The COC Protocol™ in Early-Stage Cancer
This article outlines some of the evidence supporting the use of COC Protocol medications in earlier stage cancer.
Early diagnosis and treatment of cancer can be key to a better chance of successful cure and improved survival. This is because early‑stage cancers are generally smaller and more localised to one place in the body. For this reason they tend to be easier and more successful to treat.
The state of the evidence
In comparison to advanced cancers which have spread, the standard treatment approach for early-stage cancers is more often intended as a cure, and prevention of recurrence. Within this context, several studies have investigated the use of one or more of the COC Protocol medications alongside or immediately prior to these standard curative treatments. Much of this evidence is for metformin, and statins, and many of these studies take the form of retrospective and observational population studies in patients with or without diabetes.
For example, a major 2016 meta-analysis of adjuvant metformin use in early-stage cancer identified 23 publications and 4 conference abstracts which assessed survival outcomes in this context (Coyle et al., 2016). The findings of this study were broadly positive, particularly for prostate cancer and bowel cancer, and are discussed in more detail below.
There also exists some promising prospective biomarker evidence from small-scale randomised trials, particularly for adjuvant use of statins or metformin for early-stage breast cancer and endometrial cancer. Some of these studies are also outlined below. It is evident that the time is now ripe for more major studies into the clinical benefits of adjuvant use of metformin and other COC Protocol medications in early-stage disease.
Population studies for metformin use in earlier stage prostate cancer are mixed, but overall appear promising. A 2016 meta-analysis of 6 retrospective studies looking at adjuvant metformin use found that metformin use in patients undergoing standard curative treatment was associated with significantly better overall survival and cancer-specific survival, and also borderline significantly better recurrence-free survival (Coyle et al., 2016).
Use of both metformin and statins have been associated with lower prostate serum antigen (PSA) levels (and therefore potentially less advanced disease) in observational studies of men with newly diagnosed prostate cancer (Babcook et al, 2016). One population study showed that in men who had been diagnosed with prostate cancer and were presenting for radiation therapy, PSA levels was 20% lower for statin users (p = 0.002) and 33% lower for metformin users (p = 0.004), compared with men who were not on these medications (Liu et al., 2017).
Biological marker evidence from a small prospective study (Joshua et al., 2014) is supportive of the above findings. In this study men with localised prostate cancer who had elected to undergo radical prostatectomy were treated with metformin from the time of their decision up to the point of surgery. Metformin significantly reduced Ki67, a molecular marker used to measure the presence of fast dividing cells (proliferation), which is characteristic of cancer cells. A trend towards reduced blood levels of PSA was also noted.
These preliminary findings are exciting and better evidence on optimal dose and duration, as well as further investigation into efficacy is required.
Several prospective studies have generated data which potentially supports the use of metformin and statins in patients with early-stage or newly diagnosed breast cancer.
In one pre-surgical study in patients with newly diagnosed non-diabetic breast cancer, 39 patients received metformin in the time period from diagnostic biopsy to surgery (median 18 days). Promising results were noted in markers of cell division (ie, Ki67) and also a form of cell death, called apoptosis. Summing up these findings, the researchers concluded ‘short-term preoperative metformin was well tolerated and resulted in clinical and cellular changes consistent with beneficial anti-cancer effects’. They went on to call for the proper evaluation of these findings and of the potential survival benefits of metformin in this population using randomised trials (Niraula et al., 2012).
Other studies have also reported similar potentially beneficial changes to cancer cell markers and cancer-related gene expression in patients who took metformin or statins while waiting for surgery (Hadad et al., 2011, Bjarnadottir et al., 2013).
Importantly, metformin appears to be more effective in some patients compared to others, with metabolic characteristics such as insulin resistance implicated. The characteristics of these patients are now subject to intense investigation (Cazzaniga et al., 2013, Bonanni et al., 2012, Kalinsky et al., 2014).
For example, disease response and metformin intake was investigated in a retrospective population study of 2,529 patients who received neoadjuvant chemotherapy for early-stage breast cancer between 1990 and 2007 (Jiralerspong et al., 2009). In the patients who had diabetes, rate of pathologic complete response was 24% for metformin group (n=64) vs. 8.0% in the non-metformin group (n=87). In the non-diabetic group (who did not take metformin, n=2,374), the complete response rate was 16%. Metformin use was independently predictive of complete response (odds ratio, 2.95; P=0.04) after adjustment for diabetes, body mass index, age, stage, grade, receptor status, and neoadjuvant taxane use.
