Association of statin use with a pathologic complete response to neoadjuvant chemoradiation for rectal cancer

doi:10.1016/j.ijrobp.2004.12.033

International Journal of Radiation OncologyBiologyPhysics

Volume 62, Issue 5, 1 August 2005, Pages 1363-1370

https://doi.org/10.1016/j.ijrobp.2004.12.033 Get rights and content

Purpose: To assess whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, might enhance the efficacy of neoadjuvant chemoradiation in rectal cancer.

Methods and Materials: Between 1996 and 2001, 358 patients with clinically resectable, nonmetastatic rectal cancer underwent surgery at Memorial Sloan-Kettering Cancer Center after neoadjuvant chemoradiation for either locally advanced tumors or low-lying tumors that would require abdominoperineal resection. We excluded 9 patients for radiation therapy dose <45 Gy or if statin use was unknown, leaving 349 evaluable patients. Median radiation therapy dose was 50.4 Gy (range, 45–55.8 Gy), and 308 patients (88%) received 5-flurouracil-based chemotherapy. Medication use, comorbid illnesses, clinical stage as assessed by digital rectal examination and ultrasound, and type of chemotherapy were analyzed for associations with pathologic complete response (pCR), defined as no microscopic evidence of tumor. Fisher’s exact test was used for categoric variables, Mantel-Haenszel test for ordered categoric variables, and logistic regression for multivariate analysis.

Results: Thirty-three patients (9%) used a statin, with no differences in clinical stage according to digital rectal examination or ultrasound compared with the other 324 patients. At the time of surgery, 23 nonstatin patients (7%) were found to have metastatic disease, compared with 0% for statin patients. The unadjusted pCR rates with and without statin use were 30% and 17%, respectively (p = 0.10). Variables significant univariately at the p = 0.15 level were entered into a multivariate model, as were nonsteroidal anti-inflammatory drugs (NSAIDs), which were strongly associated with statin use. The odds ratio for statin use on pCR was 4.2 (95% confidence interval, 1.7–12.1; p = 0.003) after adjusting for NSAID use, clinical stage, and type of chemotherapy.

Conclusion: In multivariate analysis, statin use is associated with an improved pCR rate after neoadjuvant chemoradiation for rectal cancer. The low prevalence of statin use limits the power to detect a significant difference at a type I error threshold of p = 0.05 in this analysis. Although no definitive conclusions can be drawn on the basis of this retrospective study, the unusually high incidence of pCR after chemoradiation suggests that the use of statins in the treatment of rectal cancer warrants further evaluation.

Introduction

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, or statins, are cholesterol-lowering medications in widespread use to reduce the risk of heart disease and all-cause mortality (1, 2). There has been growing interest in the potential anticancer activity of these medications (3, 4), including experimental evidence in colorectal cancer (5, 6, 7, 8). Furthermore, a recently reported case-control study suggests that statin use might reduce the risk of colorectal cancer in healthy subjects by as much as 46% (9). Limited clinical data suggest that statins might have some benefit in other solid malignancies (10, 11), but the potential impact of statin use on standard therapy for rectal cancer is unknown.

Adjuvant chemoradiation for rectal cancer is an established treatment that improves clinical outcomes compared with surgical resection alone in patients with transmural or node-positive disease (12, 13, 14). Neoadjuvant chemoradiation has been increasingly used for sphincter preservation with equivalent outcomes (15), and pathologic response to neoadjuvant therapy might have prognostic significance (16, 17, 18, 19). We hypothesized that statin use might improve the efficacy of neoadjuvant chemoradiation in rectal cancer. Therefore, we retrospectively investigated the possible association of HMG CoA reductase inhibitor use with a higher pathologic complete response (pCR) rate.

Section snippets

Methods and materials

A total of 423 patients in the prospective colorectal surgery database underwent surgery at Memorial Sloan-Kettering Cancer Center (MSKCC) between January 1996 and June 2001 after neoadjuvant chemoradiation for rectal cancer. We excluded 65 patients who either had clinical evidence of metastatic disease at presentation or required intraoperative radiation therapy, leaving a cohort of 358 subjects who all received external beam radiation therapy with concurrent chemotherapy before surgery at

Perioperative findings and pathologic complete response rate

At the time of surgery, 23 patients (7%) were found to have evidence of metastatic disease on either radiologic or intraoperative restaging; all were non-statin users. The results of the findings at the time of surgery are presented in Table 3. Of the 349 patients, a total of 65 (18.7%) achieved a pCR. On univariate analysis, only lower T-stage according to DRE or ultrasound had a statistically significant difference in the likelihood of a pCR (Table 4). There was a trend toward a higher pCR

Discussion

In this retrospective study, we found a possible association of statin use with an improved pCR rate after neoadjuvant chemoradiation. Although there has been increasing preclinical evidence to suggest that statins might have anticancer activity, and recently presented data suggests a possible role for statins in colon cancer chemoprevention (3, 4, 9), there are few published data on humans demonstrating that these drugs have any therapeutic effect in patients with established cancers. To our

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: B.M. receives research support and honoraria and serves as a consultant and on the speaker’s bureau for Pfizer. L.B.S. is an advisor for Pfizer and receives research funding from Pfizer and Bristol Myers Squibb.

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Clinical investigationRectumAssociation of statin use with a pathologic complete response to neoadjuvant chemoradiation for rectal cancer

Introduction

Section snippets

Methods and materials

Perioperative findings and pathologic complete response rate

Discussion

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Semin Radiat Oncol

J Am Coll Surg

Radiother Oncol

Ann Oncol

J Biol Chem

Cancer Lett

Effect of statins on risk of coronary diseaseA meta-analysis of randomized controlled trials

JAMA

Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and strokeSystematic review and meta-analysis

BMJ

The statins as anticancer agents

Clin Cancer Res

Potential antitumor effects of statins

Int J Oncol

Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells

Clin Cancer Res

Evidence for deficiency of low density lipoprotein receptor on human colonic carcinoma cell lines

Cancer Res

Synergistic interaction between highly specific cyclooxygenase-2 inhibitor, MF-tricyclic and lovastatin in murine colorectal cancer cell lines

Oncol Rep

Low density lipoproteins and lovastatin modulate the organ-specific transendothelial migration of primary and metastatic human colon adenocarcinoma cell lines in vitro

Clin Exp Metastasis

HMG CoA reductase inhibitors and the risk of colorectal cancer

Proc ASCO

Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial

Br J Cancer

Prolongation of the disease-free interval in surgically treated rectal carcinoma

N Engl J Med

Survival after postoperative combination treatment of rectal cancer

N Engl J Med

Randomized controlled trial of postoperative radiotherapy and short-term time-scheduled 5-fluorouracil against surgery alone in the treatment of Dukes B and C rectal cancer. Norwegian Adjuvant Rectal Cancer Project Group

Br J Surg

Preoperative versus postoperative chemoradiotherapy for rectal cancer

New Engl J Med

Improved overall survival among responders to preoperative chemoradiation for locally advanced rectal cancer

Am J Clin Oncol

Clinical investigation
Rectum
Association of statin use with a pathologic complete response to neoadjuvant chemoradiation for rectal cancer