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

      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.


      To read this article in full you will need to make a payment
      ASTRO Member Login
      ASTRO Members, full access to the journal is a member benefit. Use your society credentials to access all journal content and features.

      Purchase one-time access:

      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • LaRosa J.C.
        • He J.
        • Vupputuri S.
        Effect of statins on risk of coronary disease.
        JAMA. 1999; 282: 2340-2346
        • Law M.R.
        • Wald N.J.
        • Rudnicka A.R.
        Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke.
        BMJ. 2003; 326: 1423-1429
        • Chan K.K.
        • Oza A.M.
        • Siu L.L.
        The statins as anticancer agents.
        Clin Cancer Res. 2003; 9: 10-19
        • Jakobisiak M.
        • Golab J.
        Potential antitumor effects of statins.
        Int J Oncol. 2003; 23: 1055-1069
        • Agarwal B.
        • Bhendwal S.
        • Halmos B.
        • et al.
        Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells.
        Clin Cancer Res. 1999; 5: 2223-2229
        • Fabricant M.
        • Broitman S.A.
        Evidence for deficiency of low density lipoprotein receptor on human colonic carcinoma cell lines.
        Cancer Res. 1990; 50: 632-636
        • Feleszko W.
        • Jalili A.
        • Olszewska D.
        • et al.
        Synergistic interaction between highly specific cyclooxygenase-2 inhibitor, MF-tricyclic and lovastatin in murine colorectal cancer cell lines.
        Oncol Rep. 2002; 9: 879-885
        • Mehta N.
        • Hordines J.
        • Sykes D.
        • et al.
        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. 1998; 16: 587-594
        • Poynter J.N.
        • Rennert G.
        • Bonner J.D.
        • et al.
        HMG CoA reductase inhibitors and the risk of colorectal cancer.
        Proc ASCO. 2004; 22 ([abstract]): 1S
        • Katz M.S.
        • Zelefsky M.J.
        • Marion C.
        • et al.
        Statin use is associated with improved biochemical outcome after high dose radiotherapy for clinically localized prostate cancer.
        Int J Radiat Oncol Biol Phys. 2003; 57 ([abstract]): S271
        • Kawata S.
        • Yamasaki E.
        • Nagase T.
        • et al.
        Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial.
        Br J Cancer. 2001; 84: 886-891
        • Gastrointestinal Tumor Study Group
        Prolongation of the disease-free interval in surgically treated rectal carcinoma.
        N Engl J Med. 1985; 312: 1465-1472
        • Gastrointestinal Tumor Study Group
        Survival after postoperative combination treatment of rectal cancer.
        N Engl J Med. 1986; 315: 1294-1295
        • Tveit K.M.
        • Gudvog I.
        • Hagen S.
        • et al.
        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. 1997; 84: 1130-1135
        • Sauer R.
        • Becker H.
        • Hohenberger W.
        • et al.
        Preoperative versus postoperative chemoradiotherapy for rectal cancer.
        New Engl J Med. 2004; 351: 1731-1740
        • Janjan N.A.
        • Crane C.
        • Feig B.W.
        • et al.
        Improved overall survival among responders to preoperative chemoradiation for locally advanced rectal cancer.
        Am J Clin Oncol. 2001; 24: 107-112
        • Garcia-Aguilar J.
        • Hernandez de Anda E.
        • Sirivongs P.
        • et al.
        A pathologic complete response to preoperative chemoradiation is associated with lower local recurrence and improved survival in rectal cancer patients treated by mesorectal excision.
        Dis Colon Rectum. 2003; 46: 298-304
        • Ruo L.
        • Tickoo S.
        • Klimstra D.S.
        • et al.
        Long-term prognostic significance of extent of rectal cancer response to preoperative radiation and chemotherapy.
        Ann Surg. 2002; 236: 75-81
        • Theodoropoulos G.
        • Wise W.E.
        • Padmanabhan A.
        • et al.
        T-level downstaging and complete pathologic response after preoperative chemoradiation for advanced rectal cancer result in decreased recurrence and improved disease-free survival.
        Dis Colon Rectum. 2002; 45: 895-903
        • Meyerhardt J.A.
        • Catalano P.J.
        • Haller D.G.
        • et al.
        Impact of diabetes mellitus on outcomes in patients with colon cancer.
        J Clin Oncol. 2003; 21: 433-440
        • Grann A.
        • Feng C.
        • Wong D.
        • et al.
        Preoperative combined modality therapy for clinically respectable UT3 rectal adenocarcinoma.
        Int J Radiat Oncol Biol Phys. 2001; 49: 987-995
        • Minsky B.D.
        Pelvic radiation therapy in rectal cancer.
        Semin Radiat Oncol. 1993; 3: 42-47
        • Heald R.J.
        • Moran B.J.
        • Ryall R.D.
        • et al.
        Rectal cancer.
        Arch Surg. 1998; 133: 894-899
        • Enker W.E.
        • Thaler H.T.
        • Cranor M.L.
        • et al.
        Total mesorectal excision in the operative treatment of carcinoma of the rectum.
        J Am Coll Surg. 1995; 181: 335-346
        • Hiotis S.P.