In the meta-analysis of retrospective studies conducted by Coyle et al (2016), 3 studies including 2045 patients were analysed. In these studies, there was a trend towards improved recurrence free survival with metformin, but no change in overall survival and cancer specific survival was noted.
Progestin therapy is often used as a fertility-sparing treatment for patients with endometrial cancer or atypical endometrial hyperplasia (AEH). Progestin can achieve high response rates, but cancer recurrence rates can also be high with this treatment – around 30-40% (Gallos et al., 2012; Gunderson et al., 2012). There is obviously a need for finding ways to reduce the recurrence rate of endometrial cancer in women who wish to go on to conceive. This combined with a known link between endometrial cancer and insulin resistance in some patient groups has led to a number of small studies investigating metformin as a treatment option for early-stage endometrial cancer.
Similar to both breast cancer and prostate cancer, small clinical studies have provided convincing evidence that metformin has potentially beneficial anticancer activity in women with early stage endometrial cancer awaiting surgery. In these studies, women with operable endometrial cancer who took metformin in the weeks preceding surgery had encouraging changes in various cell markers associated with cancer cell division and growth, suggesting that metformin inhibited cancer cell growth in these women (Mitsuhashi, 2014; Laskov, 2014, Schuler et al., 2015). Beneficial shifts in lipid and glycogen metabolism and circulating metabolic factors were also noted, and associated with a better response in some patients (Schuler et al., 2015, Mitsuhashi et al., 2014).
This preliminary evidence was further supported by a prospective study in 2016 which looked at disease response and recurrence rates in 29 women with AEH and early-stage endometrial cancer who wanted fertility-sparing treatment. In this study metformin was given alongside the standard therapy of medroxyprogesterone acetate (MPA), and metformin therapy was continued after MPA treatment had stopped up until conception or disease recurrence. The 3-year recurrence rate for patients taking metformin was just 10%, and the researchers concluded that metformin inhibited disease relapse after MPA therapy (Mitsuhashi et al., 2016).
Taken together these studies provide compelling evidence for the further investigation of metformin use in fertility-sparing treatment of endometrial cancer.
Evidence for COC Protocol use in early-stage bowel cancer is limited, but promising.
A meta-analysis conducted by Coyle et al in 2016 of 5 studies (including one prospective cohort study) found that metformin was associated with significant improvements in recurrence free survival and cancer specific survival.
In another interesting pilot study, Hosono et al, (2010) set out to evaluate whether metformin could help supress aberrant crypt foci, one of the earliest changes detected in the bowel which may lead to bowel cancer.
A total of 26 non-diabetic patients with aberrant crypt foci were treated with metformin (n=12) or no metformin (n=14) for a month. The researchers found that after one month, aberrant crypt foci numbers had decreased significantly in patients treated with metformin, but did not change in the control group. Markers for actively dividing cells in the lining of the bowel were also decreased in patients taking metformin.
The researchers suggest that this study provides preliminary evidence that metformin can potentially suppress early markers of bowel cancer in humans.
In a recent US-based retrospective study (Kozak et al., 2016), 171 patients with resectable pancreatic cancer were analysed according to their use of metformin and statins before and after surgical treatment. The researchers found that patients who took statins or metformin had better overall survival compared to those that did not.
The effects of metformin and statins on the prognosis of earlier-stage kidney cancer patients with diabetes are inconclusive, and more studies are needed.
Two recent population studies showed no survival benefit for patients who were taking metformin at the time of cancer diagnosis or surgery (Nayan et al., 2016, 2017).
However, in Cheng et al (2016), a retrospective analysis of 390 kidney cancer patients with diabetes (of which 290 had localised disease), metformin users with localised kidney cancer had significantly better disease free survival and cancer-specific survival than non-users. In addition, a meta-analysis of existing population studies (which included the three above) of 254,329 kidney cancer patients also found association between the use of metformin and improved overall survival and cancer-specific survival. In particular, patients with localised, early-stage disease appeared to benefit from metformin use (OS: HR 0.634, 95% CI 0.440–0.913, P = 0.014; CSS: HR 0.476, 95% CI 0.295– 0.768, P = 0.002) (Li et al., 2017).
