No Effect of Statins on Biochemical Outcomes After Radiotherapy for Localized Prostate Cancer

doi:10.1016/j.urology.2008.02.055

Urology

Volume 73, Issue 1, January 2009, Pages 158-162

https://doi.org/10.1016/j.urology.2008.02.055 Get rights and content

Objectives

To examine the effect of concurrent statin use during definitive radiotherapy (RT) on the biochemical outcomes for localized prostate cancer.

Methods

A total of 968 patients treated with RT had information about medication use available. Of these, 23% had been taking using statins during RT. Progression-free survival (PFS) was determined by a biochemical failure definition of prostate-specific antigen nadir plus 2 ng/mL, clinical failure, start of androgen deprivation therapy, or death.

Results

The mean patient age was 68 years. The median radiation dose was 76 Gy. Of the patients, 29% underwent androgen deprivation therapy. The 5-year overall survival rate was 83%. The median PFS time was 7.8 years versus 6.4 years, and the 5-year PFS rate was 70% versus 59% in favor of the statin users (P = 0.03). The analysis by risk group demonstrated no significant statin effect in any of the three risk strata. Stratification by hydrophilic versus hydrophobic statin agents revealed similar results. Multivariate analysis revealed that T stage (P <0.0001), pretreatment prostate-specific antigen level (P <0.0001), and Gleason score (P = 0.0026) were significant predictors of PFS; however, statin use (P = 0.48), androgen deprivation therapy (P = 0.95), pelvic RT (P = 0.96), radiation dose (P = 0.13), age (P = 0.19), and year of treatment (P = 0.07) were not.

Conclusions

Statin use did not affect PFS after adjusting for differences in treatment year and multiple prognostic factors. However, T stage, baseline prostate-specific antigen level, and Gleason score were critical determinants of prostate-specific antigen failure. These results did not differ when hydrophilic pravastatin was excluded.

Section snippets

Patient Selection

With institutional review board approval, we retrospectively reviewed the medical records of patients with localized prostate cancer who were treated with three-dimensional conformal radiotherapy (RT) or intensity-modulated RT with curative intent at the University of Michigan Cancer Center from January 1987 to July 2006. The required data for inclusion in this study included documentation of T stage, initial prostate-specific antigen (iPSA) level, Gleason score, and medication use before the

Patient Characteristics

We identified 968 patients who met our inclusion criteria. The median patient age was 68 years; 91% were white. The median iPSA level was 7.9 ng/mL, and 57% of patients had a Gleason score of 7 or greater. ADT was used in 29% of the patients. Overall, 42% and 30% were intermediate and high-risk patients, respectively. The clinical and treatment characteristics for the cohort are listed in Table 1. Of the 968 patients, 220 (23%) were taking a statin during RT. The statins used included

Comment

In 1987 the Food and Drug Administration approved the first agent from the drug class of HMG-CoA reductase inhibitors, commonly known as statins, for use as a treatment of hypercholesteremia. These agents have since been widely adopted for use because of their benefits against vascular disease. Drugs in this class include lovastatin, simvastatin, pravastatin, pitavastatin, fluvastatin, atorvastatin, and cerivastatin. The last of these, also known as Baycol, was removed from the market during

Conclusions

In this single-institution cohort, we observed no effect of statin use on PSA failure. Excluding hydrophilic pravastatin from the analysis resulted in the same conclusion. Given the interest in improving cancer outcomes with the use of systemic radiosensitizers and the in vitro data supporting statin use, future research could focus on studies using specific classes of statin agents, larger sample sizes, more intermediate/high-risk patients, longer follow-up, and, if possible, prospectively

Acknowledgment

To Steven Kronenberg for assistance with the generation of figures.

