Following early reports associating favorable outcomes in cancer patients with the use of statins,1,2 further observational studies in this area have provided mixed findings.3 As recently reported in the Journal of Clinical Oncology, and reviewed in this issue of The ASCO Post, Seckl and colleagues conducted a large, multicenter, phase III trial in which patients with metastatic small cell lung cancer had pravastatin at a 40-mg daily dose added to standard etoposide plus cisplatin or carboplatin for up to 6 cycles, with pravastatin use continuing for up to 2 years.4 No survival benefit was seen with the addition of pravastatin to chemotherapy, overall or in subgroups.4
Seckl and colleagues concluded that currently ongoing trials of statin addition in various cancer settings should “examine interim analyses and consider stopping early if there is sufficient evidence for futility.” 4 This is quite reasonable, but this approach is already an integral component of current analytic plans of cooperative group randomized trials.
Limitations of Statin Studies
The authors note that most studies of statin influence on cancer incidence or outcome have involved observational study designs with “inherent design problems including confounding and biases.” However, randomized placebo-controlled, full-scale trials evaluating agents such as statins, which did not emerge from usual anticancer preclinical development, also have potential limitations. In such cases, a particular statin from a particular class of statins is selected for use at a particular dose and provided for a given duration. A decision must be made regarding when to initiate intervention. Should it be in the metastatic setting, adjuvant setting, or a primary cancer prevention trial? Equally important, a particular cancer type is selected. As a result, in many cases, randomized trials may not be directly attempting to confirm findings from observational studies.
Oncologists should ensure that cancer survivors under their care are receiving optimal preventive strategies not only for cancer but also for cardiovascular disease, by meeting criteria for statin use and optimal blood pressure control….— Rowan T. Chlebowski, MD, PhD, FASCO
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While comprehensive review of the relatively large literature regarding statin use and cancer incidence and outcome is beyond the scope of this commentary, findings from one recent report are illustrative. Wang and colleagues5 evaluated statin influence on survival in cancer patients as a prospective cohort study in the Women’s Health Initiative. Among 14,326 participants followed for nearly 15 years, 23,067 incident cancers and 3,152 cancer deaths were observed. Compared with statin never-users, current statin use was associated with a 22% lower risk of cancer deaths (P < .001) and a 20% lower all-cause mortality.5
Of potential relevance to the report by Seckl and colleagues, the study by Wang et al found statin use was associated with a significantly lower risk of cancer deaths in breast cancer, ovarian cancer, and colorectal cancer.5 However, the hazard ratio for lung cancer death was 1.17, with a 95% confidence interval of 0.97 to 1.40. In retrospect, the study of statins in a disease with short survival—where cause of death almost exclusively is related to cancer progress—may not have been an ideal selection.
Increasing attention has focused on the issue of cardiovascular disease as a competing cause of death in cancer survivors, especially in disease commonly associated with long survival, such as breast cancer.6,7 In such environments, statin use could provide an opportunity for influencing two major causes of death.
Comprehensive Health Care
Seckl and colleagues are correct when they suggest that future trials of statins in any cancer setting will become more difficult as an increasing proportion of older individuals are being identified as potentially benefiting from statin use. This issue previously emerged regarding the evaluation of a potential role for vitamin D use in breast cancer management.8 In that setting, a survey of breast cancer patients in North America found that vitamin D use was so common as to preclude clinical trial evaluations.9
The extremely limited side effects of pravastatin added to chemotherapy seen in the setting of metastatic small cell lung cancer provide a reminder that cancer survivors need comprehensive health care. Oncologists should ensure that cancer survivors under their care are receiving optimal preventive strategies not only for cancer but also for cardiovascular disease, by meeting criteria for statin use10 and optimal blood pressure control, through close collaboration with primary care physicians as outlined in the ASCO survivorship guideline.11 ■
Dr. Chlebowski is Chief of Medical Oncology/Hematology and Professor of Medicine at the David Geffen School of Medicine and Harbor-UCLA Medical Center, Torrance, California.
DISCLOSURE: Dr. Chlebowski has had a consulting or advisory role with Novartis, Genentech, Amgen, Pfizer, and AstraZeneca and is a member of the speakers bureau for Novartis and Genentech.
References
1. Cauley JA, McTiernan A, Rodabough RJ, et al: Statin use and breast cancer: Prospective results from the Women’s Health Initiative. J Natl Cancer Inst 98:700-707, 2006.
2. Dale KM, Coleman CI, Henyan NN, et al: Statins and cancer risk: A meta-analysis. JAMA 295:74-80, 2006.
3. Zhong S, Zhang X, Chen L, et al: Statin use and mortality in cancer patients: Systematic review and meta-analysis of observational studies. Cancer 41:554-567, 2015.
4. 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.
5. Wang A, Aragaki AK, Tang JY, et al: Statin use and all-cancer survival: Prospective results from the Women’s Health Initiative. Br J Cancer 115:129-135, 2016.
6. Barac A, Murtagh G, Carver JR, et al: Cardiovascular health of patients with cancer and cancer survivors: A roadmap to the next level. J Am Coll Cardiol 65:2739-2746, 2015.
7. Bardia A, Arieas ET, Zhang Z, et al: Comparison of breast cancer recurrence risk and cardiovascular disease incidence risk among postmenopausal women with breast cancer. Breast Cancer Res Treat 131:907-914, 2012.
8. Cescon DW, Ganz PA, Hallak S, et al: Feasibility of a randomized controlled trial of vitamin D vs placebo in recently diagnosed breast cancer patients. Breast Cancer Res Treat 134:759-767, 2012.
9. Chlebowski RT, Johnson KC, Kooperberg C, et al: Calcium plus vitamin D supplementation and the risk of breast cancer. J Natl Cancer Inst 100:1581-1591, 2008.
10. Stone NJ, Robinson JG, Lichtenstein AH, et al: ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report of the American College of Cardiology/American Heart Association task force on practice guidelines. J Am Coll Cardiol 63:2889-2934, 2014.
11. Runowicz CD, Leach CR, Henry NL, et al: American Cancer Society/American Society of Clinical Oncology breast cancer survivorship care guideline. J Clin Oncol 34:611-635, 2016.