In contrast, a Canadian population-based study in 613 patients with newly diagnosed diabetes and a ‘subsequent diagnosis’ of kidney cancer found survival of these patients was not associated with metformin or NSAID use, but was associated with statin use (Nayan et al., 2016). Patients on statins had a reduced risk of death from any cause, and also from kidney cancer (adjusted hazard ratio 0.71; 95% CI 0.51–0.97). Interestingly, the benefits in survival noted with statin use in this population was not associated with cumulative use, but with ‘active’ use, meaning that the length of time the patient had been taking statins prior to or after diagnosis had no bearing on their survival. What this means in the context of early-stage kidney cancer therefore requires further investigation. The authors state that this finding supports initiation of a full randomised trial to investigate whether it is beneficial to start kidney cancer patients on statins at the time of diagnosis.
An observational study was conducted on 135 patients with early-stage hepatocellular carcinoma (liver cancer) who underwent radiofrequency ablation. A total of 53 patients were diabetic, including 21 metformin users and 32 non-metformin users.
Diabetic patients with liver cancer fared less well than non-diabetic patients, with 5-year survival rates of 41.3% vs 64.7% (P = 0.004), and within the diabetic population, metformin users had better survival outcome (adjusted hazard ratio [HR] 0.24; 95% confidence interval [CI], 0.07-0.80; P = 0.020) compared to non-metformin users (Chen et al., 2011).
Results for metformin use in early-stage lung cancer are based on recent population analyses, and prospective trials are required.
A retrospective analysis investigating the association of diabetes and metformin with survival in 409 patients (including 71 who were diabetic and 41 who used metformin) undergoing resection of stage I non-small cell lung cancer (NSCLC) found that metformin (but not diabetes) use was associated with improved overall survival. In this study, metformin use was an important predictor of good survival in multivariate analysis (hazard ratio=3.08; P<0.01) after adjusting for age, gender, pathologic stage, histology and smoking status. (Dhillon et al., 2014).
Furthermore, a larger retrospective analysis of 682 patients (59 metformin users, 623 control patients) in locally advanced (Stage II-III) NSCLC who were receiving chemoradiotherapy found that metformin use was associated with improved disease metastasis free survival and progression free survival (58% versus 37% at 2 years, and a median PFS of 41 months versus 15 months; p = 0.01). However, no difference was noted in overall survival or locoregional recurrence free survival (Wink et al, 2016).
And in a similar (though smaller) retrospective study which investigated survival outcomes in 40 diabetic patients with locally-advanced, inoperable NSCLC treated with definitive chemoradiation found no significant difference or numerical trend in overall survival, progression-free survival, locoregional recurrence-free survival or distant metastasis-free survival (Ahmed et al, 2015).
Purpose of this article
This article is an overview of some of the scientific and medical published literature concerning the medications which comprise the patented Care Oncology protocol. Care has been taken to select relevant articles supporting the off-label use of these medicines in a clinical setting for the adjunct treatment of cancer. This article does not purport to be a comprehensive review of all the evidence, nor does it capture all of the potential side-effects of such treatment.
This article is for information purposes only and it does NOT constitute medical advice. The medicines discussed herein are available on prescription-only and should not be taken without consultation with your doctor or other professional healthcare provider. Care Oncology doctors will discuss the suitability of these medicines with you and will liaise with your doctor or oncologist to discuss their suitability for you.
You must NOT rely on the information in this article as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter you should consult your doctor or other professional healthcare provider. If you think you may be suffering from any medical condition you should seek immediate medical attention. You should never delay seeking medical advice, disregard medical advice, or discontinue medical treatment because of information contained in this article.
The copyright in this article is owned by Health Clinics LLC and its licensors.
The Care Oncology (“COC”) Protocol is protected by United States patent US9622982B2 and by various additional international patents.
Ahmed, I., Ferro, A., Cohler, A., Langenfeld, J., Surakanti, S.G., Aisner, J., Zou, W., Haffty, B.G., and Jabbour, S.K. (2015). Impact of metformin use on survival in locally-advanced, inoperable non-small cell lung cancer treated with definitive chemoradiation. Journal of Thoracic Disease 7, 346–355.
Babcook, M.A., Joshi, A., Montellano, J.A., Shankar, E., and Gupta, S. (2016). Statin Use in Prostate Cancer: An Update. Nutrition and Metabolic Insights 9, NMI.S38362.