References (21)

H.K. Tsai et al.
Association of statin use with improved local control in patients treated with selective bladder preservation for muscle-invasive bladder cancer
Urology
(2006)
M.S. Katz et al.
Association of statin use with a pathologic complete response to neoadjuvant chemoradiation for rectal cancer
Int J Radiat Oncol Biol Phys
(2005)
M. Roach et al.
Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference
Int J Radiat Oncol Biol Phys
(2006)
M.F. Demierre et al.
Statins and cancer prevention
Nat Rev Cancer
(2005)
P. Cafforio et al.
Statins activate the mitochondrial pathway of apoptosis in human lymphoblasts and myeloma cells
Carcinogenesis
(2005)
J. Dimitroulakos et al.
Differential sensitivity of various pediatric cancers and squamous cell carcinomas to lovastatin-induced apoptosis: therapeutic implications
Clin Cancer Res
(2001)
M.R. Graaf et al.
The risk of cancer in users of statins
J Clin Oncol
(2004)
A.C. Miller et al.
Increased radioresistance of EJras-transformed human osteosarcoma cells and its modulation by lovastatin, an inhibitor of p21ras isoprenylation
Int J Cancer
(1993)
G. Fritz et al.
Lovastatin causes sensitization of HeLa cells to ionizing radiation-induced apoptosis by the abrogation of G2 blockage
Int J Radiat Biol.
(2003)
Katz MZ, M. Marion C, Yamada Y, et al: Statin use is associated with improved biochemical outcome after high-dose...

There are more references available in the full text version of this article.

