma, as well as a consulting role with and stock ownership in Merck. Cardwell, Gerber, Ramos, Singh and Walker report no relevant financial disclosures.
Would a prospective, randomized phase 3 trial of statin use post-diagnosis be worth the investment?
Yes.
There are so many unanswered questions regarding statins that it would be an interesting area to study.
The connection between statin use and cancer has been controversial. Questions include whether statins cause cancer, prevent cancer, or lead to cancer that is less aggressive or less advanced after diagnosis. There are issues surrounding the potential protective nature of statins related to graft-versus-host disease in patients with cancer.
The answer to the question of the role statins play in patients with cancer is important. Many of the risk factors for atherosclerosis or cardiac disease and the risk factors for cancer are the same. The co-incidence of both diseases remains high. Withholding statin treatment from patients with cancer when it may not have a negative effect — or when it may, in fact, have a positive effect on treatment — is an important question to answer. Because of the large co-incidence of cardiac conditions and cancer, it is important that while we try to cure people with cancer, we make sure that they are not going to die from heart disease.
There are potential issues, including the magnitude of conducting such a study. Each individual cancer might have a different answer. Papers have been published for nearly every different cancer. Some suggest a positive association between statins and cancer prognosis, and others suggest a negative correlation. There also is the question of which statin — and which dose — you would choose.
To try to answer these questions broadly may pose a challenge. Yet, from a safety standpoint, I doubt that there is any downside. In my heart of hearts, I believe that if I received a cancer diagnosis, I would continue to take a statin.
Pharmaceutical companies have large databases of patients. A more in-depth meta-analysis of all existing databases of patients who take statins vs. patients who do not might be worthwhile if a randomized trial cannot be conducted.
Joseph R. Carver, MD, is clinical professor of medicine at University of Pennsylvania and chief of staff at Abramson Family Cancer Research Institute. He can be reached at joseph.carver2@uphs.upenn.edu. Disclosure: Carver reports no relevant financial disclosures.
No.
Although statin use post-cancer diagnosis has shown promising results, one must consider several complex factors before deciding to pursue a prospective randomized controlled trial (RCT):
- Which specific cancer(s) should be included?
- Which statin(s) should be investigated?
- Should therapy be administered in the adjuvant or neoadjuvant setting?
- Should the statin be administered concomitantly with chemotherapy?
- Should the study include all stages of disease? and
- What sample size is required?
From a strictly clinical standpoint, the current data regarding statin use in patients with cancer may warrant confirmatory phase 3 trials. However, given the aforementioned complexities in developing an RCT, the return on investment may not yield significant value.
Importantly, a randomized study should involve a placebo arm, which may be logistically and ethically difficult to conduct in this setting. According to the American College of Cardiology and American Heart Association guidelines, approximately 40% of the overall population is considered eligible for statin therapy. Among those eligible, but not currently receiving a statin, approximately 6% to 8% develop cardiovascular disease (CVD) compared with only 1% among those not eligible.
Administration of statins to eligible populations significantly reduces CVD risk and overall mortality. Given the increased risk for CVD in patients with cancer and the percentage of the general population eligible to receive a statin, an RCT may not be ethically feasible by withholding those in the placebo arm from receiving a statin. Further, excluding patients at intermediate or high risk for CVD would limit generalizability of the study and impede enrollment, resulting in several years — if not decades — of accrual. Marginally significant HRs for cancer-related mortality also will require large sample sizes in the several thousands to determine a true statistical difference. Unfortunately, the chance of successfully completing an RCT is very low, as evident by the early termination of a previously attempted RCT — NSABP-P5 — designed to investigate post-diagnosis statin use.
RCTs aside, the majority of studies and meta-analyses have demonstrated clinical benefit with post-diagnosis statin use. Considering the risk–benefit profile of statins, it may be appropriate to consider the use of statins in appropriate populations, including patients with cancer who have atherosclerotic CVD, high low-density lipoprotein cholesterol, diabetes, estimated 10-year atherosclerotic CVD risk 7.5% or greater, and/or characteristics conferring an intermediate or high Framingham risk assessment. However, it is critical to evaluate the risks of statin use, including toxicity — particularly hepatotoxicity and myopathy — and drug–drug interactions, which can lead to increased statin levels and/or increased oral chemotherapy concentrations.
Ultimately, the potential benefits may outweigh risks in eligible populations with regard to both CVD and cancer-related mortality risk reduction. However, statins are not likely to outperform current anticancer therapies, while data suggests the effect of statins on cancer-related mortality is lower when given concomitantly with chemotherapy. As such, statins should not be used as a replacement for approved anticancer drugs nor for the sole indication of reducing cancer-related mortality, and RCTs are not likely to yield significant returns on investment for this purpose.
Jai N. Patel, PharmD, is chief of pharmacology research and phase 1 trials at Levine Cancer Institute at Carolinas HealthCare System. He also is a HemOnc Today Editorial Board member. He can be reached at jai.patel@carolinashealthcare.org. Disclosure: Patel reports no relevant financial disclosures.