Bjarnadottir, O., Romero, Q., Bendahl, P.-O., Jirström, K., Rydén, L., Loman, N., Uhlén, M., Johannesson, H., Rose, C., Grabau, D., et al. (2013). Targeting HMG-CoA reductase with statins in a window-of-opportunity breast cancer trial. Breast Cancer Res. Treat. 138, 499–508.
Bonanni, B., Puntoni, M., Cazzaniga, M., Pruneri, G., Serrano, D., Guerrieri-Gonzaga, A., Gennari, A., Trabacca, M.S., Galimberti, V., Veronesi, P., et al. (2012). Dual effect of metformin on breast cancer proliferation in a randomized presurgical trial. J. Clin. Oncol. 30, 2593–2600.
Cazzaniga, M., DeCensi, A., Pruneri, G., Puntoni, M., Bottiglieri, L., Varricchio, C., Guerrieri-Gonzaga, A., Gentilini, O.D., Pagani, G., Dell’Orto, P., et al. (2013). The effect of metformin on apoptosis in a breast cancer presurgical trial. Br J Cancer 109, 2792–2797.
Chae, Y.K., Yousaf, M., Malecek, M.-K., Carneiro, B., Chandra, S., Kaplan, J., Kalyan, A., Sassano, A., Platanias, L.C., and Giles, F. (2015). Statins as anti-cancer therapy; Can we translate preclinical and epidemiologic data into clinical benefit? Discov Med 20, 413–427.
Chen, T.-M., Lin, C.-C., Huang, P.-T., and Wen, C.-F. (2011). Metformin associated with lower mortality in diabetic patients with early stage hepatocellular carcinoma after radiofrequency ablation. J. Gastroenterol. Hepatol. 26, 858–865.
Cheng, J.J.S., Li, H., Tan, H.S., Tan, P.H., Ng, L.G., Ng, Q.S., Toh, C.K., Kanesvaran, R., and Tan, M.-H. (2016). Metformin Use in Relation With Survival Outcomes of Patients With Renal Cell Carcinoma. Clinical Genitourinary Cancer 14, 168–175.
Coyle, C., Cafferty, F.H., Vale, C., and Langley, R.E. (2016). Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis. Ann Oncol 27, 2184–2195.
Dhillon, S.S., Groman, A., Meagher, A., Demmy, T., Warren, G.W., and Yendamuri, S. (2014). Metformin and Not Diabetes Influences the Survival of Resected Early Stage NSCLC Patients. J Cancer Sci Ther 6, 217–222.
Gallos, I.D., Yap, J., Rajkhowa, M., Luesley, D.M., Coomarasamy, A., and Gupta, J.K. (2012). Regression, relapse, and live birth rates with fertility-sparing therapy for endometrial cancer and atypical complex endometrial hyperplasia: a systematic review and metaanalysis. Am. J. Obstet. Gynecol. 207, 266.e1-12.
Gunderson, C.C., Fader, A.N., Carson, K.A., and Bristow, R.E. (2012). Oncologic and reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 adenocarcinoma: a systematic review. Gynecol. Oncol. 125, 477–482.
Hadad, S., Iwamoto, T., Jordan, L., Purdie, C., Bray, S., Baker, L., Jellema, G., Deharo, S., Hardie, D.G., Pusztai, L., et al. (2011). Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial. Breast Cancer Res Treat 128, 783–794.
Hosono, K., Endo, H., Takahashi, H., Sugiyama, M., Sakai, E., Uchiyama, T., Suzuki, K., Iida, H., Sakamoto, Y., Yoneda, K., et al. (2010). Metformin Suppresses Colorectal Aberrant Crypt Foci in a Short-term Clinical Trial. Cancer Prev Res 3, 1077–1083.
Joshua, A.M., Zannella, V.E., Downes, M.R., Bowes, B., Hersey, K., Koritzinsky, M., Schwab, M., Hofmann, U., Evans, A., Kwast, T. van der, et al. (2014). A pilot ‘window of opportunity’ neoadjuvant study of metformin in localised prostate cancer. Prostate Cancer and Prostatic Diseases 17, 252–258.
Jiralerspong, S., Palla, S.L., Giordano, S.H., Meric-Bernstam, F., Liedtke, C., Barnett, C.M., Hsu, L., Hung, M.-C., Hortobagyi, G.N., and Gonzalez-Angulo, A.M. (2009). Metformin and Pathologic Complete Responses to Neoadjuvant Chemotherapy in Diabetic Patients With Breast Cancer. J Clin Oncol 27, 3297–3302.