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2017, Technical Innovations and Patient Support in Radiation Oncology
Patients receiving cancer treatment often have one or more co-morbid conditions that are treated pharmacologically. Co-morbidities are recorded in clinical trials usually only at baseline. However, co-morbidities evolve and new ones emerge during cancer treatment. The interaction between multi-morbidity and cancer recovery is significant but poorly understood.
To investigate the effect of co-morbidities (e.g. cardiovascular and diabetes) and medications (e.g. statins, antihypertensives, metformin) on radiotherapy-related toxicity and long-term symptoms in order to identify potential risk factors. The possible protective effect of medications such as statins or antihypertensives in reducing radiotherapy-related toxicity will also be explored.
Two datasets will be linked. (1) CHHiP (Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer) randomised control trial. CHHiP contains pelvic symptoms and radiation-related toxicity reported by patients and clinicians. (2) GP (General Practice) data from RCGP RSC (Royal College of General Practitioners Research and Surveillance Centre). The GP records of CHHiP patients will be extracted, including cardiovascular co-morbidities, diabetes and prescription medications. Statistical analysis of the combined dataset will be performed in order to investigate the effect.
Linking two sources of healthcare data is an exciting area of big healthcare data research. With limited data in clinical trials (not all clinical trials collect information on co-morbidities or medications) and limited lengths of follow-up, linking different sources of information is increasingly needed to investigate long-term outcomes. With increasing pressures to collect detailed information in clinical trials (e.g. co-morbidities, medications), linkage to routinely collected data offers the potential to support efficient conduct of clinical trials.
Statin use not associated with improved outcomes in patients treated with brachytherapy for prostate cancer
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Associations between statin use and a decreased risk of advanced prostate cancer (3) have been described. Although some series have shown a decreased risk of biochemical failure after radical prostatectomy (4) and radiation therapy (RT) (5–7) with statin use, others have shown no significant benefit (8, 9). To further investigate the effect of statin therapy on brachytherapy for prostate cancer, we examined the association between statin use and biochemical and clinical outcomes in intermediate- and high-risk patients treated with brachytherapy-based regimens for prostate cancer.
To investigate the association between statin use and prostate cancer outcomes in intermediate- and high-risk patients treated with brachytherapy for prostate cancer.
Between 1998 and 2010, 754 men with National Comprehensive Cancer Network intermediate- (n = 627) and high-risk (n = 127) prostate cancer were treated with prostate brachytherapy at our institution. Patients received either low-dose-rate or high-dose-rate brachytherapy as monotherapy or in combination with supplemental external beam radiotherapy. Two hundred eighty-five patients (37.8%) also received androgen-deprivation therapy. Two hundred seventy-three men (36.2%) were identified as taking statin medication before initiating radiation therapy. Prostate-specific antigen relapse–free survival (PSA-RFS), distant metastasis–free survival (DMFS), and overall survival were compared using log-rank tests. Associations of patient and treatment characteristics with outcomes were analyzed with univariate and multivariate regression. The median followup was 48 months.
The 8-year PSA-RFS for intermediate-risk, high-risk, and all patients was 92.2%, 64.1%, and 87.7%, respectively. The 8-year DMFS was 97.1%, 82.9%, and 94.9%, respectively. The 8-year overall survival for the entire cohort was 86.6%. There were no significant differences between statin users and nonusers when stratified by risk group, nor when analyzed as a full cohort. On multivariate analysis, Gleason score 4 + 3 = 7 and >7 were significantly associated with worse PSA-RFS (p ≤ 0.003 and <0.001, respectively). Gleason score > 7 (p = 0.008) and the use of neoadjuvant androgen-deprivation therapy (p = 0.03) was associated with worse DMFS. Statin use did not significantly impact PSA-RFS or DMFS.
Pretreatment statin use is not associated with improved outcomes in intermediate- and high-risk patients undergoing prostate brachytherapy-based regimens for prostate cancer.
Statin therapy is not associated with prostate cancer recurrence among patients who underwent radiation therapy
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Given the anti-inflammatory and other anti-cancer properties of statins, we hypothesized that use of statins may reduce the rate of prostate cancer recurrence in patients treated with radiation therapy. To date, several studies have examined the associations between statin use and risk of recurrence and/or survival after radiation therapy or brachytherapy [18–22]. However, these studies report conflicting results.
We investigated whether statin use is associated with reduced risk of recurrence in prostate cancer patients who undergo radiotherapy. A retrospective cohort of 774 patients from a California health plan was followed for 5 years. Statin use prior to, during and after radiotherapy was not associated with prostate cancer recurrence [hazard ratio = 0.99 (0.70–1.39), 0.87 (0.62–1.22) and 0.78 (0.55–1.09), respectively] in multivariable Cox models. No clear dose–response relationship was observed for average daily statin dose or duration of statin use. Our findings do not support a preventive benefit of statins in prostate cancer recurrence after radiotherapy.
How can i help myself? A critical review of modifiable behaviors, medications, and complementary alternative medicine for men receiving radiotherapy for prostate cancer
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Among 691 men treated definitively with external radiotherapy, brachytherapy, or both at the University of Chicago, men who used statins at the time of consultation or during follow-up had improved freedom from biochemical failure (HR: 0.43; 95% CI: 0.25-0.73; P = 0.002), regardless of their initial risk group, statin dose (<40 mg, ≥40 mg simvastatin equivalents), or timing of statin use (before radiotherapy vs after radiotherapy).24 Given that statin users tend to present with more favorable disease characteristics,24-26 it is unclear whether reduced biochemical recurrence reflects an imbalanced distribution of adverse prognostic factors versus a true therapeutic benefit of statins on prostate cancer progression. However, in studies from both Memorial Sloan-Kettering Cancer Center and University of Chicago, statin use remained an independent predictor after adjusting for pathologic characteristics.24,25
Men receiving radiation for prostate cancer frequently want to know what steps they can take to optimize their chance of cure and reduce their risk of side effects. A variety of modifiable behaviors, medications, and complementary alternative medicine interventions have been investigated in this regard. In this review, we summarize data on tobacco use, exercise, statins and aspirin, and vitamins. There is limited randomized data supporting any of the interventions and additional studies are needed before clinicians can confidently inform their patients regarding what steps to take to improve their outcomes.
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Impact of Statin Use on Localized Prostate Cancer Outcomes after Radiation Therapy: Long-Term Follow-Up
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OncologyNo Effect of Statins on Biochemical Outcomes After Radiotherapy for Localized Prostate Cancer

Objectives

Methods

Results

Conclusions

Section snippets

Patient Selection

Patient Characteristics

Comment

Conclusions

Acknowledgment

Urology

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Statins and cancer prevention

Nat Rev Cancer

Statins activate the mitochondrial pathway of apoptosis in human lymphoblasts and myeloma cells

Carcinogenesis

Differential sensitivity of various pediatric cancers and squamous cell carcinomas to lovastatin-induced apoptosis: therapeutic implications

Clin Cancer Res

The risk of cancer in users of statins

J Clin Oncol

Increased radioresistance of EJras-transformed human osteosarcoma cells and its modulation by lovastatin, an inhibitor of p21ras isoprenylation

Int J Cancer

Lovastatin causes sensitization of HeLa cells to ionizing radiation-induced apoptosis by the abrogation of G2 blockage

Int J Radiat Biol.

Oncology
No Effect of Statins on Biochemical Outcomes After Radiotherapy for Localized Prostate Cancer