        • Weber S.M.
        • Cohen A.M.
        • et al.
        Assessing the predictive value of clinical complete response to neoadjuvant therapy for rectal cancer.
        J Am Coll Surg. 2002; 194: 131-135
        • Agresti A.
        Categorical data analysis.
        John Wiley & Sons, New York1990
        • Mantel N.
        Chi-square tests with one degree of freedom.
        J Am Stat Assoc. 1963; 58: 690-700
        • Breslow N.E.
        • Day N.E.
        Statistical methods in cancer research, volume I.
        International Agency for Research on Cancer, Lyon, France1980
        • Hosmer Jr., D.W.
        • Lemeshow S.
        Applied logistic regression.
        2nd ed. John Wiley & Sons, New York2000
        • Thun M.J.
        • Henley S.J.
        • Patrono C.
        Nonsteroidal anti-inflammatory drugs as anticancer agents.
        J Natl Cancer Inst. 2002; 94: 252-266
        • Bujko K.
        • Nowacki M.P.
        • Nasierowska-Guttmejer A.
        • et al.
        Sphincter preservation following preoperative radiotherapy for rectal cancer.
        Radiother Oncol. 2004; 72: 15-24
        • Calvo F.
        • Serrano F.
        • Gomez-Espi M.
        • et al.
        Induction oxaliplatin + 5-FU improves further the incidence of pT0 downstaged surgical specimens in ≥cT3 rectal cancer treated with preoperative chemoradiation.
        Int J Radiat Oncol Biol Phys. 2004; 57 ([Abstract]): S178-S179
        • Mitchell E.P.
        • Winter K.
        • Mohiuddin M.
        • et al.
        Randomized phase II trial of preoperative combined modality chemoradiation for distal rectal cancer.
        Proc ASCO. 2004; 22 ([abstract]): 253S
        • Goldstein J.L.
        • Brown M.S.
        Regulation of the mevalonate pathway.
        Nature. 1990; 343: 425-430
        • FitzGerald T.J.
        • Daugherty C.
        • Kase K.
        • et al.
        Activated human N-ras oncogene enhances x-irradiation repair of mammalian cells in vitro less effectively at low dose rate. Implications for increased therapeutic ratio of low dose rate irradiation.
        Am J Clin Oncol. 1985; 8: 517-522
        • Sklar M.D.
        The ras oncogenes increase the intrinsic resistance of NIH 3T3 cells to ionizing radiation.
        Science. 1988; 239: 645-647
        • Bernhard E.J.
        • McKenna W.G.
        • Hamilton A.D.
        • et al.
        Inhibiting Ras prenylation increases the radiosensitivity of human tumor cell lines with activating mutations of ras oncogenes.
        Cancer Res. 1998; 58: 1754-1761
        • Sharma S.
        • Kemeny N.
        • Kelsen D.P.
        • et al.
        A phase II trial of farnesyl protein transferase inhibitor SCH 66336, given by twice-daily oral administration, in patients with metastatic colorectal cancer refractory to 5-fluorouracil and irinotecan.
        Ann Oncol. 2002; 13: 1067-1071
        • Laufs U.
        • Liao J.K.
        Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase.
        J Biol Chem. 1998; 273: 24266-24271
        • Aznar S.
        • Fernandez-Valeron P.
        • Espina C.
        • et al.
        Rho GTPases.
        Cancer Lett. 2004; 206: 181-191
        • Graaf M.R.
        • Beiderbeck A.B.
        • Egberts A.C.G.
        • et al.
        The risk of cancer in users of statins.
        J Clin Oncol. 2004; 22: 2388-2394
        • Caruso M.G.
        • Osella A.R.
        • Notarnicola M.
        • et al.
        Prognostic value of low density lipoprotein receptor expression in colorectal carcinoma.
        Oncol Rep. 1998; 5: 927-930
        • Caruso M.G.
        • Notarnicola M.
        • Santillo M.
        • et al.
        Enhanced 3-hydroxy-3-methyl-glutaryl coenzyme A reductase activity in human colorectal cancer not expressing low density lipoprotein receptor.
        Anticancer Res. 1999; 19: 451-454
        • Jain R.K.
        Barriers to drug delivery in solid tumors.
        Sci Am. 1994; 271: 58-65
        • Thibault A.
        • Samid D.
        • Tompkins A.C.
        • et al.
        Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer.
        Clin Cancer Res. 1996; 2: 483-491
        • Kim W.S.
        • Kim M.M.
        • Choi H.J.
        • et al.
        Phase II study of high-dose lovastatin in patients with advanced gastric adenocarcinoma.
        Invest New Drugs. 2001; 19: 81-83
        • Larner J.
        • Jane J.
        • Laws E.
        • et al.
        A phase I-II trial of lovastatin for anaplastic astrocytoma and glioblastoma multiforme.
        Am J Clin Oncol. 1998; 21: 579-583


      Commenting Guidelines

      To submit a comment for a journal article, please use the space above and note the following:

      • We will review submitted comments as soon as possible, striving for within two business days.
      • This forum is intended for constructive dialogue. Comments that are commercial or promotional in nature, pertain to specific medical cases, are not relevant to the article for which they have been submitted, or are otherwise inappropriate will not be posted.
      • We require that commenters identify themselves with names and affiliations.
      • Comments must be in compliance with our Terms & Conditions.
      • Comments are not peer-reviewed.