Kalinsky, K., Crew, K.D., Refice, S., Xiao, T., Wang, A., Feldman, S.M., Taback, B., Ahmad, A., Cremers, S., Hibshoosh, H., et al. (2014). Presurgical trial of metformin in overweight and obese patients with newly diagnosed breast cancer. Cancer Invest. 32, 150–157.
Kozak, M.M., Anderson, E.M., Eyben, R. von, Pai, J.S., Poultsides, G.A., Visser, B.C., Norton, J.A., Koong, A.C., and Chang, D.T. (2016). Statin and Metformin Use Prolongs Survival in Patients With Resectable Pancreatic Cancer. Pancreas 45, 64–70.
Laskov, I., Drudi, L., Beauchamp, M.-C., Yasmeen, A., Ferenczy, A., Pollak, M., and Gotlieb, W.H. (2014). Anti-diabetic doses of metformin decrease proliferation markers in tumors of patients with endometrial cancer. Gynecol. Oncol. 134, 607–614.
Li, Y., Hu, L., Xia, Q., Yuan, Y., and Mi, Y. (2017). The impact of metformin use on survival in kidney cancer patients with diabetes: a meta-analysis. Int Urol Nephrol 49, 975–981.
Liu, X., Li, J., Schild, S.E., Schild, M.H., Wong, W., Vora, S., Herman, M.G., and Fatyga, M. (2017). Statins and Metformin Use Is Associated with Lower PSA Levels in Prostate Cancer Patients Presenting for Radiation Therapy. J Cancer Ther 8, 73–85.
Mitsuhashi, A., Kiyokawa, T., Sato, Y., and Shozu, M. (2014). Effects of metformin on endometrial cancer cell growth in vivo: a preoperative prospective trial. Cancer 120, 2986–2995.
Mitsuhashi, A., Sato, Y., Kiyokawa, T., Koshizaka, M., Hanaoka, H., and Shozu, M. (2016). Phase II study of medroxyprogesterone acetate plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer. Ann Oncol 27, 262–266.
Nayan, M., Macdonald, E.M., Juurlink, D.N., Austin, P.C., Finelli, A., Kulkarni, G.S., and Hamilton, R.J. (2016). Medication use and survival in diabetic patients with kidney cancer: A population-based cohort study. Pharmacological Research 113, 468–474.
Nayan, M., Finelli, A., Jewett, M.A.S., Juurlink, D.N., Austin, P.C., Kulkarni, G.S., and Hamilton, R.J. (2017). Metformin Use and Kidney Cancer Outcomes in Patients With Diabetes: A Propensity Score Analysis. Clinical Genitourinary Cancer 15, 300–305
Niraula, S., Dowling, R.J.O., Ennis, M., Chang, M.C., Done, S.J., Hood, N., Escallon, J., Leong, W.L., McCready, D.R., Reedijk, M., et al. (2012). Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study. Breast Cancer Res Treat 135, 821–830.
Schuler, K.M., Rambally, B.S., DiFurio, M.J., Sampey, B.P., Gehrig, P.A., Makowski, L., and Bae-Jump, V.L. (2015). Antiproliferative and metabolic effects of metformin in a preoperative window clinical trial for endometrial cancer. Cancer Med 4, 161–173.
Singh, P.P., Srinivasa, S., Bambarawana, S., Lemanu, D.P., Kahokehr, A.A., Zargar-Shoshtari, K., and Hill, A.G. (2012). Perioperative use of statins in elective colectomy. Dis. Colon Rectum 55, 205–210.
Wink, K.C.J., Belderbos, J.S.A., Dieleman, E.M.T., Rossi, M., Rasch, C.R.N., Damhuis, R.A.M., Houben, R.M.A., and Troost, E.G.C. (2016). Improved progression free survival for patients with diabetes and locally advanced non-small cell lung cancer (NSCLC) using metformin during concurrent chemoradiotherapy. Radiother Oncol 118, 453–459.
Zhang, L., Xu, L., Zhang, F., and Vlashi, E. (2017). Doxycycline inhibits the cancer stem cell phenotype and epithelial-to-mesenchymal transition in breast cancer. Cell Cycle 16, 737–745.